Role of mitochondria in pathogenesis and therapy of renal fibrosis.

Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.

HDL-C and creatinine levels at 1 month are associated with patient 12-month survival rate after kidney transplantation.

BACKGROUND: Many factors affect the survival rate after kidney transplantation, including laboratory tests, medicine therapy and pharmacogenomics. Tacrolimus, mycophenolate mofetil and methylprednisolone were used as an immunosuppressive regimen after kidney transplantation. The primary goal of this study was to investigate the factors affecting the tacrolimus concentrations and mycophenolate mofetil area under the curve of mycophenolic acid AUC-MPA. Secondary goals were to study the association between perioperative period laboratory tests, medicine therapy, CYP3A5 genetic polymorphisms, and survival rate in kidney renal transplant patients. METHODS: A total of 303 patients aged above 18 years were enrolled in this study. Their clinical characteristics, laboratory tests, and medicine therapy regimens were collected. We followed the patients for survival for 1 year after kidney transplantation. RESULTS: Multivariable logistic analyses reveal that age greater than 50 years, and the CY3A5 *3*3 genotype were independently, positively, and significantly related to tacrolimus C/D ratio at 7 days. At 1 month of follow-up, only CYP3A5 *3*3 was associated with tacrolimus C/D ratio. Basiliximab, Imipenem and cilastatin sodium, sex were associated with mycophenolate mofetil AUC-MPA at 7 days. In the COX regression analysis, a high-density lipoprotein cholesterol level≥1 mmol/L was identified as a positive independent risk factors for the survival rate, while a creatinine level ≥200 µmol/L was a negatively independent risk factors for survival rate. CONCLUSION: These results suggest that age, genes, and drug-drug interaction can affect the concentration of tacrolimus.

Unravelling Species Diversity and Pathogenicity of Fusarium spp. Associated with Soybean Leaf and Root in Heilongjiang Province, China.

Soybean (Glycine max L.) holds significant global importance and is extensively cultivated in Heilongjiang Province, China. Soybean can be infected by Fusarium species, causing root rot, seed decay, stem rot, and leaf blight. In 2021 to 2022, a field survey of soybean diseases was carried out in 11 regions of Heilongjiang Province, and 186 soybean leaves with leaf blight symptoms and 123 soybean roots with root rot symptoms were collected. Unexpectedly, a considerable number of Fusarium isolates were obtained not only from root samples but also from leaf samples. A total of 584 Fusarium isolates (416 from leaves and 168 from roots) were obtained and identified as 18 Fusarium species based on morphological features and multilocus phylogenetic analyses with tef1 and rpb2 sequences. Fusarium graminearum and Fusarium sp. 1 in FOSC were the dominant species within soybean leaf and root samples, respectively. Pathogenicity tests were conducted for all Fusarium isolates on both soybean leaves and roots. Results showed that F. graminearum, F. ipomoeae, F. citri, F. compactum, F. flagelliforme, F. acuminatum, and F. sporotrichioides were pathogenic to both soybean leaves and roots. F. solani, F. avenaceum, F. pentaseptatum, F. serpentinum, F. annulatum, and Fusarium sp. 1 in FOSC were pathogenic to soybean roots, not to leaves. To our knowledge, this is the first study to thoroughly investigate soybean-associated Fusarium populations in leaves and roots in Heilongjiang Province.

Diversity and Pathogenicity of Fungi Associated with Fruit Rot of Winter Jujube in Shandong Province, China.

Winter jujube originated from China and had an extremely high nutritional value. In 2021, symptomatic winter jujube fruits were collected from eight locations in Zhanhua District of Binzhou City, Shandong Province. In total, 108 fungal isolates were obtained and grouped into 11 species based on morphological characteristics and multilocus phylogenetic analysis, including Nothophoma quercina (43.52%), Fusarium lateritium (20.37%), Alternaria alternata (12.03%), F. proliferatum (7.41%), F. graminearum (4.63%), Botryosphaeria dothidea (3.70%), Fusarium sp. (2.78%), A. tenuissima (2.78%), Diaporthe eres (1.85%), Nigrospora oryzae (0.93%), and Cercospora nicotianae (0.93%). All fungal isolates obtained in this study showed aggressiveness on detached winter jujube fruits except N. oryzae and C. nicotianae isolates, of which F. proliferatum was the most virulent, while A. alternata isolates, which have been considered the major pathogen of winter jujube fruit rot, showed a relatively low-level virulence in this study. Furthermore, D. eres, F. graminearum, F. lateritium, and an unclassified Fusarium species were first reported as causal agents of winter jujube fruit rot. The typical symptoms of winter jujube fruit rot observed in this study could be distinguished into two types. N. quercina, A. alternata, A. tenuissima, Fusarium sp., D. nobilis, and F. lateritium isolates caused reddish brown to dark gray lesions on the peel, while B. dothidea, F. graminearum, and F. proliferatum isolates caused peel and pulp decay, resulting in red to reddish brown and water-soaked lesions. In addition, haplotype analysis of N. quercina isolates obtained in this study and validly published articles showed that there were 11 haplotypes worldwide; the isolates obtained in the current study were grouped into three haplotypes (Hap 1, Hap 2, and Hap 11), and two of them (Hap 2 and Hap 11) were confirmed as new haplotypes.

