Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.

Metabolic reprogramming is a potential treatment strategy for autosomal dominant polycystic kidney disease (ADPKD). Metformin has been shown to inhibit the early stages of cyst formation in animal models. However, metformin can lead to lactic acidosis in diabetic patients with advanced chronic kidney disease, and its efficacy in ADPKD is still not fully understood. Here, we investigated the effect of metformin in an established hypomorphic mouse model of PKD that presents stable and heritable knockdown of Pkd1. The Pkd1 miRNA transgenic mice of both genders were randomized to receive metformin or saline injections. Metformin was administrated through daily intraperitoneal injection from postnatal day 35 for 4 weeks. Unexpectedly, metformin treatment at a concentration of 150 mg/kg increased disease severity, including kidney-to-body weight ratio, cystic index and plasma BUN levels, and was associated with increased renal tubular cell proliferation and plasma lactate levels. Functional enrichment analysis for cDNA microarrays from kidney samples revealed significant enrichment of several pro-proliferative pathways including ß-catenin, hypoxia-inducible factor-1α, protein kinase Cα and Notch signaling pathways in the metformin-treated mutant mice. The plasma metformin concentrations were still within the recommended therapeutic range for type 2 diabetic patients. Short-term metformin treatment in a second Pkd1 hypomorphic model (Pkd1RC/RC) was however neutral. These results demonstrate that metformin may exacerbate late-stage cyst growth associated with the activation of lactate-related signaling pathways in Pkd1 deficiency. Our findings indicate that using metformin in the later stage of ADPKD might accelerate disease progression and call for the cautious use of metformin in these patients.

Transcriptome landscape reveals the chronic inflammatory response in kidneys affected by the combinatory effect of leptospirosis and nephrotoxic injury.

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD.

Corylin Attenuates CCl4-Induced Liver Fibrosis in Mice by Regulating the GAS6/AXL Signaling Pathway in Hepatic Stellate Cells.

Liver fibrosis is reversible when treated in its early stages and when liver inflammatory factors are inhibited. Limited studies have investigated the therapeutic effects of corylin, a flavonoid extracted from Psoralea corylifolia L. (Fabaceae), on liver fibrosis. Therefore, we evaluated the anti-inflammatory activity of corylin and investigated its efficacy and mechanism of action in ameliorating liver fibrosis. Corylin significantly inhibited inflammatory responses by inhibiting the activation of mitogen-activated protein kinase signaling pathways and the expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha in human THP-1 and mouse RAW264.7 macrophages. Furthermore, corylin inhibited the expression of growth arrest-specific gene 6 in human hepatic stellate cells (HSCs) and the activation of the downstream phosphoinositide 3-kinase/protein kinase B pathway. This inhibited the activation of HSCs and the expression of extracellular matrix proteins, including α-smooth muscle actin and type I collagen. Additionally, corylin induced caspase 9 and caspase 3 activation, which promoted apoptosis in HSCs. Moreover, in vivo experiments confirmed the regulatory effects of corylin on these proteins, and corylin alleviated the symptoms of carbon tetrachloride-induced liver fibrosis in mice. These findings revealed that corylin has anti-inflammatory activity and inhibits HSC activation; thus, it presents as a potential adjuvant in the treatment of liver fibrosis.

Transcriptomic signatures of exacerbated progression in leptospirosis subclinical chronic kidney disease with secondary nephrotoxic injury.

High-incidence regions of leptospirosis caused by Leptospira spp. coincide with chronic kidney disease. This study investigated whether asymptomatic leptospirosis is an emerging culprit that predisposes to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole transcriptomic profiles were evaluated for Leptospira-infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on Leptospira-infected mice, were significantly increased compared with mice following infection or adenine diet alone, and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed that integrin-ß- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase-signaling pathway, which were upregulated in 0.2% adenine-fed Leptospira-infected mice but not in 0.2% adenine-fed mice, indicating that background subclinical Leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene expression patterns with unilateral ureteric obstruction-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin-α2, PDZ-binding kinase, and DNA topoisomerase II-α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.NEW & NOTEWORTHYLeptospira-infected mice followed by secondary nephrotoxic injury exacerbated immune/inflammatory responses and renal fibrosis. Comparison with the murine model revealed candidates involved in the progression of renal fibrosis in chronic kidney disease (CKD). Comparative transcriptome study suggests that secondary nephrotoxic injury in Leptospira-infected mice recapitulates the gene expression signatures found in CKD patients. This study indicates that secondary nephrotoxic injury may exacerbate CKD in chronic Leptospira infection implicating in the progression of CKD of unknown etiology.

