Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent pyroptosis.

Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.

Investigation of the Metabolism of Astragaloside IV in a Puromycin-Damaged Rat Model by UPLC-Q-TOF-MS/MS Analysis.

Astragaloside IV (AS-IV) has been shown to provide renal protection in various kidney injury models. However, the metabolic profile variation of AS-IV in pathological models in vivo is not well established. This study aims to explore the metabolic pathway of AS-IV in vivo in the classical puromycin aminonucleoside (PAN)-induced kidney injury in a rat model. Twelve Wistar rats were randomly divided into the AS-IV (CA) and the PAN+AS-IV (PA) treatment groups. PAN was injected by a single tail intravenous (i. v.) injection at 5 mg/100 g body weight, and AS-IV was administered intragastrically (i. g.) at 40 mg/kg for 10 days. Fecal samples of these rats were collected, and metabolites of AS-IV were detected by ultra-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) to explore the AS-IV metabolic pathway. The metabolic differences between the AS-IV and PAN+AS-IV groups were compared. A total of 25 metabolites were detected, and deglycosylation, deoxygenation, and methyl oxidation were found to be the main metabolic pathways of AS-IV in vivo. The abundance of most of these metabolites in the PAN+AS-IV group was lower than that in the AS-IV treatment group, and differences for seven of them were statistically significant. Our study indicates that AS-IV metabolism is affected in the PAN-induced kidney injury rat model.

Jian-Pi-Yi-Shen formula alleviates renal fibrosis by restoring NAD+ biosynthesis in vivo and in vitro.

BACKGROUND: Patients with chronic kidney disease (CKD) lack efficacious treatment. Jian-Pi-Yi-Shen formula (JPYSF) has demonstrated significant clinical efficacy in treating CKD for decades. However, its renoprotective mechanism has not been fully elucidated. This study aimed to determine whether JPYSF could delay renal fibrosis progression in CKD by restoring nicotinamide adenine dinucleotide (NAD+) biosynthesis. METHODS: Adenine-diet feeding was used to model CKD in C57BL/6 mice. JPYSF was orally administered for 4 weeks. Human proximal tubular epithelial cells (HK-2) cells were stimulated with transforming growth factor-ß1 (TGF-ß1) with or without JPYSF treatment. Renal function of mice was assessed by serum creatinine and blood urea nitrogen levels. Renal histopathological changes were assessed using Periodic acid-Schiff and Masson's trichrome staining. Cell viability was assessed using a cell counting kit-8 assay. NAD+ concentrations were detected by a NAD+/NADH assay kit. Western blotting, immunohistochemistry, and immunofluorescence were employed to examine fibrosis-related proteins and key NAD+ biosynthesis enzymes expression in the CKD kidney and TGF-ß1-induced HK-2 cells. RESULTS: JPYSF treatment could not only improve renal function and pathological injury but also inhibit renal fibrosis in CKD mice. Additionally, JPYSF reversed fibrotic response in TGF-ß1-induced HK-2 cells. Moreover, JPYSF rescued the decreased NAD+ content in CKD mice and TGF-ß1-induced HK-2 cells through restoring expression of key enzymes in NAD+ biosynthesis, including quinolinate phosphoribosyltransferase, nicotinamide mononucleotide adenylyltransferase 1, and nicotinamide riboside kinase 1. CONCLUSIONS: JPYSF alleviated renal fibrosis in CKD mice and reversed fibrotic response in TGF-ß1-induced HK-2 cells, which may be related to the restoration of NAD+ biosynthesis.

Huangqi-Danshen decoction protects against cisplatin-induced acute kidney injury in mice.

