The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway is frequently activated in liver cancer, which is one of the most lethal cancers in humans. In addition to genetic mutation leading to persistent activation of effector molecules in the MAPK/ERK signaling cascade, there are alternative means by which the MAPK/ERK signaling pathway is activated in cancer. In this review, we will introduce the diverse modulators regulating the MAPK/ERK signaling pathway and consider the possibility of targeting the effectors and regulators in order to suppress the pro-tumorigenic MAPK/ERK signaling pathway, especially in liver cancer.Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC. The World Health Organization reported that the number of deaths due to liver cancer reached 830,000 in 2020 and ranked it the third most lethal cancer. Around one million people were diagnosed with HCC in 2020 ,2. HepatEpidemiological and molecular studies have demonstrated that the development of HCC spans several decades. Patients with hepatitis B (HBV) or hepatitis C (HCV) chronic infection, especially when accompanied by liver cirrhosis, are at a much higher risk of developing HCC than healthy people. Other risk factors for HCC include alcohol abuse, diabetes, obesity, and metabolic syndromes . The chrHCC is a phenotypically and genetically heterogeneous tumor and its tumorigenesis is driven by a variety of molecular mechanisms . Recent In this review, we describe the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and clinical trials targeting the signaling pathway in HCC. In addition, we propose new, promising therapeutic options targeting the MAPK/ERK signaling pathway. There are at least three different MAPK signaling pathways that transduce extracellular signals into the nucleus to induce responsive genes in mammalian cells, including ERK, c-Jun NH2-terminal kinase (JNK), and p38. The ERK kinase family consists of ERK1 (p44) and ERK2 (p42). The JNK kinase family consists of JNK1, JNK2, and JNK3. Finally, the p38 MAPK family is divided into the following groups: p38α, p38β, p38γ, and p38δ . SignalsThe MAPK/ERK signaling pathway is activated through signal transduction from cell surface receptors such as receptor tyrosine kinases (RTKs) or G-protein-coupled receptors (GPCRs) . ImpropeLigand binding to these receptors leads to the activation of cytoplasmic tyrosine kinases (TKs), which phosphorylate tyrosine residues at the cytoplasmic tails. This event recruits the growth-factor-receptor bound-2 (GRB2)/Shc/son of sevenless (SOS) adapter molecular complexes to the plasma membrane, which subsequently convert GDP-bound RAS to active GTP-bound RAS. After RAS activation, serine/threonine kinase RAF  is recruited to the cell membrane and activated in a complex series of processes including phosphorylation and dimerization with scaffolding complexes . RAF proSince the MAPK/ERK signaling pathway plays a fundamental role in the control of key cellular processes, including cell survival and proliferation, its aberrant activation is associated with cellular transformation and carcinogenesis . The EtsThe MAPK/ERK signaling pathway plays a pivotal role in tumorigenesis, and mutations in its components are highly prevalent in human cancers . ApproxiHowever, the importance of the MAPK/ERK pathway in human HCC has been neglected for a long time, mainly because mutations in RAS and RAF have not been frequently detected, found in less than 5% of HCC cases . DespiteFrequent activation of the MAPK/ERK signaling pathway in HCC is explained not so much by RAS and RAF mutations as by alternative mechanisms such as aberrant activation of upstream growth factors and receptors, downregulation of negative regulators of the MAPK/ERK signaling pathway, or upregulation of its positive modulators. In line with this, in most human HCCs, activation of the MAPK/ERK signaling pathway is observed in the presence of the wild-type genes of RAS, RAF, and downstream components .The activity of the MAPK/ERK signaling pathway is tightly regulated through the core pathway components, such as RTK, RAS, RAF, MEK, and ERK. Aberrant activation of the signaling pathway in human cancers is achieved via a constitutively activating mutation in genes encoding the core effector molecules as well as overexpression of the proteins. In addition to direct activation of the signaling pathway through the major effector molecules, MAPK/ERK signaling can also be affected by various modulators that activate and repress this signaling ,21. For RAS genes . A. A109]. As described in RAS in human cancer, various attempts have been made to directly inhibit the RAS proteins. However, RAS is difficult to treat with drugs due to the lack of suitable docking sites for small-molecule inhibitors with high affinity and selectivity [Due to frequent observations of a constitutively activating mutation in ectivity . A few eectivity ,136. Becectivity ,138. Howectivity .Considering that RAS proteins are almost impossible to treat with drugs, molecules downstream of RAS are more attractive targets to suppress activated MAPK/ERK signaling in cancers. Selective B-RAF inhibitors such as vemurafenib and dabrafenib have been approved for metastatic and unresectable B-RAF-mutated melanomas . These BAlthough there are currently no FDA-approved inhibitors targeting ERK, the recognition that ERK reactivation arises in resistant cancers following prolonged treatment with RAF and MEK inhibitors has generated renewed interest in targeting ERK see . SelectiAlthough targeted therapies against RTKs have high potency and selectivity, they are susceptible to the emergence of drug resistance . ReactivDespite the initial clinical benefits of B-RAF inhibitors, continuous treatment with B-RAF inhibitors results in drug resistance. For example, all ATP-competitive B-RAF inhibitors, including vemurafenib, dabrafenib, and sorafenib, gave rise to reactivation of the MAPK/ERK signaling by triggering conformational changes in RAF molecules or by acquiring an activating mutation in the downstream MEK and ERK ,154. RecApart from reactivation of the MAPK/ERK signaling pathway, cancers acquire resistance to MAPK/ERK signaling-based target therapy by recruiting an alternative signaling pathway that induces cell proliferation and growth. In particular, activation of the PI3K/AKT and yes-associated protein (YAP) signaling pathways stand out as the bypass mechanisms for resistance to therapeutic interventions of the MAPK/ERK signaling . For exaChromatin remodeling or epigenetic mechanisms are also significantly involved in drug resistance to MAPK/ERK inhibition. Melanoma cells with the BRAFV600E mutation became resistant to RAF inhibition (dabrafenib) alone or in combination with MEK inhibition (trametinib) through downregulation of histone deacetylase SIRT6 . InteresA precise understanding of the molecular pathway toward carcinogenesis will allow the patient response to targeted therapies to be predicted, which can have a substantial impact on clinical decision-making. The development of HCC is a complex, multi-step process accompanied by alterations in multiple signaling cascades . Among tTo date, MAPK/ERK signaling-based target therapy in cancer has focused on the core molecules in the signaling see . There a


It is generally accepted that plants use the complex signaling system regulated by light and abscisic acid (ABA) signaling components to optimize growth and development in different situations. The role of ABA–light interactions is evident in the coupling of stress defense reactions with seed germination and root development, maintaining of stem cell identity and stem cell specification, stem elongation and leaf development, flowering and fruit formation, senescence, and shade avoidance. All these processes are regulated jointly by the ABA–light signaling system. Although a lot of work has been devoted to ABA–light signal interactions, there is still no systematic description of central signaling components and protein modules, which jointly regulate plant development. New data have emerged to promote understanding of how ABA and light signals are integrated at the molecular level, representing an extensively growing area of research. This work is intended to fill existing gaps by using literature data combined with bioinformatics analysis. Several years ago, Arabidopsis thaliana (Arabidopsis), we used a systematic approach based on the analysis of literature data, databases, and analysis of protein interaction networks. By analyzing these data, we determined which Arabidopsis protein modules connect ABA and light signaling components. We created an integral picture of known interactions but left aside the signaling of phototropins, cryptochromes, and ultraviolet-B receptor UVR8 because their modules are still poorly resolved. Brassinosteroid (BR) and ethylene (ET) signaling were not considered in this work, although they participate in the regulation of ABA–light interplay. The reason for this is that the combined system BR–ET–ABA–light is very cumbersome to visualize and difficult to understand. Thus, this article describes only ABA–light interactions. We concentrated mainly on the balance between stress reactions