Discovery and Biosynthetic Studies of a Highly Reduced Cinnamoyl Lipid, Tripmycin A, from an Endophytic Streptomyces sp.

A Tripterygium wilfordii endophyte, Streptomyces sp. CB04723, was shown to produce an unusually highly reduced cytotoxic cinnamoyl lipid, tripmycin A (1). Structure-activity relationship studies revealed that both the cinnamyl moiety and the saturated fatty acid side chain are indispensable to the over 400-fold cytotoxicity improvement of 1 against the triple-negative breast cancer cell line MDA-MB-231 compared to 5-(2-methylphenyl)-4-pentenoic acid (2). Bioinformatical analysis, gene inactivation, and overexpression revealed that Hxs15 most likely acted as an enoyl reductase and was involved with the side chain reduction of 1, which provides a new insight into the biosynthesis of cinnamoyl lipids.

Pharmacological and genetic inhibition of fatty acid-binding protein 4 alleviated cisplatin-induced acute kidney injury.

Fatty acid-binding protein 4 (FABP4) has been confirmed to be involved in the pathogenesis of ischaemia/reperfusion- and rhabdomyolysis-induced acute kidney injury (AKI), and targeting inhibition of FABP4 might be a potential strategy for AKI. Cisplatin as a commonly used cancer chemotherapeutic drug possessed a dose-limited side effect of nephrotoxicity. However, whether FABP4 inhibition exerted a favourable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by renal dysfunction and pathological changes, companied by the high expression of FABP4 in tubular epithelial cells. Selective inhibition of FABP4 by BMS309403 at 40 mg/kg/d for 3 days and genetic knockout of FABP4 significantly attenuated the serum creatinine, blood urea nitrogen level and renal tubular damage. Mechanistically, cisplatin injection induced the increased apoptosis and regulated the corresponding protein expression of BCL-2, BCL-XL, BAX, cleaved caspase 3 and caspase 12 in the injured kidney tissues. Cisplatin also triggered multiple signal mediators of endoplasmic reticulum (ER) stress including double-stranded RNA-activated protein kinase-like ER kinase, activating transcription factor-6 and inositol-requiring enzyme-1 pathway, as well as CHOP, GRP78 and p-JNK proteins in the kidneys. Oral administration of BMS309403 significantly reduced the number of renal TUNEL-positive apoptotic cells. Knockout of FABP4 and BMS309403 notably improved ER stress-related apoptotic responses. In summary, pharmacological and genetic inhibition of FABP4 modulated apoptosis via the inactivation of ER stress in the tubular epithelial cells of cisplatin-induced AKI.

Clinical efficacy and safety of sodium cantharidinate plus chemotherapy in non-small-cell lung cancer: A systematic review and meta-analysis of 38 randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Sodium cantharidinate has been widely used in lung cancer treatment in China. To investigate whether sodium cantharidinate improves clinical effectiveness in non-small-cell lung cancer, we systematically re-evaluated all related studies. METHODS: All studies of cantharidinate for non-small-cell lung cancers (NSCLC) were selected from the MEDLINE, EMBASE, Web of Science (ISI), China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journals Full-Text Database (VIP), Wanfang, China Biological Medicine Database (CBM), Cochrane Central Register of Controlled Trials (CENTRAL), Chinese clinical trial registry (Chi-CTR), WHO International Clinical Trials Registry Platform (WHO-ICTRP) and US-clinical trials databases (established to September 2017). Their quality was evaluated using the Cochrane evaluation handbook of randomized controlled trials (RCTs) (5.1.0). The data were extracted following PICO principles and synthesized through meta-analysis. RESULTS AND DISCUSSION: We included 38 trials involving 2845 patients, but most trials had an unclear risk of bias. Sodium cantharidinate could increase the objective response rate (ORR) (1.52, (1.40-1.66]), disease control rate (DCR) (1.20, [1.16-1.25]) and quality of life (QOL) (1.76, [1.56-1.98]), but not the 1-year overall survival (OS) rate (1.16, [0.91-1.47]) and the 2-year OS rate (1.21, [0.51-2.91]). Subgroup analysis revealed that sodium cantharidinate and vitamin B6 at 0.5, 0.4 or 0.3 mg, and cantharidinate at 0.5 mg could all increase the ORR and DCR. Cantharidinate therapy had a lower risk of neutropenia (0.58, [0.50-0.67]), thrombocytopenia (0.57, [0.45-0.72]), gastrointestinal reaction (0.65, [0.52-0.82]) and nausea/vomiting (0.56, [0.41-0.76]) than that of chemotherapy alone. Sensitivity analysis showed that the results had good robustness. WHAT IS NEW AND CONCLUSION: Current evidence reveals that sodium cantharidinate can improve tumour responses and QOL with a lower risk of haematotoxicity and gastrointestinal toxicity than chemotherapy alone in NSCLC. However, the evidence does not indicate that it can improve long-term survival rates.

SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling.

Sepsis-associated acute kidney injury (SA-AKI) is one of common critical illnesses with high morbidity and mortality. At present, effective therapeutic drugs for SA-AKI are remain lacking. SKLB023 is a synthetic small-molecule compound which exerts potent anti-inflammatory effects in our previous studies. Here, this study aimed to characterize the protective effect of SKLB023 on SA-AKI and explore its underlying mechanism. The SA-AKI experimental models have been established by cecum ligation/puncture (CLP) and lipopolysaccharide (LPS) injection in male C57BL/6J mice. SKLB023 was administered by gavage (50 or 25 mg/kg in CLP model and 50 mg/kg in LPS model) daily 3 days in advance and 30 min earlier on the day of modeling. Our results confirmed SKLB023 treatment could improve the survival of SA-AKI mice and ameliorate renal pathological injury, inflammation, and apoptosis in the two types of septic AKI mice. Mechanically, SKLB023 deceased the expression of TLR4 in LPS-triggered renal tubular epithelial cells, and inhibited the activation of downstream pathways including NF-κB and MAPK pathways. Our study suggested that SKLB023 is expected to be a potential drug for the prevention and treatment of septic AKI.

A dual αvß1/αvß6 integrin inhibitor Bexotegrast (PLN-74809) ameliorates organ injury and fibrogenesis in fibrotic kidney disease.

Chronic kidney disease (CKD) is a global public health problem, involving about 10% of the global population. Unfortunately, there are currently no effective drugs. Kidney fibrosis is the main pathology of CKD, where integrins play crucial roles in renal fibrogenesis. Recently, Bexotegrast (PLN-74809) as a dual integrin αvß1/αvß6 inhibitor could reduce the degree of lung fibrosis in patients with idiopathic pulmonary fibrosis. However, the role of PLN-74809 remains unclear in fibrotic kidney disease. Here, we have revealed that PLN-74809 administration dose-dependently delayed the progression of renal fibrosis in both adenine diet- and unilateral ureteral obstruction (UUO)-induced mice. Mechanistically, PLN-74809 targeted integrin αvß1/αvß6 to inhibit FAK/Src/Akt/ß-catenin cascade in fibrotic kidneys. In summary, our results for the first time highlighted the αvß1/αvß6 inhibitor PLN-74809 exerted potential therapeutic against kidney fibrosis.

Natural intestinal metabolite xylitol reduces BRD4 levels to mitigate renal fibrosis.