Background: Acute kidney injury (AKI) induced by cisplatin remains a major impediment to the clinical application of cisplatin, necessitating urgent exploration for promising solutions. Huangqi-Danshen decoction (HDD), a Chinese herbal preparation, has been shown by our group to have a reno-protective effect in adenine-induced chronic kidney disease mice and diabetic db/db mice. However, the effect of HDD on cisplatin-induced AKI and its underlying mechanisms are unknown. Methods: The AKI model was established by intraperitoneal injection of cisplatin (20 mg/kg) in C57BL/6 mice. The mice in the treatment group were administrated with HDD (6.8 g/kg/d) for 5 consecutive days before cisplatin challenge. After 72 h cisplatin injection, blood and kidney tissue were subsequently collected for biochemical detection, histopathological evaluation, Western blot analysis, immunohistochemical staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to detect changes in renal metabolites. Results: The results showed that HDD significantly reduced serum creatinine and blood urea nitrogen levels and alleviated renal histopathological injury in cisplatin-induced AKI mice. And HDD treatment demonstrated a significant inhibition in apoptosis, inflammation, and oxidative stress in AKI mice. Moreover, non-target metabolomics revealed that HDD significantly restored 165 altered metabolites in AKI mice. Subsequent enrichment analysis and pathway analysis of these metabolites indicated that nicotinate and nicotinamide metabolism was the primary pathway affected by HDD intervention. Further investigation showed that HDD could upregulate nicotinamide adenine dinucleotide (NAD+) biosynthesis-related enzymes quinolinate phosphoribosyltransferase, nicotinamide mononucleotide adenylyltransferase 1, and nicotinamide phosphoribosyltransferase to replenish NAD+ content in the kidney of AKI mice. Conclusion: In summary, HDD exerted a protective effect against cisplatin-induced AKI and suppressed apoptosis, inflammation, and oxidative stress in the kidney of AKI mice, which may be attributed to the modulation of NAD+ biosynthesis.

Huangqi-Danshen decoction reshapes renal glucose metabolism profiles that delays chronic kidney disease progression.

Huangqi-Danshen decoction (HDD), a Chinese herbal preparation, is effective in clinical treatment of chronic kidney disease (CKD). However, the underlying mechanism remains to be clarified. In this study, we aimed to investigate the role of HDD in the regulation of renal glucose metabolism in a CKD mouse model. The 0.2% adenine-induced CKD mouse model was administered HDD extract at a dose of 6.8 g/kg/day for 4 weeks. Detection of renal glucose metabolites was performed by ultra-performance liquid chromatography-tandem mass spectrometry. The expression of renal fibrosis and glucose metabolism-related proteins was tested by Western blotting, immunohistochemistry, and immunofluorescence. The results showed that HDD treatment could significantly reduce serum creatinine (0.36 ± 0.10 mg/dL vs. 0.51 ± 0.07 mg/dL, P < 0.05) and blood urea nitrogen (40.02 ± 3.73 mg/dL vs. 62.91 ± 10 mg/dL, P < 0.001) levels, and improve renal pathological injury and fibrosis. Aberrant glucose metabolism was found in the kidneys of CKD mice, manifested by enhanced glycolysis and pentose phosphate pathway, and tricarboxylic acid cycle inhibition, which could be partially restored by HDD treatment. Furthermore, HDD regulated the expression of hexokinase 2, phosphofructokinase, pyruvate kinase M2, pyruvate dehydrogenase E1, oxoglutarate dehydrogenase, and glucose-6-phosphate dehydrogenase in CKD mice. In conclusion, HDD protected against adenine-induced CKD, reshaped glucose metabolism profiles, and restored the expression of key enzymes of glucose metabolism in the kidneys of CKD mice. This study sheds light on targeting glucose metabolism for the treatment of CKD and screening small molecule compounds from herbal medicine to slow CKD progression.

Study on the Mechanism of Radix Astragali against Renal Aging Based on Network Pharmacology.

Radix Astragali is widely used in the traditional Chinese medicine with the effect of antiaging. The purpose of this study is to explore the main active ingredients and targets of Radix Astragali against renal aging by network pharmacology and further to verify the mechanism of the main active ingredients in vitro. TCMSP, ETCM, and TCMID databases were used to screen active ingredients of Radix Astragali. Targets of active ingredients were predicted using BATMAN-TCM and cross validated using kidney aging-related genes obtained from GeneCards and NCBI database. Pathways enrichment and protein-protein interaction (PPI) analysis were performed on core targets. Additionally, a pharmacological network was constructed based on the active ingredients-targets-pathways. HK-2 cell was treated with D-galactose to generate a cell model of senescence. CCK-8 and ß-galactosidase were used to detect the effect of Radix Astragali active components on cell proliferation and aging. ELISA was used to detect the expression of senescence-associated secreted protein (TGF-ß and IL-6) in the cell culture supernatant. Western blot was used to detect the expression of key proteins in the SIRT1/p53 pathway. Five active ingredients (Astragaloside I, II, III, IV and choline) were identified from Radix Astragali, and all these active ingredients target a total of 128 genes. Enrichment analysis showed these genes were implicated in 153 KEGG pathways, including the p53, FoxO, and AMPK pathway. 117 proteins and 572 interactions were found in PPI network. TP53 and SIRT1 were two hub genes in PPI network, which interacted with each other. The pharmacological network showed that the five main active ingredients target on some coincident genes, including TP53 and SIRT1. These targeted genes were involved in the p53, FoxO, and AMPK pathway. Proliferation of HK-2 cells was increased by Astragaloside IV treatment compared with that of the D-Gal treatment group. However, the proliferation of the SA-ß-gal positive cells were inhibited. The expression of TGF-ß and IL-6 in the D-Gal group was higher than that in the normal group, and the treatment of Astragaloside IV could significantly reduce the expression of TGF-ß and IL-6. The expression of SIRT1 in the Astragaloside IV group was higher than that in the D-Gal group. However, the expression of p53 and p21 was less in the Astragaloside IV group than that in the D-Gal group. This study suggested that Astragaloside IV is an important active ingredient of Radix Astragali in the treatment of kidney aging via the SITR1-p53 pathway.

