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Autosomal dominant polycystic kidney disease (ADPKD) is a common kidney disease caused by mutations in PKD1 or PKD2 . Metformin reduces cyst growth in mouse models of PKD1 . However, metformin has not been studied in animal models of PKD2 , and the cellular mechanism underlying its effectiveness is not entirely clear. This study investigated the effects of metformin on cyst formation in a zebrafish model of polycystin-2 deficiency resulting from morpholino knockdown of pkd2 . We added metformin (2.5 to 20 mM) to the embryo media between 4 and 48 hours post fertilisation and observed pronephric cyst formation by using the wt1b promoter-driven GFP signal in Tg ( wt1b:GFP ) pkd2 morphants. Metformin inhibited pronephric cyst formation by 42–61% compared with the untreated controls. Metformin also reduced the number of proliferating cells in the pronephric ducts, the degree of dorsal body curvature, and the infiltration of leukocytes surrounding the pronephros. Moreover, metformin treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced autophagy in the pronephros. Our data suggest that metformin reduces cyst formation through activation of the AMPK pathway and modulation of defective cellular events such as proliferation and autophagy. These results also imply that metformin could have therapeutic potential for ADPKD treatment.

We develop a vertical differentiation model to analyze welfare implications of environmental policies in a competitive market with production and consumption heterogeneity. Consumers with heterogeneous preferences choose between non-green and certified green products, while producers with heterogeneous production costs decide whether to engage in green production. In order for green products to be recognized by consumers, producers must join a green club. Key findings are summarized as follows. (i) The number of green producers, environmental standard, and overall welfare under the market solution are all socially sub-optimal. (ii) The introduction of a subsidy policy for greener production and standards is shown to increase social welfare, but is not Pareto optimal. (iii) A dual policy, which combines abatement subsidizes for a greener production standard and a tax charge for green certification, is shown to be the Pareto-optimal outcome.

Tuberculous peritonitis (TBP) is a rare but fatal complication in patients on peritoneal dialysis (PD). In this study, we aimed to determine the demographic features, clinical features, laboratory parameters, and clinical outcomes of PD patients with TBP and to clarify possible risk factors for mortality. We retrospectively reviewed 2084 PD patients from January 1985 to December 2019. The diagnosis of TBP was established by positive peritoneal fluid culture for Mycobacterium tuberculosis. 18 patients were diagnosed with TBP. The incidence was 2.029 episodes per 1000 patient-years. The most common symptom was fever (94.4%), followed by cloudy effluent (83.3%) and abdominal pain (83.3%). The average peritoneal dialysis effluent (PDE) white blood cell (WBC) count was 172.7 cells/μL. Nine patients (50%) had WBC counts lower than 100 cells/μL and 13 patients (72.2%) had neutrophilic predominant WBC counts. Acid fast stain (AFS) was positive in 7 patients (38.9%). Only 2 patients (11.1%) continued with PD after TB infection, while 10 patients (55.6%) changed to hemodialysis. Seven patients (38.9%) died within 1 year. Significant differences were observed in sex (p = 0.040), the presence of diabetes mellitus (p = 0.024), and PD catheter removal (p < 0.001) between TBP patients with and without mortality. However, none of them was a significant factor for 1-year mortality in multivariate Cox regression model. Physicians should pay attention to the unusual presentations of peritonitis, especially if symptoms include fever or an initial low PDE WBC count. Catheter removal is not mandatory if early diagnosis and appropriate therapy are available.

