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Niclosamide (NCL) is repurposed to treat inflammatory bowel disease due to its anti-inflammatory properties and potential to reduce oxidative stress. This therapeutic activity remains challenging if administered directly due to its low solubility and high recrystallization tendency in gastric pH. Solid dispersions using pH-dependent polymer will be a better idea to improve the solubility, dissolution and targeted delivery at the colon. Hot melt extrusion was used to formulate a solid dispersion with 30% NCL utilising hydroxypropyl methylcellulose acetate succinate as a pH-dependent polymer. In vitro drug release studies revealed formulation (F1) containing 10%w/w Tween 80 showed minimal release (2.06%) at the end of 2 h, followed by 47.87% and 82.15% drug release at 6 h and 14 h, respectively, indicating the maximum amount of drug release in the colon. The drug release from the formulations containing no plasticiser and 5%w/w plasticiser was comparable to the pure crystalline drug (approximately 25%). Solid-state analysis confirmed particle conversion of crystalline NCL to amorphous form, and the optimised formulation was stable for 6 months without significant changes in dissolution profile. In contrast to pure NCL, the F1 formulation substantially reduced the disease activity index, colonic inflammation, histological alterations and oxidative damage in colitis mice. These findings reveal that the prepared formulation can potentially deliver the drug locally at the colon, making it an effective tool in treating ulcerative colitis.

Rheumatoid arthritis is an inflammatory condition primarily affecting the joints. Nuciferine (NCF), a key bioactive aporphine alkaloid biosynthesized in lotus leaves, exhibits promising anti-inflammatory and antioxidant properties. In this study, we investigated whether NCF could alleviate inflammatory arthritis conditions in a complete Freund's adjuvant (CFA)-mediated arthritis model in rats. The arthritis model was established through intradermal injection of CFA (100 μL) in the sub-plantar region of the right hind paw. The arthritic animals were treated orally with NCF at 5 and 10 mg/kg and indomethacin (Indo) at 5 mg/kg body weight as reference control. NCF treatment remarkably alleviated inflammatory joint swelling and arthritic index. The radiological and histological analysis revealed evidence of the beneficial effects of NCF. NCF treatment decreased the content of pro-inflammatory cytokines (TNF-α and IL-1β) and myeloperoxidase (MPO) activity and restored the anti-inflammatory cytokine (IL-10) in the paw joints. The serum levels of pro-inflammatory cytokines were also markedly reduced in the NCF (10 mg/kg) treatment group. Moreover, the arthritis-induced inflammatory mediators, including cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the toll-like receptor (TLR)-4, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling proteins were substantially decreased in the NCF treatment groups. NCF treatment also restored the antioxidant defense enzymes and abrogated lipid peroxidation in the paw tissue. Our findings strongly suggest that NCF is a promising therapeutic molecule for rheumatoid arthritis, inspiring further research, and development in this area., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is pivotal in orchestrating the immune response induced by nanoparticle adjuvants. Understanding the intricate mechanisms underlying the activation of NLRP3 inflammasome by these adjuvants is crucial for deciphering their immunomodulatory properties. This review explores the involvement of the NLRP3 inflammasome in mediating immune responses triggered by nanoparticle adjuvants. It delves into the signaling pathways and cellular mechanisms involved in NLRP3 activation, highlighting its significance in modulating the efficacy and safety of nanoparticle-based adjuvants. A comprehensive grasp of the interplay between NLRP3 inflammasome and nanoparticle adjuvants holds promise for optimizing vaccine design and advancing immunotherapeutic strategies.