and growth mediated jointly by the ABA–light signaling system. A recent review article by Although many articles consider particular aspects of cooperation between ABA and light signaling, there are no works that summarize all protein modules involved in the cooperation. For the description of the ABA–light signaling system in 2 entry into leaves and limiting photosynthesis and increasing tolerance to stress conditions . PP2C inactivation activates class 3 sucrose nonfermenting-1-related protein kinases (SnRK2s) that phosphorylate ABA-responsive element binding factors (ABFs). Activated ABFs initiate the expression of responsive genes by binding to the nt ABRE, . The basA. thaliana genome encodes five phytochrome proteins: phyA mediates responses to far-red light (FR), and phyB-phyE mediates shade avoidance and classical red light (R)/FR-reversible responses  domain, which is necessary for interaction with light-activated phyB. PIF1 and PIF3 also bind to phyA through an additional phyA-binding (APA) domain . Accordinditions . PIF4 isnditions . The rolnditions .Arabidopsis PAIR database  genes  genes . The autR) genes . HY5 alsR) genes .ABI5 induces H2O2 production via the activation of respiratory burst oxidase homolog 1  on ABI5  and far-red impaired response 1 (FAR1) are positive regulators of ABA signaling because they bind to the sduction . Disruptsduction . The fhy1 MIPS1; .In addition to its well-known function in plant growth and development during the vegetative stage, FHY3 plays an essential role in floral meristem determinacy and shoot apical meristem maintenance . FHY3 diABI1, ABI3, ABI4, and ABI5 , which is an important modulator of the light signaling system . During and ABI5 . The autand ABI5 . The DETdarkness . The croABI5 promoter , recruiting HDA6 to the promoter . This inin vivo . The CCA1 protein responds to environmental light and temperature signals and, therefore, may maintain circadian rhythms as well as adapting plants to the environment .ABI1, ABI2, SnRK2.2, and ABF1 but activating the expression of ABI5 . However, the ABRE motif (ABA-specific motif) was over-represented only in LHY-specific target promoters, but not in CCA1-specific target promoters . CommentThus, both LHY and CCA1 transcription factors, acting in conjunction with the ABA signaling system, regulate the adaptation of plants to cold, high temperature, lack of water, and osmotic stress, thereby optimizing defense responses under circadian rhythms.via PIFs. PIF4 and PIF5 are required for shade avoidance and dark-induced senescence acting as positive regulators, while HFR1 inhibits these responses (ABI5 (ABI5 (An important player in shade avoidance and dark-induced senescence is transcription factor HFR1 (long hypocotyl in FR light1), which is the non-DNA binding atypical HLH factor . Like FHesponses . PIF4 anesponses  by direces  → FLC pathway  with ABA signaling components has not been described.ELF3 encodes a nuclear protein that is expressed rhythmically and interacts with phyB to regulate plant development and flowering. The important role of this regulator, as a component of the ELF3-ELF4-LUX ARRHYTHMO (LUX) evening complex, is to modulate light input to the circadian clock and connect light signaling with thermotolerance. ELF3 negatively regulates the activity of eratures , establiRecent studies of rhythmic chromatin modifications revealed a role of chromatin remodeling factors in ELF3 functioning . For insvia the CBF-COR cold signaling pathway . Transcription factor ICE1 (inducer of CBF expression 1) represents another important protein in establishing cold resistance. The intersection of the signaling pathways of these cold resistance factors is of great interest for bioengineering purposes. The SnRK2.6/OST1-HOS1-ICE1 signaling module controls cold tolerance  pathway . In this pathway . In hos1degraded , which l pathway . ICE1 inromoters . The modromoters , therebyromoters . Therefovia ABI5, as indicated in Arabidopsis to intense light are dependent on the function OST1/SnRK2.6 . The intersection of their signaling occurs /SnRK2.6 . These r/SnRK2.6 . The pross light . ConsideRbohD and HOS1 —‖ PIF4 → ABI5 → RbohD, which have an overlap in ROS regulation via ABI5 function  on the light signaling system is an important new topic.Interaction of ABA receptors with PIFs, because this new topic directly links early ABA signaling to light signaling.Part of the research that deals with ROS, as more and more data point to the role of ROS in ABA–light cooperation.FLC signaling sequence is also a key, because FCA/FLC system is now under deep investigation and FCA/FLC affect ABA signaling and ABA signaling affects FCA/FLC. By itself, FLC significantly reduces plant water use because it binds to multiple target genes involved in the response to water shortage. In turn, FCA regulates the function of many genes involved in adaptation to stress-induced ROS, heat, cold, and drought through FLC and ABI5, and regulates the function of defense genes through chromatin modification.The FCA → ABI5 → Chromatin modifications, because many of the ABA signaling components and light signaling components are under the control of chromatin modifiers. There are currently no review articles describing the ABA–light interaction from this point of view, but new experimental data are constantly being added.VB contributed to conception, data analysis, and manuscript writing. OK performed analysis and interpretation of data, revising for important intellectual content, and final approval. All authors contributed to the article and approved the submitted version.Financial support was provided by the Russian Science Foundation, Grant No. 20-16-00016 (VB).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Wnt signaling is an important pathway mainly active during embryonic development and controlling cell proliferation. This regulatory pathway is aberrantly activated in several human diseases. Ion channels are known modulators of several important cellular functions ranging from the tuning of the membrane potential to modulation of intracellular pathways, in particular the influence of ion channels in Wnt signaling regulation has been widely investigated. This review will discuss the known links between ion channels and canonical Wnt signaling, focusing on their possible roles in human metabolic diseases, neurological disorders, and cancer. D. melanogaster and M. musculus, respectively wingless (wg) and Mammary tumor virus integration 1(Int1) ,382+ conel Kv1.3 , affectsel Kv1.3 ; (ii) Brel Kv1.3 ; (iii) sonophore , downregonophore .2+ concentration plays a critical role in the Wnt/AKT crosstalk [2+ release, which activates PI3K and AKT. Subsequently, AKT both inactivates GSK3β by phosphorylation and promotes β-catenin activity through direct phosphorylation of Ser-552 in the activation domain. These reactions eventually result in the blocking of the β-catenin destruction complex, thus favoring its nuclear translocation  in cancer physiopathology . Some ofMoreover, ion channels and Wnt signaling interplay in tumors have been thoroughly and nicely reviewed by Mauss et al. .Thus, the purpose of this section will be to shed light on channels and transporters poorly investigated up to now, especially focusing on AQPs and subcellular channels  modulation of Wnt signaling in the context of cancer.AQPs belong to the major intrinsic protein (MIP) family and consist of ubiquitous tissue and organ-specific channels regulating water flux and small molecules trafficking across cell membranes . FurtherEmerging data reveal the existence of an interplay between AQP3 and canonical Wnt signaling in tumors, although contrasting results have been obtained, probably due to tissue-specific expression and function of this channel. Indeed, in 2016, Zhou et al. demonstrated that AQP3 promotes stem-like hallmarks in human gastric cancer cells, enhancing CD44 levels through Wnt/GSK3β/β-catenin signaling pathway. AQP3 overexpression in human gastric cancer cells is associated with an increase in the level of phosphorylated GSK3β inactive form, resulting in a rise of nuclear β-catenin . On the Furthermore, overexpression of AQP9 is reported to suppress the levels of GSK3β, cyclin D1, and β-catenin in hepatocellular carcinoma cells, enhancing cell apoptosis and inhibiting tumor growth and metastasis formation both in in vitro and in in vivo studies , while AConcerning intracellular channels, emerging hints suggest that mitochondrial ion channels, which strongly impact mitochondrial function regulation, could be addressed as potential oncological targets against cancer diseases ,69. For + channel Kv1.3 inhibitors (PAPTP and PCARBTP) [2+ uptake in the ER, thus enhancing ER-stress levels [Indeed in 2019, Costa et al. demonstrated that treatment with sublethal doses of mitochondrial voltage-gated KPCARBTP)  could dos levels .KCNA1, encoding the voltage-gated K+ channel Kv1.1, resulted in being an oncogene strongly expressed in cervical cancer, supporting carcinogenesis by upregulation of Hedgehog, Wnt, and Notch signaling pathways and, eventually, affecting mitochondrial function [Along with these findings, function .Wnt, Hippo, and Notch signaling are all affected by mutations