Fusarium Species Associated with Maize Leaf Blight in Heilongjiang Province, China.

Fusarium spp. are among the most important plant pathogens in the world. A survey on maize leaf blight was carried out in Heilongjiang province from 2019 to 2021. Based on morphological characteristics and a phylogenetic analysis on translation elongation factor (tef1) and second-largest subunit of RNA polymerase II (rpb2) genes, 146 Fusarium isolates were obtained and grouped into 14 Fusarium species, including F. ipomoeae (20.5%), F. compactum (17.1%), F. sporotrichioides (9.59%), F. graminearum (9.59%), F. citri (8.9%), F. asiaticum (6.85%), F. verticillioides (6.85%), F. acuminatum (5.48%), F. glycines (5.48%), F. temperatum (2.74%), F. armeniacum (2.74%), Fusarium sp. (2.05%), F. flagelliforme (1.4%), and F. annulatum (0.68%). The Fusarium incarnatum-equiseti species complex (FIESC, including F. ipomoeae, F. compactum, F. citri, and F. flagelliforme) was the most prevalent, indicating an evolving occurrence of the Fusarium species causing maize leaf blight. The typical symptoms observed on the maize leaves were oval to long strip lesions, with a gray to dark gray or brownish red coloration in the center and a chlorotic area at the edges. Based on the tef1 gene, seven haplotypes of FIESC were identified in Heilongjiang province, suggesting a population expansion. This is the first report of F. ipomoeae, F. compactum, F. flagelliforme, F. citri, F. sporotrichioides, F. graminearum, F. asiaticum, F. acuminatum, F. glycines, F. temperatum, F. armeniacum, Fusarium sp., and F. annulatum causing maize leaf blight in Heilongjiang province, China. The current research is informative for managing disease, exploring the phylogenetic relationship among Fusarium species, and clarifying the diversity of Fusarium species associated with maize leaf blight.

Identification, Pathogenicity, and Genetic Diversity of Fusarium spp. Associated with Maize Sheath Rot in Heilongjiang Province, China.

Maize sheath rot is a prevalent maize disease in China. From 2020 to 2021, symptomatic samples were collected from the main maize-growing regions of Heilongjiang province. To clarify the population and genetic diversity, as well as the virulence of pathogens responsible for maize sheath rot, a total of 132 Fusarium isolates were obtained and used for follow-up studies. Ten Fusarium species were identified based on morphological characteristics, and phylogenetic analysis was conducted using the TEF-1α gene sequences, including F. verticillioides (50.00%), F. subglutinans (18.94%), the Fusarium incarnatum-equiseti species complex (14.39%), F. temperatum (5.30%), F. acuminatum (3.03%), F. solani (2.27%), F. sporotrichioides (2.27%), F. tricinctum (1.52%), F. asiaticum (1.52%), and F. proliferatum (0.76%). All 10 Fusarium species could produce oval-to-annular lesions on maize sheath, and the lesions were grayish yellow to dark brown in the center and surrounded by a dark gray-to-dark brown halo. Of these, F. tricinctum and F. proliferatum showed significantly higher virulence than the other Fusarium species. In addition, haplotype analysis based on the concatenated sequences of the ITS and TEF-1a genes showed that 99 Fusarium isolates which belonged to the Fusarium fujikuroi species complex-consisting of F. verticillioides isolates, F. subglutinans isolates, F. temperatum isolates, and F. proliferatum isolates-could be grouped into 10 haplotypes, including 5 shared haplotypes (Haps 1, 2, 4, 5, and 6) and 5 private haplotypes (Haps 3, 7, 8, 9, and 10). Furthermore, the F. verticillioides clade in the haplotype network was radial with the center of Hap 2, suggesting that population expansion occurred. This research showed that Fusarium species associated with maize sheath rot in Heilongjiang province are more diverse than previously reported, and this is the first time that F. subglutinans, F. temperatum, F. solani, F. sporotrichioides, F. tricinctum, and F. acuminatum have been confirmed as the causal agents of maize sheath rot in Heilongjiang province.