Renal fibrosis is a typical pathological change from chronic kidney disease (CKD) to end-stage renal failure, which presents significant challenges in prevention and treatment. The progression of renal fibrosis is closely associated with the "gut-kidney axis," therefore, although clinical intervention to modulate the "gut-kidney axis" imbalance associated with renal fibrosis brings hope for its treatment. In this study, we first identified the close relationship between renal fibrosis development and the intestinal microenvironment through fecal microtransplantation and non-absorbable antibiotics experiments. Then, we analyzed the specific connection between the intestinal microenvironment and renal fibrosis using microbiomics and metabolomics, screening for the differential intestinal metabolite. Potential metabolite action targets were initially identified through network simulation of molecular docking and further verified by molecular biology experiment. We used flow cytometry, TUNEL apoptosis staining, immunohistochemistry, and Western blotting to assess renal injury and fibrosis extent, exploring the potential role of gut microbial metabolite in renal fibrosis development. We discovered that CKD-triggered alterations in the intestinal microenvironment exacerbate renal injury and fibrosis. When metabolomic analysis was combined with experiments in vivo, we found that the differential metabolite xylitol delays renal injury and fibrosis development. We further validated this hypothesis at the cellular level. Mechanically, bromodomain-containing protein 4 (BRD4) protein exhibits strong binding with xylitol, and xylitol alleviates renal fibrosis by inhibiting BRD4 and its downstream transforming growth factor-ß (TGF-ß) pathway. In summary, our findings suggest that the natural intestinal metabolite xylitol mitigates renal fibrosis by inhibiting the BRD4-regulated TGF-ß pathway.

Pectolinarigenin alleviated septic acute kidney injury via inhibiting Jak2/Stat3 signaling and mitochondria dysfunction.

Sepsis is a systemic inflammatory response to infection, where sepsis-associated acute kidney injury (AKI) is a common morbid disease with a high morbidity and mortality, and however at present no effective therapy exists. Increasing evidence have shown that mitochondrial damage and inflammatory response are important initiating factors in pathogenesis of septic AKI. Natural flavonoid pectolinarigenin exerted anti-inflammatory properties in previous studies, while its role in septic AKI remains unknown. In the study, pectolinarigenin administration significantly ameliorated the dramatic rise of serum creatinine and blood urea nitrogen in lipopolysaccharide (LPS)- and cecal ligation/puncture (CLP)-induced septic mice, respectively. Consistently, LPS/CLP-induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by pectolinarigenin. Meanwhile, LPS/CLP triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, pectolinarigenin inhibited renal expression of IL-6, IL-1ß, TNF-α, and MCP-1 to improve inflammatory response. Furthermore, pectolinarigenin upregulated Bcl-2 protein expression and suppressed apoptotic protein of BAX and cleaved caspase-3 in the kidneys of CLP-induced septic AKI. Mechanistically, LPS could induce the high expression of IL-6 and trigger the phosphorylation of Jak2 and Stat3, while pectolinarigenin remarkably reduced their corresponding levels. Notably, CLP-induced kidney injury of mice significantly reduced the expression of PGC-1α, OPA1 and increased the expression of Drp1, Cyt-C, where pectolinarigenin pretreatment significantly restored their corresponding expression in mice. In summary, pectolinarigenin improved septic AKI via inhibiting JAK2/STAT3 signaling and mitochondria dysfunction.

Identification and Validation of Cuproptosis-Related LncRNA Signatures in the Prognosis and Immunotherapy of Clear Cell Renal Cell Carcinoma Using Machine Learning.