that impair the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) pump functional activity in the ER, as demonstrated in the in vivo Drosophila model by Suisse et al. . ConcernWnt signaling contribution in the insurgence and the progression of neurodegenerative diseases has only recently been discovered. Because of Wnt fundamental role in orchestrating different neuronal functions in the central nervous system , the dysregulation of these pathways has emerged as a crucial player in the pathogenesis of common neurological disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and other neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) .In AD, Wnt signaling impairment accelerates the onset of the disease and provokes the development of three AD hallmarks: (i) the production and aggregation of β-amyloid; (ii) tau protein hyper-phosphorylation process that involves GSK3β and Dikkopf 1 (DKK1), and generates neurofibrillary tangles within neurons; (iii) hippocampal-dependent cognitive impairment ,74,75.In PD, the evidence of relationships among the early stage of the disease and dysregulated Wnt signaling has been elucidated in the latest years, mainly due to the prominent role of this pathway in the control of midbrain dopaminergic neurons survival and development but also the neuronal rescue and regeneration of PD midbrain ,77.The role of Wnt signaling is highly debated in ALS, where the degeneration of motor neurons in the brain cortex could be partly due to the alterations of some Wnt effectors, in particular the dysregulation in β-catenin homeostasis ,79.CHRNA7), a Ca2+ channel, could represent a potential therapeutic target for neurodegenerative diseases. In AD, its level is drastically reduced in neocortical and hippocampal neurons, together with reducing acetylcholine. It has been demonstrated that activation of canonical Wnt signaling by WNT7A induces CHRNA7 expression and assembly because its gene promoter contains T-cell factor/lymphoid enhancer factor (TCF/LEF) sites [New evidence revealed a direct regulation of the Wnt/β-catenin signaling pathway over channels in neurodegeneration. Specifically, the α7-nicotinic acetylcholine receptor (F) sites ,81.CHRNA7-induced protection of dopaminergic neurons, suppressing neuroinflammation [+ current and mobilizes intracellular Ca2+ from voltage-gated Ca2+ channels to upregulate the trafficking of N-methyl-D-aspartate receptors (NMDARs) into synapses, in a SNARE dependent fashion. This mechanism could be of great importance in neuropsychiatric disorders, such as AD, where deregulation of NMDARs occurs [Moreover, in PD, Wnt signaling is a critical effector of ammation . McQuates occurs .On the other side, only few recent discoveries remark the influence of channels on Wnt signaling. As for cancer and metabolic diseases, even in AD, AQPS has been demonstrated to play an important role in the pathogenesis of the disease. Indeed, the higher expression of AQP1 inhibits Wnt signaling in a mouse AD model, whereas its silencing could activate the pathway, alleviating neuronal apoptosis and improving cognitive function .New insights in the AD non-amyloidogenic pathway that block Aβ production and generate soluble amyloid precursor protein α (APP-α), granting neuroprotection, showed an interplay among NMDARs and Wnt signaling. In particular, NMDAR activation stimulates the secretion of WNT3A, which in turn activates extracellular signal-regulated kinases (ERKs), to elicit A disintegrin and metalloproteinase 10 (ADAM10) —one of the leading α-secretase candidates—responsible for the non-amyloidogenic pathway-expression, likely via β-catenin regulation .2+ homeostasis has been demonstrated to be essential for the maintenance of bone marrow mesenchymal stem cells. Considering the Ca2+ TRP channel superfamily, it has been elucidated that an impairment in the activity of these channels is related to a decreased Ca2+ flux that ultimately downregulates Wnt/β-catenin signaling, leading to the dysregulation of osteogenic differentiation [V1.2. Downregulation of CaV1.2 has been found in aging models characterized by an altered osteogenic differentiation that is ultimately caused by the inhibition of the canonical Wnt signaling pathway [2+ channels and homeostasis can be a promising strategy for bone diseases like osteoporosis.Several studies show the importance of the interplay between ion channels and Wnt signaling in the insurgence of metabolic disorders. In this respect, Cantiation . Another pathway . Thus, tPKD1 and PKD2 genes, involved in the transport of Ca2+ inside the cell. Mutations in such genes represent the leading cause of ADPKD development [Regarding the role of other cation channels, we can consider polycystins in developing autosomal-dominant polycystic kidney disease (ADPKD) . Polycyselopment . In partelopment .The importance of AQP1 in ADPKD development has recently been proved, specifically demonstrating that AQP1 deficiency promotes cysts growth through the stimulation of the Wnt signaling cascade .In addition, aquaporins also seem to have an important role in endometriosis. Shu et al. observed that silencing of AQP1, which is upregulated in endometriosis disease, induces the activation of the Wnt signaling pathway that results in a decreased adhesion, invasion, and in the induction of apoptosis of ectopic cells .− efflux linked to the inhibition of the Wnt/β-catenin pathway. Therefore, this channel can be a promising target for preventing hyperplasia, strokes, and cerebrovascular remodeling [Finally, regarding anion channels, Lu et al. have demonstrated the importance of the chloride channel ClC-2 in proper blood vessel development in human brain vascular smooth muscle cells (HBVSMCs). The block of this channel activity mediates a decreased Clmodeling .+ and Ca2+ fluxes across cell membrane induced by changes in transmembrane potential can modulate canonical Wnt-signaling [This review summarized the major known mechanisms involved in Wnt signaling regulation by channels, ion fluxes, and transporters. Some interesting points emerged from our analysis. Firstly, many pieces of evidence lead to the idea that variation in Kignaling ,51,62. Iignaling ,51. ThusThe second aim of this review was to elucidate the consequences of the channels-Wnt signaling cascade in different diseases. As clearly reported in the literature, the Wnt/β-catenin pathway is the most associated with channels regulation in cancer disease development and progression . Indeed,Although the interplay between ion channels and oncogenesis has been unequivocally described, more in-depth investigations about their role in modulating cancerous-unrelated signaling pathways still need to be carried out in other pathologies.According to the novel findings summarized above, ion channels could be accounted as new Wnt-dependent markers for different pathological conditions, representing invaluable predictive factors for early-onset disease detection and possibly identifying new druggable targets.


This work aimed to investigate the effect of fucoidan (FPS) on urate transporters induced by uric acid (UA). The results showed that UA stimulated the expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in HK-2 cells, and FPS could reverse the effect. Moreover, UA could activate NF-κB, JNK and PI3K/Akt pathways, but both pathway inhibitors and FPS inhibited the UA-induced activation of these three pathways. These data suggested that FPS effectively inhibited the expression induction of reabsorption transporters URAT1 and GLUT9 by UA, through repressing the activation of NF-κB, JNK and PI3K/Akt signal pathways in HK-2 cells. The in vitro research findings support the in vivo results that FPS reduces serum uric acid content in hyperuricemia mice and rats through inhibiting the expression of URAT1 and GLUT9 in renal tubular epithelial cells. This study provides a theoretical basis for the application of FPS in the treatment of hyperuricemia. Hyperuricemia is considered a metabolic disease that induces gout, chronic nephrosis and insulin resistance. Hyperuricemia accelerates vasculopathy and the occurrence and development of abnormal glucose tolerance, and is closely related to hypertension, atherosis, coronary heart disease, lipid metabolism disorder, obesity and sexual dysfunction ,2. An epUrate anion transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are two important transporters for urate reabsorption. URAT1 mediates extracellular urate transport into cells; in renal tubular epithelial cells, URAT1-mediated uptake of urate from the lumen is the first step in urate reabsorption . GLUT9 iDrugs for hyperuricemia have been classified into two categories; uricostatic drugs such as allopurinol, febuxostat, topiroxostat and BCX-4208, and uricosuric drugs including probenecid, benzbromarone, sulphinpyrazone, pyrazinamide, RDEA-594 and RDEA-684. However, these clinical drugs have an unbearable, untoward effect on patients ,8,9. So,Fucoidan (FPS) is a kind of sulfated and heterogeneous polysaccharide which originates from brown seaweeds. FPS is rich in fucose and sulfate groups, and has many bioactive properties such as antitumor, antivirus, antioxidation, antithrombotic, anticoagulant, anti-inflammatory