Lipidomics reveals the potential mechanism of honokiol against adenine-induced chronic kidney disease.

Honokiol (HKL), a biphenolic compound, is derived from the bark of Magnolia officinalis, which is used in traditional Chinese medicine for gastrointestinal complaints. HKL has diverse pharmacological activities and has protective effects in various disease models. However, the role and mechanism of HKL in treating chronic kidney disease (CKD) remain unclear. This study was designed to investigate whether HKL can alleviate CKD and the potential mechanism by which it acts. Male Sprague-Dawley rats were fed 0.75% w/w adenine feed for 3 weeks to induce CKD. HKL was administered by gavage at a dose of 5 mg/kg/day for 4 weeks. Using a special kit, serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. To assess renal pathology, periodic acid-Schiff and Masson's trichrome staining were conducted. Renal lipid profiles were analyzed by ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS). The results showed that the administration of HKL reduced Scr and BUN and alleviated renal tubular atrophy and tubulointerstitial fibrosis in an adenine-induced CKD rat model. By using lipidomics, we identified 113 lipids (47 lipids in negative ion mode, 66 lipids in positive ion mode) that could be significantly reversed by HKL treatment in CKD rat kidneys. Most of these lipids belonged to the phosphatidylcholine (PC), ceramide (Cer), phosphatidylethanolamine (PE), and triacylglycerol (TAG) classes. Moreover, HKL improved fatty acid oxidation in the kidneys of CKD rats. In conclusion, this study found that HKL can protect against adenine-induced CKD, possibly through the regulation of lipid metabolism.

Jian-Pi-Yi-Shen Formula Improves Adenine-Induced Chronic Kidney Disease via Regulating Tryptophan Metabolism and Aryl Hydrocarbon Receptor Signaling.

Traditional Chinese medicine (TCM) is an important complementary and alternative branch of chronic kidney disease (CKD) therapy. Jian-Pi-Yi-Shen formula (JPYSF) is a TCM formula used for treating CKD with good efficacy. However, the underlying mechanisms of JPYSF in treating CKD remain to be elucidated. The purpose of the present study was to investigate the renoprotective effect and potential mechanism of JPYSF in treating CKD. CKD rat model was induced by feeding a diet containing 0.75% w/w adenine for 4 weeks. JPYSF was given by gavage every day, starting from the 3rd week of the adenine-containing diet and continuing for 4 weeks at the dose of 10.89 g/kg. Renal injury was evaluated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathology, and fibrotic markers expression. Serum levels of tryptophan metabolites were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Aryl hydrocarbon receptor (AHR) signaling was tested by Western blot analysis. The results found that JPYSF treatment significantly lowered Scr and BUN levels, improved renal pathological injury, and down-regulated fibrotic markers expression in CKD rats. Furthermore, JPYSF significantly reduced the levels of 10 tryptophan metabolites in the serum of CKD rats and restored the level of tryptophan. Additionally, the kidney expression of AHR signaling was enhanced in CKD rats and was further suppressed in JPYSF treated rats. These results suggested that JPYSF protected against adenine-induced CKD via modulating tryptophan metabolism and AHR activation.

Combination of Perindopril Erbumine and Huangqi-Danshen Decoction Protects Against Chronic Kidney Disease via Sirtuin3/Mitochondrial Dynamics Pathway.