(1) Objective: We aimed to mine cuproptosis-related LncRNAs with prognostic value and construct a corresponding prognostic model using machine learning. External validation of the model was performed in the ICGC database and in multiple renal cancer cell lines via qPCR. (2) Methods: TCGA and ICGC cohorts related to renal clear cell carcinoma were included. GO and KEGG analyses were conducted to determine the biological significance of differentially expressed cuproptosis-related LncRNAs (CRLRs). Machine learning (LASSO), Kaplan-Meier, and Cox analyses were conducted to determine the prognostic genes. The tumor microenvironment and tumor mutation load were further studied. TIDE and IC50 were used to evaluate the response to immunotherapy, a risk model of LncRNAs related to the cuproptosis genes was established, and the ability of this model was verified in an external independent ICGC cohort. LncRNAs were identified in normal HK-2 cells and verified in four renal cell lines via qPCR. (3) Results: We obtained 280 CRLRs and identified 66 LncRNAs included in the TCGA-KIRC cohort. Then, three hub LncRNAs (AC026401.3, FOXD2-AS1, and LASTR), which were over-expressed in the four ccRCC cell lines compared with the human renal cortex proximal tubule epithelial cell line HK-2, were identified. In the ICGC database, the expression of FOXD2-AS1 and LASTR was consistent with the qPCR and TCGA-KIRC. The results also indicated that patients with low-risk ccRCC-stratified by tumor-node metastasis stage, sex, and tumor grade-had significantly better overall survival than those with high-risk ccRCC. The predictive algorithm showed that, according to the three CRLR models, the low-risk group was more sensitive to nine target drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706, ATRA, AP.24534, axitinib, and AZ628), based on the estimated half-maximal inhibitory concentrations. In contrast, the high-risk group was more sensitive to ABT.263 and AKT inhibitors VIII and AS601245. Using the CRLR models, the correlation between the tumor immune microenvironment and cancer immunotherapy response revealed that high-risk patients are more likely to respond to immunotherapy than low-risk patients. In terms of immune marker levels, there were significant differences between the high- and low-risk groups. A high TMB score in the high-risk CRLR group was associated with worse survival, which could be a prognostic factor for KIRC. (4) Conclusions: This study elucidates the core cuproptosis-related LncRNAs, FOXD2-AS1, AC026401.3, and LASTR, in terms of potential predictive value, immunotherapeutic strategy, and outcome of ccRCC.

Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis.

Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) significantly increases morbidity and mortality. Growing evidence suggests that fatty acid-binding protein 4 (FABP4) is critically involved in kidney diseases, while its role in septic AKI remains unknown. Here, FABP4 was mainly upregulated in renal tubular epithelial cells (RTECs) following cecal ligation and puncture (CLP)- or lipopolysaccharide (LPS)-induced septic AKI. FABP4 inhibition by genetic deletion or BMS309403 treatment both attenuated kidney dysfunction and pathological injury in CLP- or LPS-treated mice. Notably, RTEC-specific deletion of FABP4 also showed similar renoprotective effects. Moreover, FABP4 inhibition alleviated inflammation and apoptosis in CLP-injured kidneys and LPS-stimulated mouse tubular epithelial cells. Mechanistically, TLR4 blockage improved sepsis-induced kidney injury, as well as suppressed c-Jun phosphorylation and FABP4 expression, where c-Jun knockdown also inhibited LPS-stimulated FABP4 level. Meanwhile, FABP4 inhibition reduced the elevated phosphorylated c-Jun, while the levels of TLR4 and MyD88 were uninfluenced. Collectively, the increased FABP4 in RTECs is dependent on TLR4/c-Jun signaling activation and contributes to kidney injury, by forming a positive feedback loop with c-Jun to aggravate inflammation and apoptosis in septic AKI. Thus, FABP4 may be a therapeutic target for septic AKI.

Natural Flavonoid Pectolinarigenin Alleviated Hyperuricemic Nephropathy via Suppressing TGFß/SMAD3 and JAK2/STAT3 Signaling Pathways.

Natural flavonoid pectolinarigenin (PEC) was reported to alleviate tubulointerstitial fibrosis of unilateral ureteral obstruction (UUO) mice in our previous study. To further investigate nephroprotective effects of PEC in hyperuricemic nephropathy (HN), adenine and potassium oxonate induced HN mice and uric acid-treated mouse kidney epithelial (TCMK-1) cells were employed in the study. As a result, PEC significantly lowered serum uric acid level and restored hyperuricemia-related kidney injury in HN mice. Meanwhile, PEC alleviated inflammation, fibrosis, and reduced adipokine FABP4 content in the kidneys of HN mice and uric acid-treated TCMK-1 cells. Mechanistically, PEC inhibited the TGF-ß1 expression as well as the phosphorylation of transcription factor SMAD3 and STAT3 to regulate the corresponding inflammatory and fibrotic gene expression in kidney tissues. In conclusion, our results suggested that PEC could inhibit the activation of SMAD3 and STAT3 signaling to suppress inflammation and fibrosis, and thereby alleviate HN in mice.