Ulcerative colitis (UC) is a chronic problem of the intestine and relapsing in nature. Biochanin A is a nature-derived isoflavonoid and has numerous bioactivities. However, its role against UC and intestinal inflammation remains obscure. We aimed to comprehensively explore the pharmacological effect of biochanin A in alleviating colitis and to evaluate the potential mechanisms. Initially, we explored the anti-inflammatory action of biochanin A (15, 30, and 60 μM) by employing lipopolysaccharide (LPS)-activated RAW 264.7 cells. In RAW 264.7 cells under LPS stimulation, biochanin A inhibited the elevation of reactive oxygen species (ROS) (p < 0.0001), interleukin (IL)-1β (p < 0.0001), IL-18 (p < 0.01), and tumor necrosis factor (TNF)-α (p < 0.01) release, nitrite production (p < 0.0001), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. Next, we studied the effectiveness of biochanin A (20 and 40 mg/kg) in mouse colitis induced with dextran sulfate sodium (DSS) by assessing colon length, disease activity index (DAI) scoring, and performing colonoscopy and histological analysis. The pro-inflammatory cytokines were estimated using ELISA. Western blot studies were performed to assess underlying mechanisms. In mice, biochanin A treatment alleviated DAI score (p < 0.0001), restored colon length (p < 0.05) and morphology, and re-established colon histopathology. Biochanin A affects the phosphorylation of proteins associated with NF-κB (p65) and mitogen-activated protein kinase (MAPK) axis and regulates colonic inflammation by reducing the expression of inflammatory cytokines and myeloperoxidase (MPO) activity. Altogether, our findings support the idea that the anticolitis potential of biochanin A is allied with anti-inflammatory activity by inhibiting the MAPK/NF-κB (p65) axis. Hence, biochanin A may be an alternative option to alleviate the risk of colitis., (© 2024 Wiley Periodicals LLC.)

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Carvedilol (CVD), an adrenoreceptor blocker, is a hydrophobic Biopharmaceutics Classification System class II drug with poor oral bioavailability due to which frequent dosing is essential to attain pharmacological effects. Quercetin (QC), a polyphenolic compound, is a potent natural antioxidant, but its oral dosing is restricted due to poor aqueous solubility and low oral bioavailability. To overcome the common limitations of both drugs and to attain synergistic cardioprotective effects, we formulated CVD- and QC-encapsulated cationic nanoliposomes (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. We designed CVD- and QC-loaded cationic nanoliposomal (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. In vitro drug release studies of CVD/QC-L.O.F. (16.25%) exhibited 18.78 ± 0.57% of QC release and 91.38 ± 0.93% of CVD release for 120 h. Ex vivo nasal permeation studies of CVD/QC-L.O.F. demonstrated better permeation of QC (within 96 h), i.e., 75.09% compared to in vitro drug release, whereas CVD permeates within 48 h, indicating the better interaction between cationic NLPs and the negatively charged biological membrane. The developed nasal gel showed a sufficient mucoadhesive property, good spreadability, higher firmness, consistency, and cohesiveness, indicating suitability for membrane application and intranasal administration. CVD-NLPs, QC-NLPs, and CVD/QC-NLPs were evaluated for in vitro cytotoxicity, in vitro ROS-induced cell viability assessment, and a cellular uptake study using H9c2 rat cardiomyocytes. The highest in vitro cellular uptake of CVD/QC-cationic NLPs by H9c2 cells implies the benefit of QC loading within the CVD nanoliposomal carrier system and gives evidence for better interaction of NLPs carrying positive charges with the negatively charged biological cells. The in vitro H 2 O 2 -induced oxidative stress cell viability assessment of H9c2 cells established the intracellular antioxidant activity and cardioprotective effect of CVD/QC-cationic NLPs with low cytotoxicity. These findings suggest the potential of cationic NLPs as a suitable drug delivery carrier for CVD and QC combination for the intranasal route in the treatment of various cardiovascular diseases like hypertension, angina pectoris, etc. and for treating neurodegenerative disorders.