Crosstalk between E-Cadherin/ß-Catenin and NF-κB Signaling Pathways: The Regulation of Host-Pathogen Interaction during Leptospirosis.

Approximately 1 million cases of leptospirosis, an emerging infectious zoonotic disease, are reported each year. Pathogenic Leptospira species express leucine-rich repeat (LRR) proteins that are rarely expressed in non-pathogenic Leptospira species. The LRR domain-containing protein family is vital for the virulence of pathogenic Leptospira species. In this study, the biological mechanisms of an essential LRR domain protein from pathogenic Leptospira were examined. The effects of Leptospira and recombinant LRR20 (rLRR20) on the expression levels of factors involved in signal transduction were examined using microarray, quantitative real-time polymerase chain reaction, and western blotting. The secreted biomarkers were measured using an enzyme-linked immunosorbent assay. rLRR20 colocalized with E-cadherin on the cell surface and activated the downstream transcription factor ß-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker. Additionally, MMP7 inhibitors were used to demonstrate that the secreted MMP7 degrades surface E-cadherin. This feedback inhibition mechanism downregulated surface E-cadherin expression and inhibited the colonization of Leptospira. The degradation of surface E-cadherin activated the NF-κB signal transduction pathway. Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-κB signal transduction pathway. A working model was proposed to illustrate the crosstalk between E-cadherin/ß-catenin and NF-κB signal transduction pathways during Leptospira infection. Thus, rLRR20 of Leptospira induces kidney injury in host cells and inhibits the adhesion and invasion of Leptospira through the upregulation of MMP7 and NGAL.

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models.

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy.

Argininosuccinate synthetase 1 (ASS1) is a rate-limited enzyme in arginine biosynthesis. The oncogenic potential of ASS1 in terms of prognosis and cancer metastasis in arginine prototrophic gastric cancer (GC) remains unclear at present. We identify differentially expressed proteins in microdissected GC tumor cells relative to adjacent nontumor epithelia by isobaric mass tag for relative and absolute quantitation proteomics analysis. GC cells with stable expression or depletion of ASS1 were further analyzed to identify downstream molecules. We investigated their effects on chemoresistance and cell invasion in the presence or absence of arginine. ASS1 was highly expressed in GC and positively correlated with GC aggressiveness and poor outcome. Depletion of ASS1 led to inhibition of tumor growth and decreased cell invasion via induction of autophagy-lysosome machinery, resulting in degradation of active ß-catenin, Snail, and Twist. Ectopic expression of ASS1 in GC cells reversed these effects and protected cancer cells from chemotherapy drug-induced apoptosis via activation of the AKT-mammalian target of rapamycin signaling pathway. ASS1 contributes to GC progression by enhancing aggressive potential resulting from active ß-catenin, Snail, and Twist accumulation. Our results propose that ASS1 might contribute to GC metastasis and support its utility as a prognostic predictor of GC.-Tsai, C.-Y., Chi, H.-C., Chi, L.-M., Yang, H.-Y., Tsai, M.-M., Lee, K.-F., Huang, H.-W., Chou, L.-F., Cheng, A.-J., Yang, C.-W., Wang, C.-S., Lin, K.-H. Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy.

Natives as international medical graduates: A nationwide analysis in Taiwan.

INTRODUCTION: International medical graduates (IMGs) play an important role in many Western countries because of globalization and physician shortages. While the IMGs investigated in most studies were immigrants, few studies have considered the situation in which people native to a given country have studied medicine abroad and then returned to practice in their home country. To illustrate that situation, our study aimed to investigate practicing IMGs in Taiwan by comparing practicing physicians' nationalities to the countries in which the medical schools the IMGs graduated from are located. METHODS: Data were obtained from the annual official statistics released by the Taiwan Medical Association from 1998 to 2017. RESULTS: The number of practicing IMGs in Taiwan increased from 834 (3.1% of 26,991 physicians) in 1998 to 1,733 (3.7% of 46,452) in 2017. Their medical schools were distributed across 37 countries, with graduates of schools in the Philippines (n = 550), Poland (n = 420), and Myanmar (n = 364) accounting for 77.0% of all practicing IMGs in 2017. However, only 29, 0, and 253 physicians were themselves Filipinos, Polish, and Myanmarese, respectively. CONCLUSION: Most of the practicing IMGs in Taiwan are native Taiwanese. The real impact of IMGs in health policy-making and the existing quota system of admissions to medical schools thus deserve further investigations.

