Tenovin-1, a Selective SIRT1/2 Inhibitor, Attenuates High-fat Diet-induced Hepatic Fibrosis via Inhibition of HSC Activation in ZDF Rats.

Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-ß1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 inhibitor. ZDF rats were divided into chow diet, HFD, and HFD + Tenovin-1 groups. Tenovin-1 reduced hepatic damage, inhibited inflammatory cell infiltration, micro/ macro-vesicular steatosis and prevented collagen deposition HFD-fed rats. Tenovin-1 reduced serum biochemical parameters, triglyceride (TG) and malondialdehyde (MDA) levels but increased glutathione, catalase, and superoxide dismutase levels. Tenovin-1 mitigated proinflammatory cytokines IL-6, IL-1ß, TNFα and fibrosis biomarkers in HFD rats, TGF-ß1-activated LX-2 and FFA treated SCC cells. Additionally, Tenovin-1 suppressed SIRT1/2 expression and inhibited JNK-1 and STAT3 phosphorylation in HFD rats and FFA-treated SCC cells. In conclusion, Tenovin-1 attenuates hepatic fibrosis by stimulating antioxidants and inhibiting inflammatory cytokines under HFD conditions in diabetic rats.

Dendropanoxide Alleviates Thioacetamide-induced Hepatic Fibrosis via Inhibition of ROS Production and Inflammation in BALB/C Mice.

Hepatic fibrosis results from overproduction and excessive accumulation of extracellular matrix (ECM) proteins in hepatocytes. Although the beneficial effects of dendropanoxide (DPx) isolated from Dendropanax morbifera have been studied, its role as an anti-fibrotic agent remains elucidated. We investigated the protective effect of DPx in BALB/C mice that received thioacetamide (TAA) intraperitoneally for 6 weeks. Later DPx (20 mg/kg/day) or silymarin (50 mg/kg/day) was administered daily for 6 weeks, followed by biochemical and histological analyses of each group. Hematoxylin and eosin staining of the livers showed TAA-induced hepatic fibrosis, which was significantly reduced in the DPx group. DPx treatment significantly decreased TAA-induced hyperlipidemia as evidenced by the decreased AST, ALT, ALP, γ-GTP and serum TG concentrations and reduced the activities of catalase (CAT) and superoxide dismutase (SOD) activity. ELISA revealed reduced levels of total glutathione (GSH), malondialdehyde (MDA) and Inflammatory factors (IL-6, IL-1ß, and TNF-α). Immunostaining showed reduced in collagen-1, α-SMA, and TGF-ß1 expression and western blotting showed reduced levels of the apoptotic proteins, TGF-ß1, p-Smad2/3, and Smad4. RT-qPCR and Western blotting revealed modifications in SIRT1, SIRT3 and SIRT4. Thus, DPx exerted a protective effect against TAA-induced hepatic fibrosis in the male BALB/C mouse model by inhibiting oxidative stress, inflammation, and apoptosis via TGF-ß1/Smads signaling.

Risk Assessment and Risk Reduction of Ptaquiloside in Bracken Fern.

This study was conducted to determine the optimal boiling time to reduce ptaquiloside (PTA) and to carry out a risk assessment for PTA, a representative toxic substance found in bracken fern (BF; Pteridium aquilinum), which is frequently consumed as food in East Asian countries. High-performance liquid chromatography showed that the concentration of PTA in BF was reduced by up to 99% after boiling for 20 min. Risk assessment results showed that the cancer margin of exposure (MOE; ≥ 25,000 = safe) to PTA for an average daily exposure scenario after boiling BF for 20 min was considered safe. In addition, the non-cancer MOE (≥ 300 = safe) to PTA under an average daily exposure scenario after BF boiling for 20 min was considered safe. However, human exposure to PTA was considered unsafe under the non-boiled BF exposure and maximum daily exposure scenarios. Therefore, boiling BF for at least 20 min is recommended before consumption, to reduce exposure to PTA as much as possible.