Background: Chronic kidney disease (CKD) is a major public health problem worldwide. Treatment with renin-angiotensin system inhibitors can achieve only partial efficacy on renal function decline and renal fibrosis in CKD patients. Huangqi-Danshen decoction (HDD) is a basic Chinese herbal pair which is commonly used to treat CKD with good efficacy. Objectives: The current study aimed to investigate the effect of perindopril erbumine (PE), an angiotensin-converting enzyme inhibitor, combined with HDD on adenine-induced CKD rat model and explore the possible mechanism from Sirtuin3/mitochondrial dynamics pathway. Method: CKD rat model was established by feeding of 0.75% w/w adenine containing diet for 3 weeks. At the same time, the treatment groups were given PE (0.42 mg/kg/d) or HDD (4.7 g/kg/d) or PE combined with HDD by gavage for 4 weeks. Renal function was evaluated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). The renal pathological injury was observed by periodic acid-Schiff (PAS) and Masson's trichrome staining. Proteins expression was determined by Western blot analysis. Mitochondrial morphology was observed by transmission electron microscopy. Results: PE in combination with HDD significantly improved renal function, reduced tubular injury and interstitial fibrosis in adenine-induced CKD rats. Moreover, PE + HDD treatment mainly activated the Sirtuin3 expression level. In addition, PE + HDD exhibited bidirectional regulation on mitochondrial dynamics by suppressing mitochondrial fission protein dynaminrelated protein 1 expression and elevating mitochondrial fusion protein optic atrophy 1 expression, resulted in restraint of mitochondrial fragmentation. Conclusion: The combination of PE and HDD attenuated adenine-induced CKD in rats, which was possibly associated with Sirtuin3/mitochondrial dynamics pathway.

Jian-Pi-Yi-Shen Formula Alleviates Chronic Kidney Disease in Two Rat Models by Modulating QPRT/NAD+/SIRT3/Mitochondrial Dynamics Pathway.

OBJECTIVE: Jian-Pi-Yi-Shen formula (JPYSF) is a traditional Chinese herbal decoction and has been used for treating chronic kidney disease (CKD) in clinics for decades. However, the potential mechanisms have not been fully elucidated. This study was designed to test the efficacy of JPYSF in treating CKD and explore the underlying mechanism. METHODS: Two CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. The intervention dose of JPYSF was 10.89 g/kg/d by gastric irrigation. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Periodic acid-Schiff (PAS) and Masson's trichrome staining were used to evaluate renal histopathological changes. The levels of nicotinamide adenine dinucleotide (NAD+) were measured by using the enzyme-linked immunosorbent assay kit. The proteins expressions of renal fibrosis, quinolinate phosphoribosyltransferase (QPRT), sirtuin 3 (SIRT3), and mitochondrial dynamics were determined and quantified by Western blot analysis. RESULTS: The results show that administration of JPYSF significantly lowered Scr and BUN levels, improved renal tubular atrophy and interstitial fibrosis, and decreased renal extracellular matrix deposition in two CKD rat models. In addition, CKD rats exhibited suppressed QPRT/NAD+/SIRT3 signal, increased mitochondrial fission, and decreased mitochondrial fusion. JPYSF treatment promoted QPRT/NAD+/SIRT3 signal and restored mitochondrial fission/fusion balance. CONCLUSION: In conclusion, administration of JPYSF effectively alleviated CKD progression in two rat models, which may be related with regulation of the QPRT/NAD+/SIRT3/mitochondrial dynamics pathway.

Identifying causality, genetic correlation, priority and pathways of large-scale complex exposures of breast and ovarian cancers.