Genetic and pharmacological inhibition of fatty acid-binding protein 4 alleviated inflammation and early fibrosis after toxin induced kidney injury.

Considerable data have suggested that acute kidney injury (AKI) is often incompletely repaired and could lead to chronic kidney disease (CKD). As we known, toxin-induced nephropathy triggers the rapid production of proinflammatory mediators and the prolonged inflammation allows the injured kidneys to develop interstitial fibrosis. In our previous study, fatty acid-binding protein 4 (Fabp4) has been reported to be involved in the process of AKI. However, whether Fabp4 plays crucial roles in toxin-induced kidney injury remained unclear. To explore the effect and mechanism of Fabp4 on toxin induced kidney injury, folic acid (FA) and aristolochic acid (AA) animal models were used. Both FA and AA injected mice developed severe renal dysfunction and dramatically inflammatory response (IL-6, MCP1 and TNF-a), which further lead to early fibrosis confirmed by the accumulation of extracellular matrix proteins (α-Sma, Fn, Col1 and Col4). Importantly, we found that FA and AA induced-kidney injury triggered the high expression of Fabp4 mRNA/protein in tubular epithelial cells. Furthermore, pharmacological and genetic inhibition of Fabp4 significantly attenuated FA and AA induced renal dysfunction, pathological damage, and early fibrosis via the regulation of inflammation, which is mediated by suppressing p-p65/p-stat3 expression via enhancing Pparγ activity. In summary, Fabp4 in tubular epithelial cells exerted the deleterious effects during the recovery of FA and AA induced kidney injury and the inhibition of Fabp4 might be an effective therapeutic strategy against the progressive AKI.

A Study on the Correlations of Anxiety and Depression With Self-Management Ability and Endogenous Creatinine Clearance Rate in Renal Transplant Recipients.

Objective: To explore the effects of anxiety and depression on the self-management ability and endogenous creatinine clearance rate of renal transplant patients. Method: Eighty-eight renal transplant recipients who were followed up in the outpatient clinic of the Affiliated Hospital of Zunyi Medical University were selected using convenient sampling. The self-made general data sheet, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and Self-Management Scale for Kidney Transplant Recipients were used. Correlation analysis was used to find factors related to endogenous creatinine clearance, while multiple linear regression was used to identify factors influencing endogenous creatinine clearance. Patients with or without anxiety and depression were divided into groups, and the indexes of the groups were compared using the independent samples t test, rank-sum test, or chi-squared test. Results: Anxiety was present in 12.5% of patients, depression in 25%, and a moderate level of self-management in 34.1%. Only 9.1% of renal transplant recipients had endogenous creatinine clearance within the normal range, and 34.1% had a body mass index not in the normal range (25% were overweight, and 9.1% were underweight). The endogenous creatinine clearance rate was negatively correlated with age and degree of depression, and positively correlated with body mass index, treatment management score, and psychosocial management score. The main influencing factors of endogenous creatinine clearance rate were age, sex, depression, body mass index, and treatment management score. The endogenous creatinine clearance rate and psychosocial management ability were significantly higher in patients without anxiety and depression than in patients with anxiety and depression (all P < 0.05). Conclusions: Anxiety and depression showed significant negative effects on the psychosocial self-management ability and endogenous creatinine clearance rate of renal transplant recipients and thus should be given more attention.

Activation of GPR120 by TUG891 ameliorated cisplatin-induced acute kidney injury via repressing ER stress and apoptosis.