Protective effect of dendropanoxide against cadmium-induced hepatotoxicity via anti-inflammatory activities in Sprague-Dawley rats.

Cadmium (Cd) accumulates in the body through contaminated foods or water and causes pathological damage to the liver via oxidative stress and inflammatory reactions. This study was conducted to explore the effects of dendropanoxide (DPx) on Cd-induced hepatotoxicity in rats. Sprague-Dawley (SD) rats were injected with CdCl2 (7 mg/kg body weight) intraperitoneally for 14 days for the induction of liver dysfunction. The CdCl2-exposed rats were subjected to DPx (10 mg/kg) or silymarin (50 mg/kg). The animals were euthanized after 24 h of the last CdCl2 injection and the serum biochemical parameters, lipid content, pro-inflammatory cytokine levels, apoptotic cell death and histopathology of the tissues were analyzed. Additionally, the activity of antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT), was measured. Compared to controls, Cd-injected rats showed significantly elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), total cholesterol, and pro-inflammatory cytokines, and a remarkable decrease in SOD and CAT activities. Importantly, Cd-induced liver damage was drastically ameliorated by treatment with DPx or silymarin. Treatment with DPx protected the Cd-induced histopathological hepatic injury, as confirmed by the evaluation of TUNEL assay. DPx treatment significantly reduced Bax and caspase-3 expression in Cd-injected rats. Additionally, HO-1 and NRF2 expressions were significantly increased after DPx administration in the liver of Cd-injected rats. Our data indicate that DPx successfully prevents Cd-induced hepatotoxicity by emphasizing the antioxidant and anti-inflammatory effect.

Optimized study of the annealing effect on the electrical and structural properties of HDLC thin-films.

The plasma-enhanced chemical vapor deposition (PECVD) technique has been utilized for the facile surface deposition of hydrogenated diamond-like carbon (HDLC) thin-films onto Si(100) substrates. The as-deposited film surface is homogenous, free of pinholes, and adheres to the substrate. Annealing of the synthesized HDLC surface in a vacuum was performed in the temperature range of 200 to 1000 °C. A host of instrumental techniques, viz. FTIR spectroscopy, AFM, STM, and EC-AFM, were successfully employed to detect the morphological transformation in the HDLC films upon annealing. EC-AFM studies show irreversible biased behavior after undergoing a surface redox couple reaction and morphological change. Raman spectroscopy was carried out along with STM and EC-AFM to determine the functional nature and conductivity of the annealed surface.

Adhesive assisted TiB2 coating effects on friction stir welded joints.

Friction stir welding is a novel technique for joining ferrous and non-ferrous materials in a solid state. The groove fill techniques are most popular and generally used by researchers to dope reinforcement in the FSWed zone to improve the properties of joints. The main drawback of this technique is that a few amounts of reinforcement material come out from the groove during the fabrication of the joint. In the present work, the adhesive-assisted reinforcement technique was used to overcome this problem for the fabrication of particulates reinforced friction stirred weld joint. In the present work, the aluminum alloy plate edges were coated with a thin layer of TiB2. The coated and non-coated edge plates were joined using friction stir welding at the rotational speed of 1400 and 2240 rpm, and welding speed of 32 mm/min using a taper threaded pin tool. The tensile strength of coated edge plate welded joints was found highest in comparison to non-coated joints which was 39.74% superior. The percentage elongation of coated edge joint was observed about 1.5 times lower than the non-coated edge plate joint. The flexure strength of TiB2 reinforced coated edge joint was found about 1.5 times higher. However, the impact strength of coated edge plate was found nearly three times lower than the uncoated edge joints. The TiB2 coated edge joints reveal 22.75% higher hardness than the non-coated edge plate joints welded at the rotational speed of 2240.