and immunomodulatory. It also has a clinical application in the treatment of renal, hepatic and uropathic disorders ,13. FPS p < 0.01), and the protein contents were positively associated with UA dosage. It was also found that a low dosage of UA failed to modify the expression level of transporter URAT1  and GLUT9 , which suggests that urate at a low concentration may not affect the renal function of urate excretion, but a high concentration does. Namely, a high urate level may inhibit urate excretion from the kidneys in hyperuricemia patients, resulting in a higher urate content. However, the UA-induced expression of the two reabsorption transporters was significantly inhibited by the natural marine polysaccharide fucoidan at a very low dosage of 25 μg/mL (p < 0.01). Moreover, along with an increase in FPS concentration, protein contents of URAT1 and GLUT9 became lower and lower, and more significant differences were observed. Interestingly, FPS (100 μg/mL or 200 μg/mL) significantly decreased the expression level of URAT1 or GLUT9 to below the normal level (p < 0.01) (The data presented in  < 0.01) . These dp < 0.01) but did not affect the expression of URAT1 and GLUT9 (p > 0.05), suggesting that QNZ could not change the urate excretion function of control renal tubular epithelial cells. However, for the cells exposed to a high dosage of UA, QNZ sharply blocked p65 protein phosphorylation caused by UA (p < 0.01), maintained the normal activation level (p > 0.05 vs. vehicle), and kept contents of GLUT9 and URAT1 in UA-exposed cells at levels of insignificant difference compared to vehicle-treated cells (p > 0.05). Data indicated that UA induced the expression of GLUT9 and URAT1 via activating the NF-κB signal pathway.p < 0.05), GLUT9 (p < 0.05) and URAT1 (p < 0.01). This reduction was almost the same as with vehicle cells (p > 0.05), indicating that the NF-κB signal pathway participated in the regulatory mechanisms of FPS, inhibiting the UA-induced expression of URAT1 and GLUT9 in HK-2 cells. It was also found that QNZ effectively promoted the inhibition of FPS towards UA-induced p65 phosphorylation (p < 0.01 vs. UA + FPS), but did not modify the inhibition of FPS on the UA-induced expression of URAT1 and GLUT9 (p > 0.05 vs. vehicle).Compared with UA-treated cells, cells co-treated with FPS and UA were observed to have significantly reduced levels of phospho-p65 (p > 0.05), indicating that FPS could not change the expression level of URAT1 and GLUT9, and the activation level of the NF-κB signal pathway. The signal pathway inhibitor, QNZ, did not modify protein contents of GLUT9 and URAT1 in FPS-exposed cells, but obviously declined the content of p65 in the cells (p < 0.01).Additionally, as for control cells, FPS had no effect on both the expression of URAT1 and GLUT9 and the phosphorylation of p65 protein (p < 0.05 or p < 0.01); contents of the two transporters in the UA + FPS and SP + UA treated cells were approximately equal to that of vehicle cells (p > 0.05). Meanwhile, both SP600125 and FPS clearly inhibited the UA-induced phosphorylation of JNK protein (p < 0.01). FPS did not change the expression of URAT1 and GLUT9, and the activation of JNK protein in control cells (p > 0.05). These results suggest that FPS inhibited the expression induction of urate reabsorption transporters through suppressing the activation of JNK by UA. In addition, inhibitor SP600125 did not change the contents of the two transporters (p > 0.05), but declined phospho-JNK protein content (p < 0.05). It could be concluded from the data in As shown in p < 0.01), but FPS did not (p > 0.05).Additionally, both the inhibitor and FPS maintained the expression level of URAT1 and GLUT9 and the phosphorylation of signal molecules JNK appeared to be at a normal level in UA-exposed cells. However, it was different that the inhibitor significantly declined the activation level of the signal pathway in control cells (p < 0.05 or p < 0.01). Additionally, FPS exposure blocked the activation of the PI3K/Akt pathway caused by UA (p < 0.01). Similarly to SP600125, wortmannin failed to reduce contents of URAT1 and GLUT9 to below normal levels in untreated cells, but decreased the activated signal molecule p-AKT in untreated cells and in UA + FPS treated cells to below normal content (p < 0.01). Additionally, wortmannin declined the activation level of the PI3K/Akt signal pathway in control cells (p < 0.01), but FPS did not (p > 0.05).Data are presented in The transport processes of UA in the kidneys mainly includes glomerular filtration, renal tubular reabsorption and secretion, and post-secretion reabsorption, etc. Except glomerular filtration, the other processes require the participation of urate transporter protein. URAT1 is a transporter in proximal convoluted tubules and is responsible for UA reabsorption from renal lumen into epithelial cells; GLUT9 successfully transports UA from epithelial cells into blood . GLUT9 aIt is documented that soluble uric acid induced the expression of GLUT9 and URAT1 in renal tubular epithelial cells of hyperuricemia mice/rats and was inhibited by FPS ,17,18,19It has been proven that UA can activate NF-κB signaling in proximal renal tubular epithelial cells and upregulate URAT1 expression . Work frIt has been reported that MAPKs are pivotal mediators in the pathophysiology of kidney insults , and thaα-SMA, CTGF, and fibronectin expression in both type 1 and type 2 diabetic models. It also decreased the phosphorylation of Akt, ERK1/2, p38 and Smad3, thereby protecting kidneys from dysfunction and fibrogenesis by inhibiting the TGF-β pathway [Increasing evidence links hyperuricemia nephropathy to epithelial−mesenchymal transition (EMT), which is an essential process during renal fibrosis ,29. The  pathway .2 atmosphere. The medium was changed every 2–3 days, and cells were subcultured at 80% confluence for the following work.HK-2 cells purchased from ATCC and were grown in an Roswell Park Memorial Institute (RPMI) 1640 medium, supplemented with 10% heat-inactivated foetal bovine serum  and 1% penicillin-streptomycin, at 37 °C in an incubator containing 5% COg rpm for 5 min at 4 °C. The supernatant was detected as the protein content, using a BCA protein assay kit, and was then diluted in a protein loading buffer followed by heat inactivation in a boiling water bath for 10 min. Samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, followed by transferal to polyvinylidene fluoride (PVDF) membranes . After being treated in 5% skim milk in TBST for 1 h, the membranes were probed overnight at 4 °C with the primary antibodies against URAT1, GLUT9, p65, p-p65, JNK, p-JNK, AKT, p-AKT or β-actin , respectively. Following washing with Tris-buffered saline Tween 20 (TBST) three times, the membranes were transferred into a corresponding secondary antibody solution, and incubated for 1 h at room temperature. Afterwards, the membranes were washed three times with TBST and were detected on a multifunction imager by using the enhanced chemiluminescence (ECL) kit. The intensity of individual bands were normalized to β-actin. Value was expressed as the ratio of treated group to vehicle group.Cells were washed with PBS, and were then lysed in RIPA buffer containing PMSF  at 4 °C. The lysate was centrifuged at 12,000× Cells were washed with PBS, and were then fixed with 4% paraformaldehyde for 20 min at room temperature. After washing with PBS, cells were permeabilized with 0.1% Triton X-100 for 15 min at room temperature. HK-2 cells were washed with PBS and were incubated in blocking buffer for 2 h at room temperature. Cells were probed at 4 °C overnight with the primary antibody against URAT1 or GLUT9. Cells washed with PBS were incubated with an FITC-conjugated secondary antibody for 1 h at room temperature. Following washing with PBS, Hoechst 33342 was used to stain nuclei for 20 min at room temperature. After washing with PBS, fluorescence was examined with a fluorescence microscope, Ts2R-FL .p < 0.05 was taken as statistical significance.The data were shown as average and standard deviation. SPSS 22.0 software was used for statistical analysis. One-way ANOVA and LSD were used to make multiple comparisons for evaluating the statistical significance. A relatively higher concentration of UA can promote the expression of GLUT9 and URAT1 via activating the NF-κB, JNK and PI3K/Akt signaling pathways in renal tubular epithelial cells. However, UA caused activation of the pathways can be inhibited by FPS, resulting in expression downregulation of the two urate reabsorption transporters. These results support the reported in vivo research findings, and prove that FPS inhibits the expression of GLUT9 and URAT1 in renal tubular epithelial cells via inhibiting the UA-associated activation of the NF-κB, JNK and PI3K/Akt signaling pathways to promote urate excretion from kidneys, consequently decreasing blood uric acid content in hyperuricemia mice. It is interesting that the bio-function of FPS only occurs in UA-exposed cells, not in control cells. These results indicate that, as a clinical nephropathy drug which has been used for nearly 20 years in China, FPS should be a potential marine drug for hyperuricemia and gout.