Lots of little ones: Analysis of charitable donations to a hospice and palliative care unit in Taiwan.

BACKGROUND: Charitable donations play a major role in the provision of hospice and palliative care (HPC) services, most of which are not reimbursed by health insurance programs. A good understanding of the constitution and use of donations is thus conducive to maintaining a high-quality HPC unit. METHODS: The data sources were the publicly available balance sheet, work report, and donor lists of a foundation exclusively supporting one of the best HPC units in Taiwan in the fiscal year of 2017. The analysis included the donation amounts and frequencies by donor type (individual, corporate, and group) and the categories of expenses. RESULTS: The foundation received 3033 donations worth a total of 7.8 million New Taiwan dollars (NTD) (approximately 258 thousand US dollars) in 2017. Two-thirds of the donations were allocated to the provision of direct care services. Of the 3033 donations, only 11 (0.4%) were worth 100 000 NTD or more, while 108 (3.6%) were valued between 10 000 and 99 999 NTD, 1268 (41.8%) were valued between 1000 and 9999 NTD, and 1646 (54.2%) were worth less than 1000 NTD. Of 1051 donors, 974 (92.7%) were individuals, 378 (36.0%) donated more than once, and 106 (10.1%) donated 12 or more times in one year. CONCLUSION: HPC services in Taiwan are sponsored by lots of individuals and small donations. For sustainability of standards-based and quality HPC services, the benevolence of the public should be thus cherished and adequately responded to.

Rural-urban disparities in family physician practice patterns: A nationwide survey in Taiwan.

INTRODUCTION: In a world with increasing urbanization, rural-urban disparities in health care utilization have been a long-term concern. However, the details regarding the practice patterns of family physicians in Taiwan have not received sufficient attention thus far. METHODS: The National Health Insurance Research Database of Taiwan offered 0.2% of the total ambulatory visit records for Taiwan in 2013. Records from community clinics of family medicine were collected, with the clinics categorized as rural, suburban, or urban area clinics according to their locations. RESULTS: Among 100 334 visits to family medicine clinics, the median patient age was 50 years for urban clinics, 51 for suburban clinics, and 58 for rural clinics. The distributions of patient ages differed in the three areas (P < 0.001). Four types of chronic diseases (cardiovascular diseases, diabetes, chronic respiratory diseases, and cancers) accounted for 10.8%, 11.3%, and 13.6%, of the visits to urban, suburban, and rural clinics, respectively. The most common procedure was wound treatment, and the pattern of the top 10 procedures was similar in the three areas. CONCLUSION: Although rural patients in Taiwan were older and had more chronic diseases than urban and suburban patients, the pattern of procedures undertaken by rural family physicians did not differ from those of urban and suburban family physicians.

Murine Renal Transcriptome Profiles Upon Leptospiral Infection: Implications for Chronic Kidney Diseases.

Background: Leptospirosis caused by pathogenic Leptospira spp leads to kidney damage that may progress to chronic kidney disease. However, how leptospiral infections induced renal damage is unclear. Methods: We apply microarray and next-generation sequencing technologies to investigate the first murine transcriptome-wide, leptospires-mediated changes in renal gene expression to identify biological pathways associated with kidney damage. Results: Leptospiral genes were detected in renal transcriptomes of mice infected with Leptospira interrogans at day 28 postinfection, suggesting colonization of leptospires within the kidney with propensity of chronicity. Comparative differential gene expression and pathway analysis were investigated in renal transcriptomes of mice infected with pathogens and nonpathogens. Pathways analysis showed that Toll-like receptor signaling, complements activation, T-helper 1 type immune response, and T cell-mediated immunity/chemotaxis/proliferation were strongly associated with progressive tubulointerstitial damage caused by pathogenic leptospiral infection. In addition, 26 genes related with complement system, immune function, and cell-cell interactions were found to be significantly up-regulated in the L interrogans-infected renal transcriptome. Conclusions: Our results provided comprehensive knowledge regarding the host transcriptional response to leptospiral infection in murine kidneys, particularly the involvement of cell-to-cell interaction in the immune response. It would provide valuable resources to explore functional studies of chronic renal damage caused by leptospiral infection.