Tenovin-1 Ameliorates Renal Fibrosis in High-Fat-Diet-Induced Diabetic Nephropathy via Antioxidant and Anti-Inflammatory Pathways.

High-fat diet (HFD)-induced obesity has been involved in the development of diabetic nephropathy (DN). Tenovin-1, a potent selective SIRT1/2 inhibitor, regulates various target proteins. The present study evaluated the protective effect of Tenovin-1 against renal fibrosis in HFD-induced Zucker diabetic fatty (ZDF) rats. Rats were fed a normal chow diet or HFD. Tenovin-1 (45 mg/kg) administered to HFD-fed rats decreased inflammatory cytokine expression in the serum of the rats. The antioxidant status and oxidative damage to lipids or DNA were significantly restored by Tenovin-1. Additionally, Tenovin-1 reduced the levels of blood urea nitrogen (BUN), serum creatinine (sCr), microalbumin, and urinary protein-based biomarkers in the urine of HFD-fed rats. The abnormal architecture of the kidney and pancreas was restored by Tenovin-1 administration. Tenovin-1 also reduced apoptosis in the kidneys of the HFD-fed rats and HG-treated NRK-52E cells. It significantly lowered the levels of ECM proteins in the kidneys of HFD-fed rats and HG-treated NRK-52E cells. Additionally, Tenovin-1 markedly reduced claudin-1, SIRT1, and SIRT2, but increased SIRT3 and SIRT4 in HFD-fed rats and NRK-52E cells treated with HG. Furthermore, Tenovin-1 altered epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-ß (PDGFR-ß), and signal transducer and activator of transcription 3 (STAT3) levels in the kidneys of HFD-fed rats. Conclusively, this study shows that Tenovin-1 can be a potential candidate drug for the treatment of HFD-induced renal fibrosis, in vivo and in vitro models.

Molineria recurvata Ameliorates Streptozotocin-Induced Diabetic Nephropathy through Antioxidant and Anti-Inflammatory Pathways.

Molineria recurvata (MR) has been traditionally used to manage diabetes mellitus in India. However, the molecular mechanism of MR on the diabetic-induced nephropathy has not been clearly investigated. Thus, this study investigates the protective effects of the MR extract on nephropathy in streptozotocin (STZ)-induced diabetic rats. Diabetes was instigated by a single intraperitoneal injection of STZ (45 mg/kg) in male Sprague-Dawley rats. Once the diabetes was successfully induced, the MR extract (200 mg/kg/day) or metformin (200 mg/kg/day) was orally administered for 14 days. Renal function, morphology changes and levels of inflammatory cytokines were measured. Blood glucose concentrations were considerably reduced in STZ-induced diabetic rats following treatment with the MR extract. The administration of the MR extract substantially restored the abnormal quantity of the oxidative DNA damage marker 8-hydroxy-2'-deoxy-guanosine (8-OHdG), malondialdehyde, glutathione, oxidized glutathione, superoxide dismutase, catalase, interleukin (IL)-1ß, IL-6, IL-10, and transforming growth factor-ß (TGF-ß). The urinary excretion of kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), selenium binding protein 1 (SBP1), and pyruvate kinase M2 (PKM2) was significantly reduced in diabetes rats after administration of the MR extracts. In the kidneys of STZ-induced diabetic rats, the MR extracts markedly downregulated the expression of fibronectin, collagen-1, and α-smooth muscle actin (α-SMA). In particular, the MR extracts markedly increased the level of SIRT1 and SIRT3 and reduced claudin-1 in the kidney. These results suggest that the MR extracts exhibits therapeutic activity in contrast to renal injury in STZ-induced diabetic rats through repressing inflammation and oxidative stress.

Sensitization Effects of Repurposed Blood Pressure-regulating Drugs on Drug-resistant Cancer Cells.