BACKGROUND: Genetic correlations, causalities and pathways between large-scale complex exposures and ovarian and breast cancers need systematic exploration. METHODS: Mendelian randomisation (MR) and genetic correlation (GC) were used to identify causal biomarkers from 95 cancer-related exposures for risk of breast cancer [BC: oestrogen receptor-positive (ER + BC) and oestrogen receptor-negative (ER - BC) subtypes] and ovarian cancer [OC: high-grade serous (HGSOC), low-grade serous, invasive mucinous (IMOC), endometrioid (EOC) and clear cell (CCOC) subtypes]. RESULTS: Of 31 identified robust risk factors, 16 were new causal biomarkers for BC and OC. Body mass index (BMI), body fat mass (BFM), comparative body size at age 10 (CBS-10), waist circumference (WC) and education attainment were shared risk factors for overall BC and OC. Childhood obesity, BMI, CBS-10, WC, schizophrenia and age at menopause were significantly associated with ER + BC and ER - BC. Omega-6:omega-3 fatty acids, body fat-free mass and basal metabolic rate were positively associated with CCOC and EOC; BFM, linoleic acid, omega-6 fatty acids, CBS-10 and birth weight were significantly associated with IMOC; and body fat percentage, BFM and adiponectin were significantly associated with HGSOC. Both GC and MR identified 13 shared factors. Factors were stratified into five priority levels, and visual causal networks were constructed for future interventions. CONCLUSIONS: With analysis of large-scale exposures for breast and ovarian cancers, causalities, genetic correlations, shared or specific factors, risk factor priority and causal pathways and networks were identified.

Untargeted Metabolomics Reveals the Protective Effect of a Traditional Chinese Herbal Decoction on Cisplatin-Induced Acute Kidney Injury.

Our previous studies have demonstrated that Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese herbal decoction, has a renoprotective effect in 5/6 nephrectomy-induced chronic kidney injury. However, the role and potential mechanisms of JPYSF in the treatment of acute kidney injury (AKI) remain unknown. This study was designed to test the beneficial effect of JPYSF in an AKI mouse model and to investigate the underlying mechanism by using metabolomics analysis. The AKI mouse model was induced by a single intraperitoneal injection of cisplatin at a dose of 20 mg/kg. The mice in the treatment group were pretreated orally with JPYSF (18.35 g/kg/d) for 5 days before cisplatin injection. Seventy-two hours after cisplatin injection, serum and kidney samples were collected for biochemical and histological examination. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was applied to analyze metabolic profiling variations in the kidney. The results showed that pretreatment with JPYSF obviously reduced the levels of serum creatinine and blood urea nitrogen and alleviated renal pathological injury in AKI mice. Orthogonal partial least-squares discriminant analysis (OPLS-DA) score plot revealed a clear separation between the AKI and AKI + JPYSF group. A total of 68 and 87 significantly differentially expressed metabolites were identified in the kidney of AKI mice responding to JPYSF treatment in negative and positive ion mode, respectively. The pivotal pathways affected by JPYSF included vitamin B6 metabolism, alanine, aspartate and glutamate metabolism, lysine biosynthesis, and butanoate metabolism. In conclusion, JPYSF can protect the kidney from cisplatin-induced AKI, which may be associated with regulating renal metabolic disorders.

Chemical characterisation and quantification of the major constituents in the Chinese herbal formula Jian-Pi-Yi-Shen pill by UPLC-Q-TOF-MS/MS and HPLC-QQQ-MS/MS.

INTRODUCTION: Jian-Pi-Yi-Shen pill (JPYSP) is a Chinese medicine formula developed for the treatment of anaemic patients with chronic kidney disease (CKD). OBJECTIVE: To investigate the chemical profile of JPYSP in the treatment of renal anaemia. METHODS: A method coupling ultra-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was established to characterise the chemical constituents present in JPYSP. Subsequently, a high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (HPLC-QQQ-MS/MS) was developed to quantify the major constituents from the identified compounds related to the treatment of CKD and anaemia. RESULTS: A total of 71 compounds were tentatively identified from JPYSP, including saponins, flavonoids, sesquiterpenoids, coumarins, phenylpropanoids, anthranones, anthraquinones, tannins, phenolic acids and others. Amongst them, 12 compounds (i.e. astragaloside IV, calycosin, calycosin 7-O-glucoside, salvianolic acid A, rosmarinic acid, rhein, liquiritin, formononetin, atractylenolide I, dioscin, tanshinone IIA, and acteoside) were further quantified simultaneously by HPLC-QQQ-MS/MS. CONCLUSION: The newly developed approach is suitable for the chemical profiling analysis and quality control of JPYSP, and could lead to additional pharmacodynamic studies involving the components of JPYSP.

Distinct Responses of Gut Microbiota to Jian-Pi-Yi-Shen Decoction Are Associated With Improved Clinical Outcomes in 5/6 Nephrectomized Rats.