Patterns of nonemergent visits to different healthcare facilities on the same day: a nationwide analysis in Taiwan.

Doctor shopping is a common phenomenon in many countries. However, patterns of switching healthcare facilities on the same day were little known. The data were obtained from the longitudinal cohort datasets (LHID2010) of Taiwan's National Health Insurance Research Database in 2010. Of 1,000,000 persons of the cohort with 13,276,928 nonemergent visits, 185,347 patients had visited different healthcare facilities within one day, with a total of 672,478 visits and 337,260 switches between facilities in 329,073 patient-days. While 63.0% (n = 212,590) of all switches occurred between facilities of the same accreditation level, 14.1% (n = 47,664) moved from lower to higher level, and 22.8% (n = 77,006) moved in the opposite direction. In 33,689 switches, patients moved to the same specialty of another facility. In 48,324 switches, patients moved to another facility with the same diagnosis, and the most frequent diagnoses were diseases of the digestive system (11,148) and diseases of the respiratory system (10,393). In a densely populated country without strict referral regulation, a high percentage of Taiwanese people had the experience of visiting different healthcare facilities on the same day. The system of family physicians as personal doctors and gatekeepers to healthcare might ameliorate the harmful impact.

Drugs cheaper than threepenny: the market of extremely low-priced drugs within the National Health Insurance in Taiwan.

While most drug policy researches paid attention to the financial impact of expensive drugs, the market situation of low-priced drugs in a country was seldom analyzed. We used the nationally representative claims datasets to explore the status within the National Health Insurance (NHI) in Taiwan. In 2007, a total of 12,443 distinct drug items had been prescribed 853,250,147 times with total expenditure of 105,216,950,198 new Taiwan dollars (NTD). Among them, 7,366 oral drug items accounted for 701,353,383 prescribed items and 68,133,988,960 NTD. Besides, 2,887 items (39.2% of oral drug items) belonged to cheap drugs with the unit price ≤ 1 NTD (about 0.03 of US dollar). While the top one item among all oral drugs had already a market share of 5.0%, 30 items 30.3% and 107 items 50.0%, the cheap drugs with aggregate 332,893,462 prescribed items (47.5% of all prescribed oral drug items) only accounted for 2,750,725,433 NTD (4.0% of expenditure for oral drugs and 2.6% of total drug expenditure). The drug market of Taiwan's NHI was abundant in cheap drugs. The unreasonably low prices of drugs might not guarantee the quality of pharmaceutical care and the sustainability of a healthy pharmaceutical industry in the long run.

Urban-rural disparity of generics prescription in Taiwan: the example of dihydropyridine derivatives.

The aim of the current study was to investigate the urban-rural disparity of prescribing generics, which were usually cheaper than branded drugs, within the universal health insurance system in Taiwan. Data sources were the cohort datasets of National Health Insurance Research Database with claims data in 2010. The generic prescribing ratios of dihydropyridine (DHP) derivatives (the proportion of DHP prescribed as generics to all prescribed DHP) of medical facilities were examined against the urbanization levels of the clinic location. Among the total 21,606,914 defined daily doses of DHP, 35.7% belonged to generics. The aggregate generic prescribing ratio rose from 6.7% at academic medical centers to 15.3% at regional hospitals, 29.4% at community hospital, and 66.1% at physician clinics. Among physician clinics, the generic prescribing ratio in urban areas was 63.9 ± 41.0% (mean ± standard deviation), lower than that in suburban (69.6 ± 38.7%) and in rural (74.1% ± 35.3%). After adjusting the related factors in the linear regression model, generic prescribing ratios of suburban and rural clinics were significantly higher than those of urban clinics (ß = 0.043 and 0.077; P = 0.024 and 0.008, resp.). The generic prescribing ratio of the most popular antihypertensive agents at a clinic was reversely associated with the urbanization level.