BACKGROUND/AIM: We investigated drugs that could sensitize KBV20C cancer cells resistant to eribulin or vincristine (VIC) treatment and assessed their associated mechanisms of action. MATERIALS AND METHODS: Such cancer cells were known to overexpress P-glycoprotein (P-gp). Considering that reserpine (P-gp inhibitor) plays a regulatory role in patients with high blood pressure, we investigated the effect of low doses of 27 blood pressure-regulating drugs on VIC-resistant KBV20C cells. This was done to identify drugs that could be repurposed for sensitizing antimitotic drug-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, rhodamine uptake tests and western-blot analysis were performed to further investigate the mechanism of action of such drugs. RESULTS: We found that co-treatment with amiodarone, nicardipine, carvedilol, or vardenafil at low doses could highly sensitize KBV20C cells treated with eribulin or VIC. These drugs reduced cellular viability, increased G2 arrest and up-regulated apoptosis when co-administered with eribulin or VIC. Considering that they sensitize with either co-treatment of eribulin or VIC, we assumed that they can be combined with other antimitotic drugs to sensitize the resistant cancer cells. Through detailed quantitative analysis, we found that eribulin with amiodarone had a higher sensitization effect than eribulin with nicardipine or eribulin with carvedilol. We found that reserpine had the highest P-gp-inhibitory activity, indicating that eribulin- or VIC-reserpine sensitization involves the P-gp inhibitory effects of reserpine. However, we found that amiodarone, nicardipine, carvedilol and vardenafil had very low P-gp inhibitory activity. Moreover, we found that cells co-treated with VIC-carvedilol down-regulated expression of pERK. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repurposed blood pressure-regulating drugs amiodarone, nicardipine, carvedilol or vardenafil. These findings indicate that the repurposed blood pressure-regulating drugs may potentially be used in drug-resistant cancer patients without any toxic effects due to P-gp inhibition.

Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells.

Ovarian cancer is a common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic role remains unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on the regulation of autophagic and apoptotic pathways in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using MTT and colony formation assays in SK-OV-3 cells. PKM2 expression was positively correlated with the severity of the tumor, and expression of pro-apoptotic proteins increased in SK-OV-3 cells following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by mTOR inhibition. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation of SK-OV-3 cells. Compound 3K treatment suppressed tumor progression in an in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected the Warburg effect and induced autophagic cell death. Therefore, use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.

Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19?

BACKGROUND: Currently, novel coronavirus disease (Covid-19) outbreak creates global panic across the continents, as people from almost all countries and territories have been affected by this highly contagious viral disease. The scenario is deteriorating due to lack of proper & specific target-oriented pharmacologically safe prophylactic agents or drugs, and or any effective vaccine. drug development is urgently required to back in the normalcy in the community and to combat this pandemic. PURPOSE: Thus, we have proposed two novel drug targets, Furin and TMPRSS2, as Covid-19 treatment strategy. We have highlighted this target-oriented novel drug delivery strategy, based on their pathophysiological implication on SARS-CoV-2 infection, as evident from earlier SARS-CoV-1, MERS, and influenza virus infection via host cell entry, priming, fusion, and endocytosis. STUDY DESIGN &  METHODS: An earlier study suggested that Furin and TMPRSS2 knockout mice had reduced level of viral load and a lower degree of organ damage such as the lung. The present study thus highlights the promise of some selected novel and potential anti-viral Phytopharmaceutical that bind to Furin and TMPRSS2 as target. RESULT: Few of them had shown promising anti-viral response in both preclinical and clinical study with acceptable therapeutic safety-index. CONCLUSION: Hence, this strategy may limit life-threatening Covid-19 infection and its mortality rate through nano-suspension based intra-nasal or oral nebulizer spray, to treat mild to moderate SARS-COV-2 infection when Furin and TMPRSS2 receptor may initiate to express and activate for processing the virus to cause cellular infection by replication within the host cell and blocking of host-viral interaction.

Biological Evaluation of Oxindole Derivative as a Novel Anticancer Agent against Human Kidney Carcinoma Cells.