Gut dysbiosis contributes to the development and progression of chronic kidney disease (CKD) and its complications. However, the effect of drugs on the gut microbiota of CKD patients and its influence on treatment outcomes remains to be explored. Here, we assessed whether the response of gut microbiota to the traditional Chinese medicine Jian-Pi-Yi-Shen (JPYS) decoction differed from that to piperazine ferulate (PF), a kidney-targeted drug, by 16S rDNA sequencing, and whether the difference could be linked with drug-specific clinical outcomes. We showed that both JPYS and PF improved renal function, but only JPYS was able to restore the blood reticulocyte counting and serum calcium level in CKD rats. We also found that weighted UniFrac beta-diversity of the gut microbiome of the JPYS treated rats was significantly different from that of PF. Microbiome markers of drug-specific response were identified and subjected to correlation network analysis, together with clinical parameters and KEGG pathways. Among the microbiome markers of CKD, Corynebacterium was found to form a network hub that was closely correlated with the JPYS responder Enterococcus, suggesting a potential indirect impact of JPYS on Corynebacterium via interspecies interactions. We also identified two network hubs of the PF responder Blautia and the JPYS-only marker Coprococcus, which were connected with many genera and clinical parameters. They might serve as keystone taxa driving the response of gut microbiota to the drugs and influence host outcomes. Moreover, the JPYS-only marker Clostridium_XIVb was found to be connected to many pathways that are associated with CKD progression and might account for the improved outcomes in the JPYS treated rats. At last, the identified keystone markers of drug response were validated by qPCR for their differential abundance between CKD and the two drugs. Taken together, our study revealed that the responses of gut microbiota to JPYS were distinct from that to PF, and pinpointed drug-specific keystone microbiome markers closely correlated to clinical parameters, which could serve as candidate microbiome targets for further studies on their roles in medicating the drug efficacy of TCM in CKD.

Huangqi-Danshen decoction alleviates diabetic nephropathy in db/db mice by inhibiting PINK1/Parkin-mediated mitophagy.

Huangqi-Danshen decoction (HDD) is composed of Astragali Radix (Huang-qi) and Salviae Miltiorrhizae Radix et Rhizoma (Dan-shen), both of which are the most commonly used herbs for the clinical treatment of diabetic nephropathy (DN) in traditional Chinese medicine and show good efficacy. However, the underlying mechanism of this effect is unclear. The aim of this study was to evaluate the effect and potential mechanism of HDD in the treatment of DN in a type 2 diabetic animal model, db/db mice. HDD extract was administered orally to db/db mice at a dose of 6.8 g/kg/day for 12 weeks. At the end of the study, serum, urine, and kidney samples were collected for biochemical and pathological examination. The expression of proteins associated with mitochondrial fission and mitophagy was determined by quantitative real-time PCR, Western blotting, and immunohistochemical analysis. The results showed that treatment with HDD substantially reduced urinary albumin excretion and improved renal injury in db/db mice. Moreover, mitochondrial fission was increased in the kidneys of the db/db mice, as evidenced by enhanced expression of dynamin-related protein 1 and mitochondrial morphological changes. Furthermore, PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy was activated in the db/db mice, which manifested as increased protein expression and obvious autophagic vacuole encapsulating mitochondria. HDD treatment significantly reversed the enhanced mitochondrial fission and PINK1/Parkin-mediated mitophagy in the db/db mice. In conclusion, this work suggested that HDD could protect against type 2 diabetes-induced kidney injury possibly by inhibiting PINK1/Parkin-mediated mitophagy.

Black phosphorus for fighting antibiotic-resistant bacteria: What is known and what is missing.

Recently, two-dimensional black phosphorus (BP) nanomaterial has captured much attention due to its superb physiochemical and electronic properties and various promising biomedical applications. However, relatively few studies have explored its antimicrobial properties, particularly for targeting antibiotic-resistant pathogens. A comprehensive understanding of the bactericidal mechanisms of BP is essential for application of this material as an antimicrobial. This review discusses the physicochemical and electronic properties of BP that are relevant for antimicrobial applications, especially the unique characteristics that may play a role in overcoming drug resistance. The literature is discussed in the context of what is known and what information is missing. We also highlight the differences and advantages of BP over other two-dimensional nanomaterials (i.e., graphene oxide and molybdenum disulfide) for bactericidal activity. Finally, we analyze existing challenges and note topics that require future investigation to overcome current inadequacies, aiming to assist the safe development of BP-based nanotechnology for pathogen control.