Climate change is likely to worsen the food security situation through its impact on food production, which may indirectly affect fertility behaviour. This study examines the direct and indirect effects of climate change  via the production of major crops, as well as their short- and long-term effects on the total fertility rate (TFR) in Bangladesh. We used structural equation modelling (SEM) to perform path analysis and distinguish the direct influence of climate change on fertility and its indirect influence on fertility through food security. We also applied the error correction model (ECM) to analyze the time-series data on temperature and precipitation, crop production and fertility rate of Bangladesh from 1966 to 2015. The results show that maximum temperature has a direct effect and indirect negative effect–via crop production–on TFR, while crop production has a direct positive effect and indirect negative effect–via infant mortality–on TFR. In the short term, TFR responds negatively to the maximum temperature but positively in the long term. The effect of rainfall on TFR is found to be direct, positive, but mainly short-term. Although indicators of economic development play an important part in the fertility decline in Bangladesh, some climate change parameters and crop production are non-negligible factors. Climate change is a major problem today and poses a threat to the entire world. The Earth’s atmosphere’s average temperature has increased by about 0.15°C to 0.2°C over the past 100 years . There aAbout 108 million people living in 48 countries at risk of food crises were highly vulnerable or already experiencing acute food insecurity in 2016 . ClimatePopulation dynamics such as mortality, migration, and fertility can undergo significant changes due to climate variability or natural disasters –23. HumaSince Bangladesh is a predominantly agricultural country, climate change could exacerbate food insecurity by affecting crop production and, indirectly, fertility. This study aims to find out if and how climate change affects fertility in the country. Specifically, the direct and indirect effects of climate change  on major crops and the short- and long-term effects on fertility are examined. The results of this study can add exciting insights and arguments to the existing literature on population dynamics and climate change impacts. They can also deepen our understanding of the linkages between climate change, food security, and fertility.The next section presents the conceptual framework of this study in relation to climate change, food security, and fertility to justify and explain the purpose of the study. This is followed by a description of the data and methodology used in the analysis. Then, the results regarding the impact of climate change and crop production on fertility are presented. Finally, a concluding section discusses the implications of the main findings and provides recommendations for further research.Crop production in South Asian countries is likely to be most affected by climate change. For example, a temperature increase between 1.0°C and 3.0°C could reduce rice production in Punjab by 3–10% . In TamiIn Bangladesh, agriculture absorbs about 44% of the workforce . 76% of Climate change, such as changes in precipitation patterns and frequent temperature fluctuations, can affect population dynamics through fertility behaviour , 58. TheNot only temperature but also precipitation is related to fertility . A studyThe short- and long-term effects of climate variability on fertility can be different. A recent study conducted in 18 sub-Saharan African countries shed light on the short- and long-term effects of climate variability on fertility. In the study, Eissler et al. found that temperature increase, both short- and long-term, has negative effects on fertility, while precipitation, both short- and long-term, has differential effects on fertility. For example, a one standard deviation increase in temperature for 12 months (short term) and 60 months (long term) leads to a 0.042 and 0.101 reduction in ideal family size, respectively. In contrast, a one standard deviation increase in precipitation is associated with a 0.052 decrease in children in the short term, while a one standard deviation increase in precipitation is associated with a 0.059 increase in women’s preference for ideal family size in the long term .The effects of climate variability may have indirect effects on fertility through food production. Food insecurity leads to a range of demographic impacts, including but are not limited to changes in fertility. Reducing human fertility–a means of controlling population growth–may be one way to cope with inadequate food supply . ChangesDrawing on insurance mechanisms and replacement theory, Finlay argues that fertility responds to both natural disasters and infant mortality . In a stThe literature section shows that Bangladesh’s economy is largely dependent on agriculture, which is extremely vulnerable to climate change. The literature also shows that the global impacts of climate change on crop production and the resulting food insecurity are visible and studied in different countries. In response to food insecurity, vulnerable populations see demographic adaptations, such as changes in fertility behaviour, as coping mechanisms. Research has already examined the effects of climate variables on crop production and fertility changes in different areas separately. However, to the best of our knowledge, there is no such attempt made to jointly study the direct and indirect, as well as short- and long-term, effects of climate variables on crop production and subsequently fertility.http://www.bmd.gov.bd) [http://www.fao.org/home/en/) [https://population.un.org/wpp/) [https://data.worldbank.org/). The dependent variable is TFR. The independent variables are temperature, rainfall, infant mortality, as well as rice, wheat, and legume production. The GDP per capita, which reflects the average income of the population, is also included as a control variable. However, because crop production is an important factor of agriculture income and a crucial contributor to the GDP in Bangladesh, GDP per capita becomes an endogenous factor. To avoid endogeneity of GDP per capita, we finally decided to take the GDP per capita from the industry and service sector, that is, GDP per capita*. Both the GDP per capita and the percent of agriculture, forest and fishing value add in GDP are from the World Bank (https://data.worldbank.org/). For simplicity, in the remaining paper, we use the term “GDP per capita” to represent “the GDP per capita from the industry and service sector”.This study incorporates climate change, production of major crops , and fertility data of Bangladesh during 1966–2015. We collected climate data from the Bangladesh Meteorological Department (BMD) (.gov.bd) . Then weome/en/) . The datrg/wpp/) . BecauseTo examine the direct and indirect impact of climate change, we adopt the structural equation model (SEM) to perform pathway analysis. Path analysis allows us to distinguish the direct impact of climate change on fertility and its indirect impact on fertility through food security. To assess the short- and long-term relationship between climate change and fertility, we apply the error correction model (ECM). ECM is a very useful econometric method for exploring time series data, which allows us to study the long-term equilibrium relationship between climate change and fertility, as well as how fertility responds to climate shock in the short term. Because agricultural production and infant mortality are endogenous, we do not include them in the ECM model. The error-correction equations are formulated asσ refers to the constant. jγ, jη, mξ are the parameters that denote the short-term elasticities. In Eq  and ln(GDPPC) are significant, with values -7.39 and 0.499, respectively. This means that in the long-term equilibrium, the increase in maximum temperature would have a positive impact on the TFR and the increase in GDP per capita would have a negative impact on the TFR.Path analysis shows that climatic factors, especially maximum temperature and precipitation, can affect fertility directly and to some extent only maximum temperature indirectly through crop production, while crop production affects fertility directly and indirectly through infant mortality. But the contribution of indicators of economic development is also crucial in influencing fertility rates directly or indirectly. Higher GDP per capita is likely to reduce fertility rates by reducing infant mortality.Indirectly speaking, the increasing maximum temperature is likely to increase crop production; increasing crop production is likely to reduce infant mortality; decreasing infant mortality contributes to the fertility decline. The positive relationship between maximum temperature and crop production is consistent with the findings from the study by Sarker et al., who also found a positive association of maximum temperature with Aus and Aman variety in Bangladesh . Crop prDifferent from findings in Winkler-Dworak’s study has that the context of sub-Saharan Africa , fertiliIn assessing the short- and long-term relationship between climate change and fertility, we ran error correction models. Fertility is found to respond negatively to maximum temperature in the short run but positively in the long run. Eissler et al. found that both short- and the long-term temperature has adverse effects on fertility . The incWhile our results confirm that GDP per capita is largely responsible for fertility decline in both the short and long run, we show that certain climate change parameters  and crop production are also non-negligible factors for fertility transition in the country. Although GDP per capita is responsible for fertility decline in both the short and long term, we show that climate change and crop production are also non-negligible factors for fertility transition in the country. This study can serve as an example and focus further research on regions or countries that are in a similar context to Bangladesh, whose economies are mainly based on agriculture and are highly vulnerable to climate change. Climate change is likely to worsen a country’s economic development and may affect fertility rates directly or indirectly, in the short or long term. Since GDP per capita is one of the determining factors for the decline in fertility rate in Bangladesh, the adverse effects of climate change may affect the rate of this decline by reducing GDP growth. The study findings advance our understanding of the impacts of climate change parameters with an indirect impact through food production on the fertility rate in Bangladesh. This study suggests further research incorporating multiple climate change parameters and crop types with a particular focus on spatial variations across the districts of Bangladesh. Further research could separate the effects of different crops in the analysis.Since crop production  is susceptible to temperature in Bangladesh, variety-specific adaptation strategies could help mitigate the adverse effects of climate change and thereby reduce the risk of food insecurity. In Bangladesh, several salt-tolerant high-yielding rice varieties have been successfully released to coastal areas in recent years, which could ensure food security for vulnerable coastal populations . Other aThere are some limitations to this study. First, TFR is used as a measure of fertility, which refers to the average number of children per woman in a given year. It is not possible to distinguish whether the change in the TFR is due to the change in the number of children desired by women or to the change in the state of health of the women who give birth or in fertility. Second, the current analysis is nationwide. Having no access to provincial and county-level data, we are unable to reveal whether the relationship between fertility and climate factors varies from one region to another. Third, this study only considered infant mortality, agricultural production and climate factors in the analysis. We are aware that there are many other agricultural inputs  and various fertility factors ; however, due to data limitation, we cannot incorporate these factors into the analysis.S1 Data(XLSX)Click here for additional data file.