Renal cell carcinoma has emerged as one of the leading causes of cancer-related deaths in the USA. Here, we examined the anticancer profile of oxindole derivatives (SH-859) in human renal cancer cells. Targeting 786-O cells by SH-859 inhibited cell growth and affected the protein kinase B/mechanistic target of rapamycin 1 pathway, which in turn downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, as well as other signaling proteins. Treatment with SH-859 altered glycolysis, mitochondrial function, and levels of adenosine triphosphate and cellular metabolites. Flow cytometry revealed the induction of apoptosis and G0/G1 cell cycle arrest in renal cancer cells following SH-859 treatment. Induction of autophagy was also confirmed after SH-859 treatment by acridine orange and monodansylcadaverine staining, immunocytochemistry, and Western blot analyses. Finally, SH-859 also inhibited the tumor development in a xenograft model. Thus, SH-859 can serve as a potential molecule for the treatment of human renal carcinoma.

Removal of As(V), Cr(VI) and Cu(II) using novel amine functionalized composite nanofiltration membranes fabricated on ceramic tubular substrate.

Novel amine functionalized composite membranes were prepared over tubular ceramic substrate using facile dip-coating and cross-flow filtration approach. The two fabricated membranes, P-60S and P-60S-EDTA with polyethyleneimine (PEI) and EDTA-modified PEI as functional layers respectively, were characterized in terms of EDX, FTIR, XPS, FESEM, AFM and contact angle analyses which confirmed their stable physical and chemical structure for use in high pressure application. Clean water permeability and MWCO study revealed the superior permeability and rejection efficiency of the P-60S-EDTA compared to the P-60S membrane. Incorporation of bulky EDTA molecules in the membrane functional layer simultaneously decreased pore size and increased membrane hydrophilicity. The removal of As(V), Cr(VI) and Cu(II) heavy metals by both membranes were found to be highly pH dependent and overall rejection improved in case of P-60S-EDTA membrane [99.82% for Cu(II), 96.75% for As(V) and 97.22% for Cr(VI)]. Interestingly, rejection of As(V) and Cr(VI) was significantly improved in presence of Cu(II) due to volume resistance provided by EDTA-Cu(II) complex towards the passage of other heavy metal ions. Excellent stability of P-60S-EDTA membrane in continuous operation of 36 h in both ideal and practical water environment suggests its promising application in real field heavy metal contaminated waste water treatment.

EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats.

Sirtuin (SIRT) is known to prevent nonalcoholic fatty liver disease (NAFLD); however, the role of SIRT4 in the progression of hepatic fibrosis remains unknown. We hypothesize that EX-527, a selective SIRT1 inhibitor, can inhibit the progression of high-fat diet (HFD)-induced hepatic fibrosis. We found that SIRT4 expression in the liver of NAFLD patients is significantly lower than that in normal subjects. In this study, EX-527 (5 µg/kg), administered to HFD rats twice a week for ten weeks, reduced the serum levels of triglyceride (TG), total cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and attenuated hepatic fibrosis evidenced by Masson's trichrome and hepatic fat by oil red-O staining. EX-527 upregulated SIRT2, SIRT3, and SIRT4 expression in the liver of HFD fed rats but downregulated transforming growth factor-ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) expression. It decreased proinflammatory cytokine production and hydroxyproline levels in the serum and SMAD4 expression and restored apoptotic protein (Bcl-2, Bax, and cleaved caspase-3) expression. These data propose a critical role for the SIRT4/SMAD4 axis in hepatic fibrogenesis. SIRT4 upregulation has the potential to counter HFD-induced lipid accumulation, inflammation, and fibrogenesis. We demonstrate that EX-527 is a promising candidate in inhibiting the progression of HFD-induced liver fibrosis.

Multiple Linear Discriminant Models for Extracting Salient Characteristic Patterns in Capsule Endoscopy Images for Multi-Disease Detection.