Leptospirosis is an overlooked zoonotic disease caused by pathogenic Leptospira depended on virulence of Leptospira and the host–pathogen interaction. Kidney is the major organ infected by Leptospira which causes tubulointerstitial nephritis. Leptospira outer membrane contains several virulence factors and an outer membrane protein A (OmpA) like protein (Loa22) is essential for virulence. Pull-down assays suggested that Loa22 was a potential Toll-Like Receptor 2 (TLR2) binding candidates from pathogenic Leptospira . Confocal microscopy was employed to observe the co-localization of TLR2 and Loa22-LPGN ( Leptospira peptidoglycan) complexes. Atomic force microscopy (AFM), side-directed mutagenesis, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the affinity between rLoa22, LPGN, and TLR2. Real time PCR was applied to measure the cytokines expression. Downstream signal transduction components were verified by western blot to evaluate the gene regulations. Mutation of two Loa22 key residues (Asp 122 and Arg 143 ) attenuated the affinities for LPGN. rLoa22-LPGN complexes were observed to co-localize with TLR2 and provoked inflammatory responses including CXCL8/IL8 , hCCL2/MCP-1 , and hTNF-α . Affinity studies suggested that Loa22-LPGN complexes elevated the affinity to TLR2 as compared to Loa22 protein. Downstream signals from TLR2 including p38, ERK, and JNK were regulated under rLoa22-LPGN complexes treatments. This study identified LPGN mediates interactions between Loa22 and TLR2 and induces downstream signals to trigger inflammatory responses. rLoa22-LPGN-TLR2 complexes reveal a novel binding mechanism for the innate immune system.

Traditional Chinese medicine (TCM) has become a standardized medical system through systematic development across global healthcare practices. However, concerns persist regarding the safety, efficacy and quality of traditional medicinal products. Traditional Chinese medicine regulatory science (TCMRS) has emerged as an interdisciplinary field to address these challenges. This discipline integrates multidisciplinary knowledge to develop new tools, standards and approaches for systematic evaluation of benefit-risk profiles. This approach aims to ensure the quality, safety, and efficacy of TCM products, while also supporting the development of scientifically grounded regulatory frameworks that accommodate traditional medicine’s distinctive characteristics. Through comprehensive quality management from raw material sourcing to production processes and clinical validation, developing and adopting TCMRS is entrusted to significantly strengthen its regulatory oversight. This review examines the critical scientific challenges in the modernization process of TCM, analyzes the conceptual foundations of TCMRS, evaluates its pivotal role in pharmaceutical transformation, and highlights its essential function in preserving traditional knowledge while fostering therapeutic innovation. Key challenges for TCMRS implementation include reconciling traditional epistemologies with modern pharmaceutical paradigms, standardizing complex herbal formulations, and developing rigorous evaluation protocols for decoctions and compound preparations. The integration of advanced methodologies, including systems biology, network pharmacology, artificial intelligence, and nanotechnology, into regulatory frameworks, combined with enhanced international cooperation, remains a crucial strategy for tackling global public health challenges. Future development trajectories for TCMRS will prioritize lifecycle management strategies, technology-driven innovation systems, and global knowledge-sharing initiatives, propelled by advancements in life sciences and information technology. This evolution requires careful balancing of three fundamental elements: theoretical development in traditional medicine, integration of emerging technologies, and maintenance of regulatory system stability. It is crucial to innovate the working mechanisms of the TCMRS researcher alliance and the global policy-coordination mechanism for TCM regulation, enhance the conversion of basic disciplines into regulatory applications, and support the establishment of an excellent TCM regulatory system with scientific decision-making. These efforts are essential for promoting the high-quality development of the TCM industry and boosting its international influence and presence.

Multiple phosphorylation sites of Drp1 have been characterized for their functional importance. However, the functional consequence of GSK3beta-mediated phosphorylation of Drp1 remains unclear. In this report, we pinpointed 11 Serine/Threonine sites spanning from residue 634~736 of the GED domain and robustly confirmed Drp1 Ser693 as a novel GSK3beta phosphorylation site. Our results suggest that GSK3beta-mediated phosphorylation at Ser693 does cause a dramatic decrease of GTPase activity; in contrast, GSK3beta-mediated phosphorylation at Ser693 appears not to affect Drp1 inter-/intra-molecular interactions. After identifying Ser693 as a GSK3beta phosphorylation site, we also determined that K679 is crucial for GSK3beta-binding, which strongly suggests that Drp1 is a novel substrate for GSK3beta. Thereafter, we found that overexpressed S693D, but not S693A mutant, caused an elongated mitochondrial morphology which is similar to that of K38A, S637D and K679A mutants. Interestedly, using H89 and LiCl to inhibit PKA and GSK3beta signaling, respectively, it appears that a portion of the elongated mitochondria switched to a fragmented phenotype. In investigating the biofunctionality of phosphorylation sites within the GED domain, cells overexpressing Drp1 S693D and S637D, but not S693A, showed an acquired resistance to H(2)O(2)-induced mitochondrial fragmentation and ensuing apoptosis, which affected cytochrome c, capase-3, -7, and PARP, but not LC3B, Atg-5, Beclin-1 and Bcl2 expressions. These results also showed that the S693D group is more effective in protecting both non-neuronal and neuronal cells from apoptotic death than the S637D group. Altogether, our data suggest that GSK3beta-mediated phosphorylation at Ser693 of Drp1 may be associated with mitochondrial elongation via down-regulating apoptosis, but not autophagy upon H(2)O(2) insult.