Strongyloides stercoralis and its association with other health conditions are unknown. A cross-sectional community-based survey was conducted in seven remote Aboriginal communities in central Australia, from 2014 to 2018. All residents aged ≥10 years were invited to complete a health survey and to provide blood for Strongyloides serology, HTLV-1 serology and HTLV-1 proviral load (PVL). Risk factors for Strongyloides seropositivity and associations with specific health conditions including diabetes and HTLV-1 were determined using logistic regression. Overall Strongyloides seroprevalence was 27% (156/576) ; adults (≥15 years), 27% (147/536), varied widely between communities (5–42%) and was not associated with an increased risk of gastrointestinal, respiratory or dermatological symptoms. Increasing age, lower HTLV-1 PVL  compared to the HTLV-1 uninfected group and community of residence were significant risk factors for Strongyloides seropositivity in an adjusted model. A modest reduction in the odds of diabetes among Strongyloides seropositive participants was found ; however, this was lost when body mass index was included in the adjusted model . Strongyloides seropositivity had no relationship with anaemia. Exploring social and environmental practices in communities with low Strongyloides seroprevalence may provide useful lessons for similar settings.In central Australia, an area that is endemic for the human T-cell leukaemia virus type-1 (HTLV-1), the prevalence of  Strongyloides stercoralis is highly prevalent in tropical and subtropical regions of the world, including Australia [Strongyloides stercoralis [Strongyloides is endemic across the tropical north of the country where prevalence rates range from 10 to 60% [Infection with the soil-transmitted helminth ustralia ,2. Globarcoralis . In Aust0 to 60% . In cont0 to 60% . Strongyloides infection can cause diverse symptoms, which reflect the organs involved in the nematode’s life cycle. These include pruritus, gastrointestinal symptoms, such as abdominal pain and diarrhoea, and respiratory symptoms, such as cough and dyspnoea [Strongyloides [Strongyloides coinfection of people with HTLV-1 induces polyclonal expansion of HTLV-1-infected cells by activating the IL-2/IL-2R system, which could increase the risk of developing HTLV-1 associated diseases [dyspnoea ,6. Immundyspnoea ,7,8,9, mdyspnoea . Both cogyloides . This isgyloides . Strongydiseases .Strongyloides is a consequence of impaired Th-2 immune response, which is modulated by the high IFN-γ levels observed in HTLV-1 infected individuals [Strongyloides larvae in stool [In a central Australian case series, seven of eleven patients with complicated strongyloidiasis were HTLV-1 seropositive, and four died . HTLV-1 ividuals . Treatmein stool . CollectStrongyloides stercoralis overlap in Australia [Strongyloides [Strongyloides have been rarely studied in central Australia. Community-based Strongyloides seroprevalence data have so far only been available from a single small community where 10 of 72 adults were Strongyloides seropositive [The endemic areas of HTLV-1 and ustralia . Relativustralia , while tustralia ,4,17. Crgyloides  and the positive . Communipositive . Strongyloides and other conditions. For example, strongyloidiasis was associated with an increased risk of anaemia in Ethiopia [A higher admission rate with strongyloidiasis was reported among adults with HTLV-1 in a retrospective cohort study in central Australia . HoweverEthiopia , and strEthiopia . Strongyloides seropositivity was associated with HTLV-1 infection and other health conditions, including diabetes and anaemia, in central Australia.We therefore collaborated with remote Aboriginal communities to determine whether 2 in which most Aboriginal people live in isolated communities. English is generally the second or third language spoken in these communities. Residents of 7 remote central Australian Aboriginal communities  [Central Australia is an area of some 1,000,000 kms, 1153)   ,23.Details of community engagement and the method of recruitment have been described previously . BrieflyParticipants were asked to complete a simple health questionnaire that recorded alcohol and tobacco consumption, and symptoms classified as respiratory , dermatological (pruritus and rash) or gastrointestinal  . The heaClinic records for five years prior to recruitment were subsequently reviewed for any evidence of comorbid conditions including smoking, harmful alcohol consumption, diabetes, hypertension, chronic kidney disease (CKD) and chronic liver disease. A diagnosis of diabetes was recorded if this was either stated in the medical record or a diabetic medication was prescribed.Whole blood was collected from participants by venepuncture into EDTA tubes. Peripheral blood buffy coats (PBBC) and plasma were prepared and stored at −80 °C at Baker Heart and Diabetes Central Australia (Baker Institute) in Alice Springs.Strongyloides serology were collected in gold top serum separator tubes (SST) and stored at 4 °C at the Baker Institute, Alice Springs. Samples were shipped to Western Diagnostic Pathology, Perth, for Strongyloides serology testing using a commercial IgG enzyme-linked immunosorbent assay , which detects IgG directed against the soluble fraction of filariform Strongyloides stercoralis larvae, in accordance with the manufacturer’s protocol.Blood samples for ® WBC DIFF System and Hemocue Hb 301 system, Ängelholm, Sweden) were used to determine haemoglobin concentrations and the total and differential  white blood cells counts in peripheral blood. Peripheral blood eosinophilia was defined as >0.6 cells/109/L.Point of care tests (HemoCue5 PBL) and high (≥1000 copies per 105 PBL). The lower limit of detection was 6.5 copies for HTLV-1  [Buffy coats and plasma were shipped to the National Serology Reference Laboratory (NRL), Melbourne, in batches at intervals during the study. HTLV-1 status was confirmed by Western blot analysis (WB)  on samples reactive on screening either by enzyme immunoassay  or particle agglutination assay . HTLV-1 PVL was determined by polymerase chain reaction (PCR) using DNA extracted from PBBC cells. Primers and probes that targeted a highly conserved region at the 5′ end of the gag gene in the p19 coding region of HTLV-1c  were expressed as HTLV-1 copies per 105 peripheral blood leucocytes (PBL). Consistent with previous studies [5.4–8.4) . HTLV-1 The study was approved by the Central Australian Human Research Ethics Committee .Strongyloides seropositive and seronegative groups were compared using Pearson’s χ2 test, Student’s t-test or Mann–Whitney test as appropriate for each variable. A multivariate logistic regression model was used to determine the factors associated with Strongyloides seropositivity . The odds ratio with 95% confidence intervals (CI) and p-value (<0.05) were used to report the associations between Strongyloides seropositivity and other variables. All analyses were conducted in Stata version14 .For categorical variables, frequency and percentages were used; for continuous variables, mean, standard deviation (SD), and median were used. Strongyloides serology was tested for 576 participants, approximately 37.5% of the estimated resident population ; adults (≥15 years), 536/1153 (46%)). Overall Strongyloides seropositivity rates for children and adults were 22% (9/40) and 27% (147/536), respectively.Strongyloides seropositive (Strongyloides + ve) and seronegative (Strongyloides − ve) groups  and lowest among the 35–44 years group (18%)   groups . Howeverup (18%) . Strongy< 0.001) .Strongyloides serostatus     . Signifi = 0.03) ; however= 0.542) .Strongyloides seroprevalence was higher in the HTLV-1 uninfected group  relative to the HTLV-1 infected group  (p = 0.043)  and HTLV-1 high PVL (25.4%) groups had lower Strongyloides seroprevalence, but it was not statistically significant (= 0.043) . When Stnificant .Strongyloides seropositivity increased with age, and was reduced among participants with a low HTLV-1 PVL compared to HTLV-1 uninfected group  of ivermectin, either alone  or in coustralia ,28 and oustralia . In one month 18 . Communimonth 18 . Neverthustralia , and no ustralia . Althougol study  and baseol study  in northmunities  in the NStrongyloides and diabetes is scarce and remains inconclusive. A reduced risk of diabetes has been reported among Aboriginal Australians with Strongyloides infection in a community clinic setting [Strongyloides seropositivity and there was no association between Strongyloides infection and diabetes in the adjusted multivariate model that included BMI. Alterations to the gut microbiome of the human host are purported to result from helminth infection, and these may reduce the risk of diabetes by modulating glucose uptake, inflammation, and insulin sensitivity [Strongyloides, the microbiome and metabolic outcomes is yet to be fully explored [Notwithstanding reports that chronic helminth infections have a protective effect on metabolic diseases including reduced risks of hyperglycaemia, type 2 diabetes, metabolic syndrome and insulin resistance , the evi setting  and in a setting . Three p setting . A nutri setting . Consist setting , we founsitivity ,36. Howeexplored .Strongyloides-mediated immune-modulation of glycaemic, hormonal, and cytokine parameters which may have anti-diabetogenic effects. Significantly reduced insulin and glucagon levels have been reported among Strongyloides infected individuals, which was confirmed by faecal microscopy, compared to those who are uninfected, and these effects reversed after anthelminthic therapy [Strongyloides infection significantly reduces the pro-inflammatory milieu in T2DM by lowering the systemic levels of cytokines and chemokines [Strongyloides infection may also confer a degree of protection against the severity of type 2 diabetes [Strongyloides seropositivity among adults with diabetes, and in the first community-based study to address this issue, we found that Strongyloides seropositivity was not associated with diabetes when BMI was included in the multivariate model.A stronger case has been made for  therapy . Strongyemokines . Decreasemokines . Modulatdiabetes . Chronicdiabetes . An epipdiabetes . This hydiabetes  and withdiabetes . Neverthdiabetes  and