BACKGROUND: Computer-aided disease detection schemes from wireless capsule endoscopy (WCE) videos have received great attention by the researchers for reducing physicians' burden due to the time-consuming and risky manual review process. While single disease classification schemes are greatly dealt by the researchers in the past, developing a unified scheme which is capable of detecting multiple gastrointestinal (GI) diseases is very challenging due to the highly irregular behavior of diseased images in terms of color patterns. METHOD: In this paper, a computer-aided method is developed to detect multiple GI diseases from WCE videos utilizing linear discriminant analysis (LDA) based region of interest (ROI) separation scheme followed by a probabilistic model fitting approach. Commonly in training phase, as pixel-labeled images are available in small number, only the image-level annotations are used for detecting diseases in WCE images, whereas pixel-level knowledge, although a major source for learning the disease characteristics, is left unused. In view of learning the characteristic disease patterns from pixel-labeled images, a set of LDA models are trained which are later used to extract the salient ROI from WCE images both in training and testing stages. The intensity patterns of ROI are then modeled by a suitable probability distribution and the fitted parameters of the distribution are utilized as features in a supervised cascaded classification scheme. RESULTS: For the purpose of validation of the proposed multi-disease detection scheme, a set of pixel-labeled images of bleeding, ulcer and tumor are used to extract the LDA models and then, a large WCE dataset is used for training and testing. A high level of accuracy is achieved even with a small number of pixel-labeled images. CONCLUSION: Therefore, the proposed scheme is expected to help physicians in reviewing a large number of WCE images to diagnose different GI diseases.

Adverse health risk from prolonged consumption of formaldehyde-preserved carps in eastern region of Indian population.

Presence of formaldehyde as a preservative in commonly available fishes (Labeo rohita, Catla catla, Anabas testudineus and Clarias gariepinus) has become a serious health concern in the public health of eastern region of India. Formaldehyde content was determined using high-performance liquid chromatography (HPLC). Results showed high formaldehyde content in frozen carp (19.66 and 23.3 mg/kg in Labeo rohita and Catla catla, respectively); however, the amount of formaldehyde was significantly reduced in boiled and fried fish (80 °C and 100 °C for 5 min) in mustard, coconut, and sesame oils. However, formaldehyde contents in non-carp fishes (Anabas testudineus and Clarias gariepinus) were almost negligible, compared to those in L. rohita and C. catla. In vivo toxicity studies showed a time-dependent increase in blood formaldehyde levels in rats after they were fed formaldehyde-contaminated fish (23.3 mg/kg) for 7 days. Histopathological analysis of the stomach of rats fed contaminated fish showed destruction and granulation of the protective mucus layer and detachment from the secretory layer. Taken together, our results indicated that continuous consumption of formaldehyde-contaminated carps commonly available in the eastern region of India may be associated with adverse health effects.

Protective effect of EX-527 against high-fat diet-induced diabetic nephropathy in Zucker rats.

High-fat diet (HFD)-induced obesity is implicated in diabetic nephropathy (DN). EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, has multiple biological functions; however, its protective effect against DN is yet to be properly understood. This study was aimed to explore the protective effect of EX-527 against DN in HFD-induced diabetic Zucker (ZDF) rats. After 21 weeks of continually feeding HFD to the rats, the apparent characteristics of progressive DN were observed, which included an increase in kidney weight (~160%), hyperglycemia, oxidative stress, and inflammatory cytokines, and subsequent renal cell damage. However, the administration of EX-527 for 10 weeks significantly reduced the blood glucose concentration and kidney weight (~59%). Furthermore, EX-527 significantly reduced the serum concentration of transforming growth factor-ß1 (49%), interleukin (IL)-1ß (52%), and IL-6 in the HFD-fed rats. Overall, the antioxidant activities significantly increased, and oxidative damage to lipids or DNA was suppressed. Particularly, EX-527 significantly reduced blood urea nitrogen (81%), serum creatinine (71%), microalbumin (43%), and urinary excretion of protein-based biomarkers. Histopathological examination revealed expansion of the extracellular mesangial matrix and suppression of glomerulosclerosis following EX-527 administration. EX-527 downregulated the expression of α-SMA (~64%), TGF-ß (25%), vimentin, α-tubulin, fibronectin, and collagen-1 in the kidneys of the HFD-fed rats. Additionally, EX-527 substantially reduced claudin-1 and SIRT1 expression, but increased the expression of SIRT3 in the kidneys of the HFD-fed rats. EX-527 also inhibited the growth factor receptors, including EGFR, PDGFR-ß, and STAT3, which are responsible for the anti-fibrotic effect of SIRT-1. Therefore, the administration of EX-527 protects against HFD-induced DN.