Involvement of Circulating Exosomal MicroRNAs in Jian-Pi-Yi-Shen Formula Protection Against Adenine-Induced Chronic Kidney Disease.

Jian-Pi-Yi-Shen formula (JPYSF) is a traditional Chinese medicine (TCM) formula used in clinic to treat chronic kidney disease (CKD) for decades. However, the mechanisms of JPYSF in treating CKD have not been fully elucidated. The aim of the present study was to test the renoprotective effect of JPYSF on CKD rat model and investigate the potential mechanism from the perspective of serum exosomal microRNAs (miRNAs). CKD rat model was induced by feeding Sprague-Dawley rats a diet containing 0.75% w/w adenine for four weeks. The rats in the treatment group were given 10.89 g/kg JPYSF by gavage every day, starting from the 3rd week of the adenine-containing diet for six weeks. Serum biochemistry and histopathology were used to evaluate the renoprotective effects of JPYSF. Serum exosomes were isolated by ExoQuick-TC PLUS exosomes extraction kit and were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. Exosomal miRNAs profiling was analyzed by small RNA sequencing. The results showed that JPYSF treatment significantly lowered serum creatinine and blood urea nitrogen levels and alleviated renal pathological injury in CKD rats. Furthermore, serum exosomes were successfully isolated and identified. Small RNA sequencing revealed that 4 exosomal miRNAs (miR-192-5p, miR-194-5p, miR-802-5p, and miR-143-3p) were significantly downregulated in the CKD group and were markedly upregulated after JPYSF treatment. At last, miR-192-5p was identified as the most relevant miRNA for CKD diagnosis and JPYSF treatment. In conclusion, JPYSF protects kidney from adenine-induced CKD, which may be associated with modulation of exosomal miRNAs.

Metabolomics Analysis Reveals the Protection Mechanism of Huangqi-Danshen Decoction on Adenine-Induced Chronic Kidney Disease in Rats.

Huangqi-Danshen decoction (HDD) is a commonly used drug pair for clinical treatment of chronic kidney disease (CKD) in traditional Chinese medicine with good efficacy. However, the potential mechanisms of this action have not been well elucidated. The aim of this study was to explore the metabolic profiling variations in response to HDD treatment in a CKD rat model. CKD rat model was induced by adding 0.75% adenine to the diet for 4 weeks. The rats in the treatment group received HDD extract orally at the dose of 4.7 g/kg/day during the experiment. At the end of the experiment, serum and kidney samples were collected for biochemical and pathological examination. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was used to analyze metabolic profiling variations in the kidney. The results showed that treatment with HDD markedly attenuated kidney injury and improved renal function. A total of 28 metabolites contributing to CKD phenotype were found and identified in the kidney samples. The primary metabolic pathways disordered in the kidney of CKD rats were glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, and citrate cycle. Partial least squares discriminant analysis (PLS-DA) score plot showed that the three groups of renal samples were obviously divided into three categories, and the metabolic trajectory of the HDD treatment group moved to the control group. (E)-Piperolein A, phosphatidylcholines (PC) (18:1/22:6), phosphatidylinositols (PI) (13:0/18:1), PI (15:0/20:3), phosphatidylserines (PS) (O-20:0/12:0), and triglyceride (TG) (22:4/24:0/O-18:0) represented potential biomarkers of the renoprotective effects of HDD against CKD. In conclusion, HDD has renoprotective effect against adenine-induced CKD, which may be mediated via partially restoration of perturbed metabolism in the kidney.

Advances on the toxicity of uranium to different organisms.

The extensive application of radioactive element uranium (U) and its compounds in the nuclear industry has significantly increased the risk of exposure to the environment. Therefore, research on the safety risks and toxicity mechanisms of U exposure has received increasing attention. This paper reviews the toxic effects of U on different species under different conditions, and summarizes the potential toxicity mechanisms. Under the exposure of U, reactive oxygen species (ROS) produced in cells will damage membrane structure in cells, and inhibit respiratory chain reaction by reducing the production of NADH and ATP. It also induce the expression of apoptosis factors such as Bcl-2, Bid, Bax, and caspase family to cause apoptosis cascade reaction, leading to DNA degradation and cell death. We innovatively list some methods to reduce the toxicity of U because some microorganisms can precipitate uranyl ions through biomineralization or reduction processes. Our work provides a solid foundation for further risk assessment of U.