Brazdiabetes  found anStrongyliodes in the human host is made challenging by the difficulty with which chronic strongyloidiasis is diagnosed and by the potential for Strongyloides serology to remain positive after resolution of infection. Although the identification of larvae in faecal samples by microscopy is considered the ‘gold standard’ method by which Strongyloides infection is diagnosed [Strongyloides diagnosis in this research has been reported as 92.3% sensitivity and 97.4% specificity relative to faecal results [Strongyloides [Strongyloides are not endemic in central Australia. An underestimation of prevalence may also occur because of false-negative results, especially in acute infections and among immunosuppressed patients [Strongyloides seroprevalence in HTLV-1 endemic areas, such as central Australia, may be underestimated by lower Strongyloides serology titres among individuals with HTLV-1 [Strongyloides seropositivity that is reported here and in other HTLV-1 endemic areas.Studying the health interactions of iagnosed , the seniagnosed . In contiagnosed . A receniagnosed . The ELI results . Cross-rgyloides ; howeverpatients . StrongyStrongyloides infection and anaemia [Strongyloides larvae in stool was associated with a five-fold increased risk of anaemia [Strongyloides and to malnutrition, might be the more important cause of anaemia and complicate the interpretation of these studies [Strongyloides seropositivity.Several studies have reported an association between  anaemia ,46. In a anaemia , althoug anaemia . Confoun studies . In the  studies , all parStrongyloides seropositivity rates were lower among participants with low HTLV-1 PVL relative to those with high HTLV-1 PVL was therefore surprising. The effect of HTLV-1 PVL on Strongyloides seropositivity has not been studied previously, and further studies are necessary to understand this finding. However, this might reflect the greater likelihood of treatment for strongyloidiasis among people who are HTLV-1 seropositive and higher rates of treatment failure in those who with high HTLV-1 PVL.Higher HTLV-1 PVL increases risk of symptomatic strongyloidiasis when this is defined by faecal microscopy , and thiStrongyloides and HTLV-1 serostatus. However, some important limitations must be recognised. We recruited less than half of all eligible community members, raising the possibility of selection bias, and the recruitment of participants with better health engagement who may be more likely to receive treatment for strongyloidiasis. This might affect estimates of Strongyloides seroprevalence, and true prevalence may be higher than that reported here. However, selection bias is unlikely to alter the interpretation of our clinical survey, which was blinded to Strongyloides and HTLV-1 serostatus. Second, our clinical findings relate only to Strongyloides seropositivity, which reflects exposure to Strongyloides rather than active strongyloidiasis and has no relationship to larval burden. Third, we found no evidence of an association between Strongyloides seropositivity and gastrointestinal symptoms, which can fluctuate over time and may not be captured in our cross-sectional study. Our inability to obtain faecal samples prevented us from estimating the Strongyloides larval burden and we were also unable to exclude other pathogens, such as giardia and cryptosporidium, which are important causes of gastrointestinal symptoms in our region. Nevertheless, the number of participants with such symptoms was low for both Strongyloides seropositive and seronegative groups. Finally, we were unable to collect data for other important community and environmental factors, such as health engagement and treatment, or behaviours that might increase exposure to Strongyloides, which could explain the variation in prevalence.Strengths of the present study are the recruitment of participants in a community setting with blinding of both researchers and participants to Strongyloides seroprevalence in an arid, HTLV-1 endemic region of remote Australia. Consistent with other recent studies from the far north of the NT [Strongyloides seropositivity was not associated with clinical symptoms in our cross-sectional study in this HTLV-1 endemic area, nor was it associated with diabetes or anaemia. The single case of complicated strongyloidiasis that has been reported from this region since awareness was raised among clinicians a decade ago [Strongyloides seroprevalence in central Australia was high, the wide variation in prevalence suggests that some Aboriginal communities may have developed protective strategies that reduce risk of infection with soil-transmitted helminths. An in-depth exploration of social and environmental practices in low-risk communities may provide useful lessons for other remote Aboriginal communities to reduce overall risk of strongyloidiasis.In conclusion, we demonstrate a high f the NT ,31, Strocade ago  followedcade ago . This su


Human T-cell lymphotropic viruses 1 and 2 (HTLV-1/2) are relatively common in Brazil but remain silent and neglected infections. HTLV-1 is associated with a range of diseases with high morbidity and mortality. There is no curative treatment for this lifelong infection, so measures to prevent transmission are essential. This narrative review discusses HTLV-1/2 transmission routes and measures to prevent its continuous dissemination. The public health policies that are currently implemented in Brazil to avoid HTLV-1/2 transmission are addressed, and further strategies are proposed. Human T-cell lymphotropic virus 1 and 2 (HTLV-1/2) are retroviruses that cause persistent infection, mainly in T-cell lymphocytes. HTLV-1 is associated with high morbidity and mortality clinical conditions, while HTLV-2 is rarely associated with disease. Transmission occurs through sexual relations, transfusion/transplantation of blood/organs infected with the virus, and from mother to child, mainly by breastfeeding. Although it has a worldwide distribution, except for Japan, low- and middle-income countries and predominantly ethnic minority population groups in high-income nations are the most affected. It has been estimated that 800,000 to 2.5 million people are living with HTLV-1 (PLHTLV) in Brazil . 2021. Available from: 10.3389/fmicb.2012.00388Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol. 2012;3:388. 10.1016/S0140-6736(18)30974-7Martin F, Tagaya Y, Gallo R. Time to eradicate HTLV-1: an open letter to WHO. Lancet. 2018;391:1893–4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149377/pdf/pjab-87-152.pdfHino S. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:152–66. Available from: 10.1590/0037-8682-0343-2019Puccioni-Sohler M, Grassi MFR, Galvão-Castro B, Caterino A, Proietti AB, Vicente ACP, et al. Increasing awareness of human T-lymphotropic virus type-1 infection: a serious, invisible, and neglected health problem in Brazil. Rev Soc Bras Med Trop. 2019;52:e20190343.


Ursolic acid (UA) is a pentacyclic triterpenoid frequently found in medicinal herbs and plants, having numerous pharmacological effects. UA and its analogs treat multiple diseases, including cancer, diabetic neuropathy, and inflammatory diseases. UA inhibits cancer proliferation, metastasis, angiogenesis, and induced cell death, scavenging free radicals and triggering numerous anti- and pro-apoptotic proteins. The biochemistry of UA has been examined broadly based on the literature, with alterations frequently having been prepared on positions C-3 (hydroxyl), C12–C13 (double bonds), and C-28 (carboxylic acid), leading to several UA derivatives with increased potency, bioavailability and water solubility. UA could be used as a protective agent to counter neural dysfunction via anti-oxidant and anti-inflammatory effects. It is a potential therapeutic drug implicated in the treatment of cancer and diabetic complications diseases provide novel machinery to the anti-inflammatory properties of UA. The pharmacological efficiency of UA is exhibited by the therapeutic theory of one-drug → several targets → one/multiple diseases. Hence, UA shows promising therapeutic potential for cancer and diabetic neuropathy diseases. This review aims to discuss mechanistic insights into promising beneficial effects of UA. We further explained the pharmacological aspects, clinical trials, and potential limitations of UA for the management of cancer and diabetic neuropathy diseases. Ursolic acid (UA) is a promising triterpenoid compound present in several plants’ leaves, flowers, and fruits . It showCancer is the leading cause of human death in economically developed countries ,20,21. TDiabetes mellitus (DM) is a chronic metabolic disorder linked with the emission and sensitivity of insulin . Based oDiabetic neuropathy (DN) is a common and challenging complication of DM, leading to the most morbidity and mortality, resulting in a vast economic burden to diabetes care ,42,43. NInflammation engages the activation and employment of phagocytes , NK cells, and the discharge of cytokines through activated cells that are crucial to the host defense system. Since the chronic inflammation that continues yet after removal of the pathogen(s) was linked with many diseases, including cancer , neoplasThe complexities of DN and inflammatory diseases have considerably evolved over the years. Efforts for understanding the etiology of DN and inflammatory diseases are in progress to design attractive therapeutic approaches. In this context, UA may be a potent therapeutic molecule for DN and inflammatory diseases. UA and its derivatives are potential therapeutic candidates that can be explored to treat DN and inflammatory diseases. In this review, we systematically collected current findings concerning biochemistry, potency, pharmacological aspect, drug delivery system, and clinical trials of UA.30H48O3 [A pentacyclic triterpenoid; UA (3β-3-hydroxy-urs-12-ene-28-oic-acid), contained a C-30 chemical structure made from units of isoprenoid through the A, B, C, D, and E rings , with a 30H48O3 . Triterp30H48O3 . UA was 30H48O3 . It is s30H48O3 . UA is g30H48O3 . UA bios30H48O3 . Table 1UA’s limited bioavailability, solubility, and quick metabolism have hindered their extra clinical functions to therapeutic consequences in various diseases. However, several