Dendropanax morbifera Protects against Renal Fibrosis in Streptozotocin-Induced Diabetic Rats.

The aquatic extract of Dendropanax morbifera (DP) is typically consumed as a beverage in Korea and China and is also used in various traditional medicines. However, the functional role of DP on diabetes-induced renal fibrosis is unclear. Here, the protective effects of DP extract against diabetes-induced renal fibrosis were evaluated. Streptozotocin (STZ, 60 mg/kg) was injected intraperitoneally in rats to induce diabetes. After 5 days, DP extract (25 mg/kg/day) and metformin (50 mg/kg/day) were administered orally to diabetic rats for 28 days. DP administration protected both body and organ weight loss in STZ-treated diabetic rats. Significant improvements in serum blood urea nitrogen (BUN), creatinine, and oxidative stress parameters were observed in diabetic rats by DP administration. DP extract markedly protected diabetic-induced histopathological damages in the kidney and pancreas. A significant reduction was observed in microalbumin, kidney injury molecule-1 (KIM-1), selenium binding protein-1 (SBP1), and pyruvate kinase muscle isozyme M2 (PKM2) levels in the urinary excretion of diabetic rats after the administration of DP extract. The expression of pro-inflammatory cytokines and fibrosis marker levels were significantly reduced in the kidney of diabetic rats. Our results strongly indicate that DP extract exhibits protective activity against diabetes-induced renal fibrosis through ameliorating oxidative stress and inflammation. Therefore, we suggest that DP extract can be used as a preventive agent on the progression of diabetic nephropathy and renal fibrosis.

Protective effects of Croton hookeri on streptozotocin-induced diabetic nephropathy.

In this study, the protective effects of Croton hookeri (CH) extract on renal injury were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single injection of STZ (45 mg/kg) to Sprague-Dawley rats. After 5 days, CH extract (200 mg/kg) was administered daily by oral gavage for 2 weeks. Administration of CH extracts significantly reduced blood glucose levels in STZ-induced diabetic rats. STZ-induced changes in total cholesterol, LDL, HDL, ALT, AST, BUN, and serum creatinine levels were significantly restored by treatment with CH extract. Abnormal levels of SOD, catalase, glutathione, and oxidized GSH (GSSG) in STZ-treated rats were also significantly recovered by CH extract treatment. CH extract markedly reduced the expression of collagen-1, fibronectin, and α-SMA in the kidney of STZ-induced diabetic rats. In particular, oxidative DNA damages, MDA, TGF-ß, IL-1ß, and IL-6 levels were significantly reduced in STZ-treated rats following treatment with CH extract, whereas IL-10 showed opposite trend. STZ-induced SIRT1, SIRT3 downregulation and cloudin-1 upregulation in the kidney were dramatically recovered by CH extract treatment. Our data suggest that CH extract protects against diabetic-induced nephropathy by inhibiting oxidative stress and inflammation. Therefore, it has potential as a food supplement to alleviate renal dysfunction caused by diabetes-induced nephropathy.