For analyzing conflict between two large open countries over external territories rich in natural resources, we develop a game-theoretic model of trade under resource appropriation possibilities. We show that greater trade openness (by lowering trade costs) reduces the overall intensity of arming when the adversary countries are symmetric in all dimensions. This finding is consistent with the liberal peace hypothesis that trade reduces conflict. We further analyze how equilibrium is affected by differences in national resource endowments. The resulting asymmetric equilibrium reveals that arming by the more endowed country exceeds that of the less endowed country and the two adversaries respond to lower trade costs differently: the more endowed country cuts back on its arming, whereas the less endowed country may increase it. Under resource endowment asymmetry, the aggregate arming allocations of the adversaries could increase despite greater trade openness.

The aberrant activation of the purinergic signaling pathway has been shown to promote cyst growth and fluid secretion in autosomal dominant polycystic kidney disease (ADPKD). Suramin is an anti-parasitic drug that has strong anti-purinergic properties. Whether suramin could have a therapeutic effect on ADPKD has not been fully investigated. We examined the effect of suramin on cyst progression in a Pkd1 microRNAs transgenic mouse model that presented stable Pkd1 knockdown and moderate disease progression. The Pkd1-deficient mice were treated with suramin (60 mg/kg) by intraperitoneal injection twice a week from postnatal days 35 to 90. Kidney-to-body weight ratios, cyst indices, and blood urea nitrogen (BUN) levels were measured. Cell proliferation and macrophage infiltration were determined by immunohistochemistry. The suramin-treated group had significantly lower renal cyst densities, cell proliferation, and macrophage infiltration compared with saline-treated controls. Suramin significantly inhibited ERK phosphorylation and the expression of Il1b, Il6, Nlrp3, Tgfb, Fn1, P2rx7, and P2ry2 mRNAs in the kidneys. However, BUN levels remained high despite the reduction in cyst growth. Furthermore, plasma cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher in the suramin-treated group compared with the control group. Periodic acid-Schiff staining revealed degenerative changes and epithelial cell vacuolation in the non-cystic renal tubules, which indicated phospholipidosis following suramin treatment. These results suggest that suramin may reduce renal cyst growth and inflammation, but the associated tubular cell injuries could limit its therapeutic potential. Other purinergic receptor antagonists with less nephrotoxicity may deserve further investigation for the treatment of ADPKD.

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 β-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/β-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.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are severe drug-induced cutaneous adverse reactions with high mortality. Acute kidney injury (AKI) was a common complication in an SJS/TEN group and noted as an independent risk factor for mortality in patients with SJS/TEN. To determine whether AKI staging can predict the outcome of patients with SJS/TEN, we compared the discriminative power of an AKI KDIGO staging system with that of SCROTEN, APACHE II, APACHE III, and SOFA. We retrospectively analyzed the data of 75 patients who were diagnosed with SJS, TEN, or SJS/TEN overlap syndrome at a tertiary care university hospital between January 1, 2011 and December 31, 2014. The baseline characteristics, biochemical analysis data, medication use, and outcomes of the patients were assessed, and the discriminative ability for predicting mortality was determined for each prognostic model. Of the 75 patients, 23 (30.7%) had AKI, of whom 13 (56.5%) died during the index admission. Of the prognostic risk models analyzed, the KDIGO staging system showed similar discriminative ability in predicting in-hospital mortality as did the other models. In addition, combining KDIGO with other scoring systems yielded significantly more accurate risk prediction for in-hospital mortality compared with the other individual scores alone, as measured by net reclassification index. The patients with KDIGO stages 2 and 3 exhibited a significantly lower 1-year survival rate than did those with KDIGO stages 0 and 1. AKI KDIGO staging has good discriminative ability and is easy to utilize for predicting mortality.