researchers have identified several alterations to improve UA potency, bioavailability, and solubility in water ,62. ManyThe molecular action of bioactive molecules might open up novel opportunities to the scientific community for developing and improving new therapeutic approaches for tackling dreadful diseases, including neurodegenerative disorders. UA is one such plant-based therapeutic metabolite, which plays a vital function in cell death, angiogenesis, metastasis, and inflammatory processes . Table 2Mycobacterium tuberculosis H37Rv has been recently reported [UA is popular due to its anti-proliferative properties, the incentive of tumor cell death, an obstacle of tumorigenesis, and inhibiting the cell cycle in tumors cells. Hence, examining one cell death mechanism that indicated UA could prevent NF-κB pathway through p65 phosphorylation repression, effecting a mandatory reduction in several downstream oncogenes, including Bcl-xL and Bcl-2. The anti-cancer effectiveness of UA is weak due to its lesser solubility that reduces the drug absorption in the human body system, which causes challenges in achieving comprehensive benefits. However, it is required for making its derivatives by semi-synthetic alterations for improving its anti-cancer action. Frequently, the modifications of UA occur on positions C-3, C12–C13, and positions C-28 ,76,95. Areported ,97. UA ireported ,99.Cell membrane permeability and pharmacokinetics are vital in the clinical development and improvement of novel biologically active agents/compounds with an outlook for considering their performance in vivo and establishing the most acceptable dosage regimen. Hence, pentacyclic triterpenoids usually suffer from less oral bioavailability . In the Moreover, aqueous solubility is exaggerated through the crystalline structure of natural UA. Decreased particle size and amorphous state remarkably increased rate of dissolution and solubility of triterpenoid . AdverseMany pharmacokinetic examinations have exposed where maximal plasma concentration subsequent oral administration of doses up to 300 mg/kg has been low, and removal half-life has been comparatively short (<1 h) ,105. ThiDM is a chronic disease, which is regulated via deficiency or insulin resistance. DM is one of the main risks for humans globally . Long-teObesity and diabetes require inhibition of the pancreatic α-amylase for the treatment because it decreases blood glucose levels in vitro and in vivo ,113. A rTreatment with UA (50 and 200 mg/kg) reduces lipid accumulation, TG levels and body weight. It enhances HDL cholesterol, insulin sensitivity, brown adipose tissue, and β-oxidation in the HFD-mediated obese rats, which improves energy expenditure . AnotherTGR5 activation via a chemical agonist might enhance incretin secretion and decrease the blood sugar level. UA has the potential effect on TGR5. UA concentration enhanced glucose uptake in the CHO-K1 cells, which express TGR5. TGR5 may improve cAMP for activating PKA and downstream pathways. UA stimulated a concentration-dependent increase in GLP-1 emission blocked through triamterene on the efficient concentrations for blocking TGR5 in NCI-H716 cells ,119. TGRNeurological disorders comprise anxiety, stroke, depression, PD, and AD ,123,124.2O2 play a critical function after SAH [Several reports suggest UA remains a vital and admired anti-oxidant reagent; for example, it has a brain defensive effect for ischemic stroke . Oxidatifter SAH . Redox-sfter SAH . Pro-inffter SAH . The resfter SAH .PD is a chronic progressive neurodegenerative disease described by motor and non-motor features ,129,130.2+ calmodulin-dependent protein kinase II mediated via a high-fat diet through activating the mTOR pathway induced via p70 S6 kinase alpha and S6 ribosomal protein in the hippocampus [Oxidative stress and excitotoxicity are the two mechanisms that have been continually demonstrated as being involved in a broad range of diseases of the brain and nervous system ,139,140.pocampus . These rpocampus .Oxidative stress and excitotoxicity usually result in mild to severe nervous system defects . InequitIn cerebral ischemia and reperfusion injury, TLRs play a critical role by inducing the making of inflammatory mediators, including ILs and TNF-α ,153,154.Mycobacterium tuberculosis and Con A-stimulated mouse splenocytes.Inflammation plays an essential role in developing and progressing multiple diseases, including neuropathy, insulin resistance, and diabetes , cancer The authors examined UA action intending to reduce COX-2 and NO synthase levels found in roused cells. Hence, UA showed a considerable inhibitory effect of cytokine levels, immunomodulatory mediators, and liberate of NO. This compound may be used for tuberculosis and antibiotic therapy due to the UA’s anti-inflammatory effectiveness in cells . The stuTerpenoids could have anti-oxidant results in vivo through mediating anti-oxidant defenses, including CAT, SOD, GPx, and GR, exhibited to their therapeutic potent in AD by a range of assays ,179,180.c from mitochondria to the cytosol. Hence, UA cleaved caspase-9 and decreased mitochondrial membrane ability. The mechanism of UA is dependent on the death receptor. UA might be used as a promising substance of biological source while it comes to cancer prevention and therapy, changing their metabolism to prevent metastasis and angiogenesis [Cancer is a complex disease due to tumor heterogeneity, a major limitation of chemoprevention ,191,192.ogenesis ,195.Researchers have examined the valuable results of UA on cell metabolism in humans and rodents. Hence, the mechanisms fundamental to the anti-tumor development of UA  and tumoAutophagy facilitates the continuance of metabolic precursors regeneration and cellular homeostasis. The function of autophagy in cancer might be viewed as a controversial procedure. The process of autophagy may be a selective as well as a non-selective mechanism. Some studies showed that autophagy inhibits cancer progression and development , and on UA and its derivatives have been involved in various pharmacological applications linked with the prevention of diseases. UA can be used as a potential applicant for developing a comprehensive capable strategy towards preventing and treating health disorders . UA dispThe study’s pH-sensitive mesoporous silica nanoparticles have been established to be biocompatible and permitted sustained liberation of UA . MoreoveThe lipid matrix influences the rate of drug discharge and agent/drug discharge patterns, showing an anti-cancer effect more significant than free UA against K562 and B16 cells. Long-circulating and pH SpHL-UA were utilized to improve drug administration intravenously, its anti-tumoral result on LNCaP and MDA-MB-231 tumor cells . Hence, Extensive studies have produced data representing the in vitro  and in v25–35 [The participation of inflammatory processes in the progression and development of AD was broadly identified . In part25–35 . This an25–35 .The final aim of cancer and neurological research is the functioning and implementation of drugs or compounds for clinical utilization. Presently, UA is undergoing phase I studies for evaluating its safety and adverse effects in the patients. Hence, due to less water solubility and low bioavailability of UA was administered as liposomes. Studies have been reported ,232,233,2), the high concentration of UA in plasma was attained in 4 h [A recent study has estimated the new formulation in 63 Chinese persons, including 4 advanced solid tumor patients and 59 normal samples. In the single administration by oral UANL (37, 74, 98, and 130 mg/md in 4 h . One clid in 4 h . In thisd in 4 h . The subd in 4 h . In addid in 4 h . Many std in 4 h , neuroged in 4 h . Multipld in 4 h , the neuUA is a natural compound, which humans have securely utilized in different forms. UA shows various biological effects and exhibits its potential effects in the prevention and treatment of several pathologies. Hence, the pharmacological results of UA showed anti-cancer, anti-diabetic, neuroprotective, and anti-inflammatory mechanisms in the cellular and animal models. A new potential opportunity could be managing cancer, diabetic neuropathy, and inflammatory diseases with UA based on its pharmacological functions. UA’s anti-cancer and neuroprotective activity might be linked with its capability to stimulate the anti-oxidant defense systems and down-regulating the pro-inflammatory signaling pathways in the neurodegeneration and ischemic brain alter models in vitro and in vivo. Several in vitro and in vivo studies identified that UA is a promising phytocompound in treating and managing cancer. The beneficial role of UA to neurodegenerative diseases is that it allocates several neurobiological mechanisms, including oxidative stress, neuroplasticity, neuro-inflammation, and impaired signaling pathways. In addition, preclinical trials have recommended the beneficial effects of UA on traumatic brain injury, cerebral ischemia, and brain hemorrhage. Hence, all these potential preclinical trial studies, merely a limited number of clinical trial studies, have examined the promising beneficial results of UA to the prevention and treatment of cancer and diabetic neuropathy diseases. Hence, UA appears to be a potential therapeutic strategy that justifies prospective clinical trial studies, believing it’s safe to utilize. Preclinical and well-conducted clinical studies have modified practice parameters and more personalized moves toward treating diabetic neuropathy and inflammatory diseases. Our perceptive of clinical studies presentation and best possible therapeutic management of cancer and diabetic neuropathy from the establishment to current paradigm modify in preclinical trials research space.Accumulating clinical and preclinical studies research in the subsequent decade may and will revolutionize this scenario. Further investigations and applications might facilitate the opportunity for UA to be improved and developed in new drugs to treat several human diseases, including cancer and diabetic neuropathy. In addition, the cellular and molecular mechanisms’ most important effects of UA in cancer and diabetic neuropathy diseases should be further investigated for implementing UA as a workout mimetic.