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice.

BACKGROUND: Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury. AIM: To elucidate whether clopidogrel is beneficial against DN by using a db/db mouse model. METHODS: db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson's trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1ß mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry. RESULTS: Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1ß and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice (P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice. CONCLUSION: Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

Prognostic Value of Immune-Related Genes in the Tumor Microenvironment of Bladder Cancer.

The tumor microenvironment (TME) is a complex system that plays an important role in tumor development and progression, but the current knowledge about its effect on bladder cancer (BC) is scarce. In this study, we performed a comprehensive analysis of the relationship between the TME and gene expression profiles to identify prognostic biomarkers for BC. The ESTIMATE algorithm was used to calculate immune and stromal scores of BC patients who were obtained from the Gene Expression Omnibus database. We found that the immune and stromal scores were associated with clinical characteristics and the prognosis of BC patients. Based on these scores, 104 immune-related differentially expressed genes were identified. Further, functional enrichment analysis revealed that these genes were mainly involved in the immune-related biological processes and signaling pathways. Three prognostic genes were then identified and used to establish a risk prediction model using Cox regression analyses. Kaplan-Meier survival analysis showed that the expression levels of COL1A1, COMP, and SERPINE2 significantly correlated with cancer-specific survival and overall survival of BC patients. Additionally, we validated the prognostic values of these genes using two independent cohorts from The Cancer Genome Atlas and Gene Expression Omnibus databases. Finally, the relationships between the three prognostic genes and several immune cells were evaluated using Tumor Immune Estimation Resource, indicating that the expression levels of COL1A1, COMP, and SERPINE2 correlated positively with the tumor infiltration levels of CD4+ T cells and macrophages. In conclusion, the current study comprehensively analyzed the TME and presented immune-related prognostic genes for BC, providing new insights into immunotherapeutic strategies for BC patients.

Polyphotosensitizer nanogels for GSH-responsive histone deacetylase inhibitors delivery and enhanced cancer photodynamic therapy.

Photodynamic therapy (PDT) is one of the non-invasive and selective treatment methodologies for cancer. However, many highly efficient photosensitizers (PSs) are usually low physiological solubility, limited bioavailability and tending aggregation, impeding the effectiveness of PDT, as well as cancer resistance of PDT further reduce its therapeutic effect. Though some smart delivery systems have been developed, the problem of photosensitizer leakage/release has not been completely solved. Herein, we developed a smart therapeutic nanoplatform based on polyphotosensitizer nanogel as novel nanophotosensitizers and drug carriers. Moreover, by loading of histone deacetylase inhibitors (SAHA), it allows for enhanced synergistic therapy strategy of prostate cancer via inhibiting HIF-1α and VEGF pathways of cancer cells involved in PDT resistance. Our study presents the well-designed nanoplatform of nanogel-Ce6, which could serve as a photodynamic agent without Ce6 molecules release in the responsive environment, offering the potential to encapsulate diverse functional components for smart drug release and imaging-guided combination therapy in vitro and in vivo.

Farnesoid X receptor ligand CDCA suppresses human prostate cancer cells growth by inhibiting lipid metabolism via targeting sterol response element binding protein 1.

AIM: A wealth of studies have demonstrated that abnormal cellular lipid metabolism plays an important role in prostate cancer (PCa) development. Therefore, manipulating lipid metabolism is a potential PCa therapy strategy. In this study, our goal is to investigate the role of farnesoid X receptor (FXR) in regulating the proliferation and lipid metabolism of human PCa cells following its ligand chenodexycholic acid (CDCA) treatment. METHODS: Oil Red O was used to stain lipid contents in PCa cells, and siRNA knockdown was performed to deplete FXR expression. To study the cell proliferation when treated by CDCA or FXR knockdown, cell counting kit 8 (CCK8) was adopted to evaluate tumor cell growth. Western blot was used for protein analysis. RESULTS: Our data suggest that activation of FXR by CDCA reduces lipid accumulation and significantly inhibits cells proliferation in prostate tumor cells. Instead, CDCA treatment doesn't affect normal prostate epithelial RWPE-1 cells growth in vitro. FXR activation decreases mRNA and protein levels of sterol regulatory element binding protein 1 (SREBP1) and some other key regulators involved in lipid metabolism. Depletion of FXR by siRNA attenuates the inhibitory effects. CONCLUSION: Our study indicates that activation of FXR inhibits lipid metabolism via SREBP1 pathway and further suppresses prostate tumor growth in vitro.