Background: Recent years of evidence suggest the crucial role of renal tubular cells in developing diabetic kidney disease. Scopoletin (SCOP) is a plant-based coumarin with numerous biological activities. This study aimed to determine the effect of SCOP on renal tubular cells in developing diabetic kidney disease and to elucidate mechanisms., Methods and Results: In this study, SCOP was evaluated in vitro using renal proximal tubular (HK-2) cells under hyperglycemic conditions to understand its mechanism of action. In HK-2 cells, SCOP alleviated the high glucose-generated reactive oxygen species (ROS), restored the levels of reduced glutathione, and decreased lipid peroxidation. High glucose-induced alteration in the mitochondrial membrane potential was markedly restored in the SCOP-treated cells. Moreover, SCOP significantly reduced the high glucose-induced apoptotic cell population in the Annexin V-FITC flow cytometry study. Furthermore, high glucose markedly elevated the mRNA expression of fibrotic and extracellular matrix (ECM) components, namely, transforming growth factor (TGF)-β, alfa-smooth muscle actin (α-SMA), collagen I, and collagen III, in HK-2 cells compared to the untreated cells. SCOP treatment reduced these mRNA expressions compared to the high glucose-treated cells. Collagen I and TGF-β protein levels were also significantly reduced in the SCOP-treated cells. Further findings in HK-2 cells revealed that SCOP interfered with the epithelial-mesenchymal transition (EMT) in the high glucose-treated HK-2 cells by normalizing E-cadherin and downregulating the vimentin and α-SMA proteins., Conclusions: In conclusion, SCOP modulates the high glucose-generated renal tubular cell oxidative damage and accumulation of ECM components and may be a promising molecule against diabetic nephropathy., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Diabetic nephropathy (DN) is a serious concern in patients with diabetes mellitus. Prolonged hyperglycemia induces oxidative damage, chronic inflammation, and build-up of extracellular matrix (ECM) components in the renal cells, leading to kidney structural and functional changes. Imperatorin (IMP) is a naturally occurring furanocoumarin derivative with proven antioxidative and anti-inflammatory properties. We investigated whether IMP could improve DN and employed high glucose (HG)-induced HK-2 cells and high-fat diet-fed streptozotocin (HFD/STZ)-generated DN experimental model in C57BL/6 mice. In vitro, IMP effectively reduced the HG-activated reactive oxygen species generation, disturbance in the mitochondrial membrane potential (MMP) and epithelial-to-mesenchymal transition (EMT)-related markers, and the transforming growth factor (TGF)-β and collagen 1 expression in HK-2 cells. In vivo, we found an elevation of serum creatinine, kidney histology alterations, and collagen build-up in the kidneys of the DN control group. Also, we found an altered expression of EMT-related markers, upregulation of the TGF-β/Smad2/3 axis, and elevated pro-inflammatory molecules, TNF-α, IL-1β, IL-18 and phospho-NF-kB (p65) in the DN control group. IMP treatment did not significantly reduce the blood glucose level compared to the DN control group. However, IMP treatment effectively improved renal damage by ameliorating kidney histological changes and serum renal injury markers. IMP treatment restored renal antioxidants and exhibited anti-inflammatory effects in the kidneys. Moreover, the abnormal manifestation of EMT-related attributes and elevated levels of TGF-β, phospho-Smad2/3, and collagen 1 were also normalized in the IMP treatment group. Our findings highlight that IMP may be a potential candidate for treating DN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, and synthesis of 4-(2-aminoethyl) phenol derivatives as HDAC inhibitors. The virtual screening and molecular docking analysis led to the identification of 10 representative compounds, which were evaluated based on their drug-like properties. The results demonstrated that these compounds effectively interacted with the active site pocket of HDAC 3 through π-stacking, Zn 2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues. Furthermore, a series of 4-(2-aminoethyl) phenol derivatives were synthesized, and their HDAC inhibitory activity was evaluated. Compounds 18 and 20 showed significant HDAC inhibitory activity of 64.94 ± 1.17% and 52.45 ± 1.45%, respectively, compared to the solvent control. The promising results of this study encourage further research on 4-(2-aminoethyl) phenol derivatives and may provide significant insight into the design of novel small molecule HDAC inhibitors to fight against target-specific malignancies of chronic obstructive pulmonary disease and nonsmall cell lung cancer in the future., (© 2023 Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Lipopolysaccharide (LPS) is a well-known agent to induce septic conditions. Sepsis-induced cardiomyopathy has an overwhelming death rate. Carvacrol (CVL), a