Blocking pathogenic Leptospira invasion with aptamer molecules targeting outer membrane LipL32 protein.

This study aimed to develop aptamers targeting LipL32, a most abundant lipoprotein in pathogenic Leptospira, to hinder bacterial invasion. The objectives were to identify high-affinity aptamers through SELEX and evaluate their specificity and inhibitory effects. SELEX was employed to generate LipL32 aptamers (L32APs) over 15 rounds of selection. L32APs' binding affinity and specificity for pathogenic Leptospira were assessed. Their ability to inhibit LipL32-ECM interaction and Leptospira invasion was investigated. Animal studies were conducted to evaluate the impact of L32AP treatment on survival rates, Leptospira colonization, and kidney damage. Three L32APs with strong binding affinity were identified. They selectively detected pathogenic Leptospira, sparing non-pathogenic strains. L32APs inhibited LipL32-ECM interaction and Leptospira invasion. In animal studies, L32AP administration significantly improved survival rates, reduced Leptospira colonies, and mitigated kidney damage compared to infection alone. This pioneering research developed functional aptamers targeting pathogenic Leptospira. The identified L32APs exhibited high affinity, pathogen selectivity, and inhibition of invasion and ECM interaction. L32AP treatment showed promising results, enhancing survival rates and reducing Leptospira colonization and kidney damage. These findings demonstrate the potential of aptamers to impede pathogenic Leptospira invasion and aid in recovery from Leptospira-induced kidney injury (190 words).

Dosing variability in prescriptions of acetaminophen to children: comparisons between pediatricians, family physicians and otolaryngologists.

BACKGROUND: To estimate the extents of dosing variability in prescriptions of acetaminophen to children among pediatricians, family physicians and otolaryngologists. METHODS: The acetaminophen prescriptions in the systematic sampling datasets from the National Health Insurance Research Database in Taiwan were analyzed. The distribution of dosages was measured and expressed in terms of coefficient of variation (CV). The analyses were stratified by patient's age, prescriber's specialty and preparation form. RESULTS: From 13,868 prescribed items of acetaminophen in 2009, liquids accounted only for 11.1% (n = 1544). More than half (56.9%) of liquids were prescribed by pediatricians. The median dose (83.3 mg, n = 1683) of acetaminophen prescriptions in infants is around half of that in preschool children (166.7 mg, n = 3921), one-third in children (250.0 mg, n = 4926) and one-sixth in adolescents (500.0 mg, n = 3338). In infants, the prescriptions by pediatricians had the highest CV (86.7%), followed by family physicians (82.3%) and otolaryngologists (70.3%). The patterns were similar in preschool children and children, but the difference of CV among specialties narrowed down with the patient's age. CONCLUSIONS: In acetaminophen prescriptions to children, pediatricians had a wider variability of dosages and a higher ratio of liquid preparations than family physicians and otolaryngologists. Further investigations can be undertaken to estimate the accuracy of dosing variability as an indicator of prescribing quality. Besides, child-suitable drug preparations should be promoted to ensure patient safety.

The rural - urban divide in ambulatory care of gastrointestinal diseases in Taiwan.

BACKGROUND: The utilization of medical care for gastrointestinal diseases increased over the past decade worldwide. The aim of the study was to investigate the difference between rural and urban patients in seeking medical service for gastrointestinal diseases at ambulatory sector in Taiwan. METHODS: From the one-million-people cohort datasets of the National Health Insurance Research Database, the utilization of ambulatory visits for gastrointestinal diseases in 2009 was analyzed. Rural patients were compared with urban and suburban patients as to diagnosis, locality of visits and choice of specialists. RESULTS: Among 295,056 patients who had ambulatory visits for gastrointestinal diseases in 2009, rural patients sought medical care for gastrointestinal diseases more frequently than urban and suburban patients (1.60 ± 3.90 vs. 1.17 ± 3.02 and 1.39 ± 3.47). 83.4% of rural patients with gastrointestinal diseases were treated by non-gastroenterologists in rural areas. Rural people had lower accessibility of specialist care, especially for hepatitis, esophageal disorders and gastroduodenal ulcer. CONCLUSION: The rural-urban disparity of medical care for gastrointestinal diseases in Taiwan highlighted the importance of the well communication between rural physicians and gastroenterologists. Besides the establishment of the referral system, the medical teleconsultation system and the arrangement of specialist outreach clinics in rural areas might be helpful.