Activation of G protein-coupled receptor 120 (GPR120) could inhibit apoptosis and inflammation in cerebral ischemic injury and liver ischemia-reperfusion injury. However, whether GPR120 agonism exerted potential for cisplatin-induced acute kidney injury and the involved mechanisms remained unknown. In our study, pharmacological activation of GPR120 by TUG891 treatment remarkably reduced the elevated serum creatinine level and attenuated tubular injury. Cisplatin triggered ATF6, PERK and IRE1 pathways of unfolded protein response (UPR) of ER stress in the injured kidney tissue, as well as the downstream molecules eIF2α, ATF4 and XBP1. Protein of ER stress-mediated apoptosis, CHOP, was overexpressed in the cisplatin group. Oral application of TUG891 displayed effective inhibition of ER stress and apoptosis. TUG891 treatment significantly decreased the TUNEL positive cells and the flow cytometry of HK-2 cells delineated the similar results that the apoptosis rates were considerably reduced in the TUG891 group compared to cisplatin group. Collectively, activation of GPR120 by TUG891 exhibited renal protection against cisplatin-induced AKI via suppressing ER-associated apoptosis in tubular epithelial cells.

Effects of Carvedilol on Cardiovascular Events and Mortality in Hemodialysis Patients, A Systematic Review and Meta-Analysis.

Carvedilol, the third generation of vasodilators; serves as the blocker of non-selective beta-adrenergic receptor and alpha1 adrenergic receptor. It could protect the cardiovascular system of patients receiving dialysis treatment. However, current clinical trials discussing the therapeutic benefit of carvedilol on patients receiving dialysis treatment remain inconsistent. Consequently, we decided to perform a meta-analysis to evaluate the clinical efficacy of carvedilol on patients receiving dialysis treatment. A search was conducted using EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Wanfang database, Chinese National Knowledge Infrastructure (CNKI), and VIP information database up to February 2020. We research publications (include English and Chinese language) that discuss the effects of carvedilol on cardiovascular events, all-cause mortality, hospitalizations or left ventricular ejection fraction (LVEF) in dialysis population. Our analysis included 4 randomized control trials and 2 observational studies. We discussed the therapeutical effects of carvedilol on all-cause mortality, cardiovascular events, hospitalizations, and LVEF of patients receiving dialysis treatment. Totally, this analysis reported 2998 hemodialysis (HD) patients. We found a significant association between carvedilol and reduced incidence of all-cause mortality, cardiovascular events and hospitalizations in HD patients. In addition, carvedilol significantly improves LVEF (n = 241; WMD = 6.95; 95% CI, 0.54 to 13.36; I2 = 90%) in HD population. Our systematic review and meta-analysis demonstrates that carvedilol is associated with a reduced incidence of cardiovascular events, all-cause mortality and hospitalizations in patients on HD. Besides; carvedilol significantly improves LVEF in HD population. Nevertheless, high-quality and well-powered evidence is still needed, so as to further confirm the impacts of carvedilol on HD patients.

[Mice cope with parabiosis − assessment of their physiological changes of life].

The purpose of this study was to establish a parabiotic mice model and assess the physiological changes of the mice under the parabiotic state. Thirteen pairs of isogenic partners were studied. The model was created by preparing a bridge of skin and subcutaneous tissues between the two mice starting distal of the elbow joint along the humerus along the lateral costal region until the end of the waist line. Physiological, social and affective qualities of life were studied in the mice through behavioural observations for 120 days following the parabiotic surgery. During the first 2-3 days following the operation, the animals suffered from severe pain and distress. During the following days and weeks, the physiological system began to recover and the animals displayed behavioral adaptations to the parabiotic condition. All animals survived at day 120. At three days post operation, the body weight began to decrease. Following this, the animals experienced a continual body weight recovery and reached pre-surgical measures at about 30 days post op. Forty-eight h post op., faecal corticosterone-metabolites were extremely elevated, but their levels returned to two to four times of levels in control females within 72 hours post op. The faecal corticosterone-metabolite levels decreased near to control values on day 75. Out of the 13 pairs, the blood exchange rate of three parabiotic partners was tested, with the result being normal post op. After 12 weeks, the total blood exchange between both partners needed 63 or 46 or 107 min, respectively. These results demonstrated that the animals could adapt behaviourally to the parabiotic situation. Therefore, this parabiosis mouse model may provide useful insights in many research areas, such as transplantation immunity, hematological system and metabolism, etc.