monoterpene phenol, has anti-inflammatory and antioxidant properties. This research aimed to investigate the effect of CVL on LPS-induced dysfunction in the heart. In this study, we evaluated the effect of CVL in LPS-stimulated H9c2 cardiomyoblast cells and Balb/C mice., Main Methods: LPS was used to induce septic conditions in H9c2 cardiomyoblast cells in vitro and in Balb/C mice. A survival study was conducted to assess the survival rate of mice after LPS and/or CVL treatment., Key Findings: In vitro studies indicated that CVL inhibits reactive oxygen species (ROS) generation and abates pyroptosis mediated by NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in H9c2 cells. In mice, CVL intervention improved the survival rate in septic conditions. The CVL administration markedly improved the echocardiographic parameters and alleviated the LPS-induced reduction in the ejection fraction (%) and fraction shortening (%). The CVL intervention restored the myocardial antioxidants and histopathological alterations and decreased the pro-inflammatory cytokine contents in the heart. Further findings disclosed that CVL reduced the protein levels of NLRP3, apoptosis-associated speck-like protein (ASC), caspase 1, interleukin (IL)-18, IL-1β, and the pyroptosis-indicative protein, gasdermin-D (GSDMD) in the heart. The autophagy-indicative proteins, beclin 1 and p62 in the heart were also restored in the CVL-treated group., Significance: Altogether, our findings demonstrated that CVL has a beneficial effect and can be a potential molecule against sepsis-induced myocardial dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Groundwater is considered safe, however, the occurrence of contaminants like arsenic and fluoride has raised a major healthcare concern. Clinical studies suggested that arsenic and fluoride co-exposure induced neurotoxicity, however efforts to explore safe and effective management of such neurotoxicity are limited. Therefore, we investigated the ameliorative effect of Fisetin against arsenic and fluoride subacute co-exposure-induced neurotoxicity, and associated biochemical and molecular changes. Male BALB/c mice were exposed to Arsenic (NaAsO 2 : 50 mg/L) and fluoride (NaF: 50 mg/L) through drinking water and fisetin (5, 10, and 20 mg/kg/day) was administered orally for 28 days. The neurobehavioral changes were recorded in the open field, rotarod, grip strength, tail suspension, forced swim, and novel object recognition test. The co-exposure resulted in anxiety-like behaviour, loss of motor coordination, depression-like behaviour, and loss of novelty-based memory, along with enhanced prooxidant, inflammatory markers and loss of cortical and hippocampal neurons. The treatment with fisetin reversed the co-exposure-induced neurobehavioral deficit along with restoration of redox & inflammatory milieu, and cortical and hippocampal neuronal density. Apart from antioxidants, inhibition of TNF-α/ NLRP3 expression has been suggested as one of the plausible neuroprotective mechanisms of Fisetin in this study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Nephropathy is the most prevalent microvascular disorder in diabetes mellitus. Oxidative stress and inflammatory cascade provoked by the persistent hyperglycemic milieu play integral roles in the aggravation of renal injury and fibrosis. We explored the impact of biochanin A (BCA), an isoflavonoid, on the inflammatory response, nod-like receptor protein 3 (NLRP3) inflammasome activation, oxidative stress, and fibrosis in diabetic kidneys. A high-fat-diet/streptozotocin (HFD/STZ)-induced experimental model of diabetic nephropathy (DN) was established in Sprague Dawley rats, and in vitro studies were performed in high-glucose-induced renal tubular epithelial (NRK-52E) cells. Persistent hyperglycemia in diabetic rats was manifested by perturbation of renal function, marked histological alterations, and oxidative and inflammatory renal damage. Therapeutic intervention of BCA mitigated histological changes, improved renal function and antioxidant capacity, and suppressed phosphorylation of nuclear factor-kappa B (NF-κB) and nuclear factor-kappa B inhibitor alpha (IκBα) proteins. Our in vitro data reveal excessive superoxide generation, apoptosis, and altered mitochondrial membrane potential in NRK-52E cells that were cultured in a high-glucose (HG) environment were subsided by BCA intervention. Meanwhile, the upregulated expressions of NLRP3 and its associated proteins, the pyroptosis-indicative protein gasdermin-D (GSDMD) in the kidneys, and HG-stimulated NRK-52E cells were significantly ameliorated by BCA treatment. Additionally, BCA blunted transforming growth factor (TGF)-β/Smad signaling and production of collagen I, collagen III, fibronectin, and alfa-smooth muscle actin (α-SMA) in diabetic kidneys. Our results indicate the plausible role of BCA in attenuating DN, presumably through modulation of the apoptotic cascade in renal tubular epithelial cells and the NF-κB/NLRP3 axis.