Neglected and Emerging Infections of The Kidney.

Individuals, societies, and the environment are affected by neglected and emerging diseases. These diseases result in a variety of severe outcomes, including permanent disabilities, chronic diseases such as chronic kidney disease, and even mortality. Consequences include high health care expenditures, loss of means of support, social stigma, and social exclusion. The burden of these diseases is exacerbated in low- and middle-income countries owing to poverty, inadequate fundamental infrastructure, and the absence of health and social protection systems. The World Health Organization is committed to promoting the following public health strategies to prevent and control neglected tropical diseases: preventive chemotherapy; intensive case management; vector control; provision of safe drinkable water, sanitation, and hygiene; and veterinary public health. In addition, it promotes a One Health strategy, which is a collaborative, multisectoral, and interdisciplinary approach to achieving the greatest health outcomes by recognizing the interdependence of human beings, animals, plants, and their shared environment. This article provides knowledge and strategies for the prevention and treatment of neglected and emerging diseases, with a particular concentration on kidney diseases, as part of a comprehensive approach to One Health.

Crystal structure of Leptospira LSS_01692 reveals a dimeric structure and induces inflammatory responses through Toll-like receptor 2-dependent NF-κB and MAPK signal transduction pathways.

Leptospirosis is a commonly overlooked zoonotic disease that occurs in tropical and subtropical regions. Recent studies have divided the Leptospira spp. into three groups based on virulence, including pathogenic, intermediate, and saprophytic species. Pathogenic species express a protein family with leucine-rich repeat (LRR) domains, which are less expressed or absent in nonpathogenic species, highlighting the importance of this protein family in leptospirosis. However, the role of LRR domain proteins in the pathogenesis of leptospirosis is still unknown and requires further investigation. In this study, the 3D structure of LSS_01692 (rLRR38) was obtained using X-ray crystallography at a resolution of 3.2 Å. The results showed that rLRR38 forms a typical horseshoe structure with 11 α-helices and 11 ß-sheets and an antiparallel dimeric structure. The interactions of rLRR38 with extracellular matrix and cell surface receptors were evaluated using ELISA and single-molecule atomic force microscopy. The results showed that rLRR38 interacted with fibronectin, collagen IV, and Toll-like receptor 2 (TLR2). Incubating HK2 cells with rLRR38 induced two downstream inflammation responses (IL-6 and MCP-1) in the TLR2 signal transduction pathway. The TLR2-TLR1 complex showed the most significant upregulation effects under rLRR38 treatment. Inhibitors also significantly inhibited nuclear factor κB and mitogen-activated protein kinases signals transduction under rLRR38 stimulation. In conclusion, rLRR38 was determined to be a novel LRR domain protein in 3D structure and demonstrated as a TLR2-binding protein that induces inflammatory responses. These structural and functional studies provide a deeper understanding of the pathogenesis of leptospirosis.

Leptospirosis kidney disease: Evolution from acute to chronic kidney disease.

Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute, chronic, and asymptomatic leptospiral infections are closely linked to acute and chronic kidney disease (CKD) and renal fibrosis. Leptospires affect renal function by infiltrating kidney cells via the renal tubules and interstitium and surviving in the kidney by circumventing the immune system. The most well-known pathogenic molecular mechanism of renal tubular damage caused by leptospiral infection is the direct binding of the bacterial outer membrane protein LipL32 to toll-like receptor-2 expressed in renal tubular epithelial cells (TECs) to induce intracellular inflammatory signaling pathways. These pathways include the production of tumor necrosis factor (TNF)-α and nuclear factor kappa activation, resulting in acute and chronic leptospirosis-related kidney injury. Few studies have investigated the relationship between acute and chronic renal diseases and leptospirosis and further evidence is necessary. In this review, we intend to discuss the roles of acute kidney injury (AKI) to/on CKD in leptospirosis. This study reviews the molecular pathways underlying the pathogenesis of leptospirosis kidney disease, which will assist in concentrating on potential future research directions.