Ethnopharmacological Relevance: Alternanthera brasiliana L. is a flowering plant belonging to the family Amaranthaceae and is popularly known as "penicillin". It is used in folk medicine to treat infections, coughs, wound healing, and inflammatory diseases., Aim of the Study: We investigated the effect of Alternanthera brasiliana L. leaves hydroalcoholic extract (AB) against oxidative stress, inflammation, and fibrotic changes in an experimental model of carbon tetrachloride (CCl 4 )-induced liver injury and fibrosis in mice., Materials and Methods: Thirty-six male Balb/C mice were randomized into five groups: normal control, AB control, CCl 4 control, CCl 4  + AB-200 mg/kg, and CCl 4  + AB-400 mg/kg. In mice, liver injury was induced by intraperitoneal injection of CCl 4 (20% in corn oil, 5 ml/kg body weight) thrice a week for six consecutive weeks. AB extract at two doses (200 mg/kg and 400 mg/kg body weight) was administered orally for six consecutive weeks. Liver injury-related serum markers (ALT, AST, ALP), antioxidants (GSH, GST, SOD, and vitamin C), pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-18, ultrasonographic and histological alterations, proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), nuclear factor-κB (p65) (NF-κB), nod-like receptor protein 3 (NLRP3), and TGF-β/Smad signaling were accessed. LC-Q-TOF-MS/MS analysis of AB was performed., Results: AB treatment significantly decreased the CCl 4 -induced rise in serum ALT, AST, and ALP activities and improved the histological alterations. Compared with the CCl 4 -treated group, treatment with AB significantly restored the hepatic antioxidants and reduced the pro-inflammatory cytokines in the liver. The antioxidant activity of AB may be attributed to its terpenoid constituents, which was confirmed by LC-Q-TOF-MS/MS analysis. The CCl 4 -induced rise in expression of MMP-2 and MMP-9 and decrease in TIMP-1 were markedly restored in the AB-treated groups. Further findings revealed a significant reduction in the protein levels of phospho-NF-κB (p65), NLRP3, TGF-β, pSmad2/3, collagen I, and α-smooth muscle actin (α-SMA) in the AB treatment groups., Conclusions: The hepatoprotective effect of AB may be attributed to the high content of terpenoid compounds and alleviates liver injury and associated fibrotic changes through modulating MMPs, NF-κB (p65), and the TGF-β/Smad axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nuciferine (NCF) is an aporphine alkaloid and a principal bioactive constituent in the lotus plant. Herewith, we investigated the potential anti-inflammatory effect and underlying mechanisms of NCF employing dextran sulfate sodium (DSS)-induced ulcerative colitis in mice, a predominant intestinal inflammatory disease, and mouse RAW 264.7 cells in vitro. Lipopolysaccharide (LPS) was used to generate an inflammatory response in the RAW 264.7 cells. The disease activity index (DAI), colon morphology, colonoscopy, and colon histopathology were performed to assess experimental colitis. The biochemical assays, enzyme-linked immunosorbent assay (ELISA), and immunoblot analysis were performed to understand the underlying mechanisms. In RAW 264.7 cells, NCF pretreatment significantly decreased the expression of inducible nitric oxide synthase (iNOS), the expression and release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α) and interfered with the activation of mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and NOD-like family pyrin domain containing 3 (NLRP3) signaling pathways. The oral treatment of NCF substantially alleviated the DSS-induced DAI, increased colon length, and restored colon morphology and histology. Compared to the DSS-induced mice, the proteins involved in the activation of MAPK/NF-κB/NLRP3 pathways and the cytokines were markedly decreased in the NCF-treated mice. Moreover, the tight junction architecture of the colon was well-maintained in NCF treatment groups by regulating the expression of claudin-1 and zonula occludens-1 (ZO-1) proteins. All these findings suggest that NCF can be a promising molecule to modulate ulcerative colitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) with diverse aetiologies is emerging as a challenging kidney disorder associated with inflammation and interstitial fibrosis. Carvacrol (CVL) is a bioactive monoterpenoid found abundantly in oregano, thyme, and bergamot, having diverse pharmacological benefits. However, the effect of CVL against fibrotic changes in the kidneys is poorly defined. In the current study, a robust mouse model of renal fibrosis induced through unilateral ureteral obstruction (UUO) is used to investigate the anti-fibrotic activity of CVL. The mice were treated with two different oral doses of CVL (25 mg kg -1 and 50 mg kg -1 body weight) for 14 consecutive days. The UUO induction resulted in impaired renal function, severe histological damage, and collagen deposition in the obstructed kidney. Our findings revealed profound activation of transforming growth factor-β1 (TGF-β1) and NF-κB (p65) signaling along with the downregulation of antioxidant proteins, nuclear factor-erythroid factor 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD) in the obstructed kidney. CVL administration markedly recovered antioxidant proteins and kidney histological changes. In addition, CVL blunted the NF-κB (p65) phosphorylation and reduced the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and cyclooxygenase 2 (COX-2) compared to the UUO control group. CVL also alleviated the increased fibrotic protein levels of TGF-β1, pSmad2/3, collagen I, collagen III, fibronectin, and myofibroblast activation and epithelial-mesenchymal transition (EMT) markers, including alpha-smooth muscle actin (α-SMA), E-cadherin, and vimentin in the kidneys. Findings from in vitro study also confirmed that CVL inhibits the EMT process in TGF-β1 stimulated renal tubular epithelial cells (NRK 52E cells). Collectively, our findings indicate that CVL administration attenuates kidney fibrosis by targeting oxidative stress and inflammation.

An outbreak of the novel beta coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first came to light in December 2019, which has unfolded rapidly and turned out to be a global pandemic. Early prognosis of viral contamination involves speedy intervention, disorder control, and good-sized management of the spread of disease. Reverse transcription-polymerase chain reaction, considered the gold standard test for detecting nucleic acids and pathogen diagnosis, provides high sensitivity and specificity. However, reliance on high-priced equipped kits, associated reagents, and skilled personnel slow down sickness detection. Lately, the improvement of clustered regularly interspaced short palindromic repeat (CRISPR)-Cas (CRISPR-associated protein)-based diagnostic systems has reshaped molecular diagnosis due to their low cost, simplicity, speed, efficiency, high sensitivity, specificity, and versatility, which is vital for accomplishing point-of-care diagnostics. We reviewed and summarized CRISPR-Cas-based point-of-care diagnostic strategies and research in these paintings while highlighting their characteristics and challenges for identifying SARS-CoV-2., (© 2022 Wiley Periodicals LLC.)

Oxidative damage and accumulation of extracellular matrix (ECM) components play a crucial role in the adverse outcome of cardiac hypertrophy. Evidence suggests that nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) can modulate oxidative damage and adverse myocardial remodeling. Daphnetin (Daph) is a coumarin obtained from the plant genus Daphne species that exerts anti-oxidative and anti-inflammatory properties. Herein, we investigated the roles of Daph in transverse aortic constriction (TAC)-induced cardiac hypertrophy and fibrosis in mice. TAC-induced alterations in cardiac hypertrophy markers, histopathological changes, and cardiac function were markedly ameliorated by oral administration of Daph in mice. We found that Daph significantly reduced the reactive oxygen species (ROS) generation, increased the nuclear translocation of Nrf2, and consequently, reinstated the protein levels of NAD(P)H quinone dehydrogenase1 (NQO1), heme oxygenase-1 (HO-1), and other antioxidants in the heart. Besides, Daph significantly inhibited the TAC-induced accumulation of ECM components, including α-smooth muscle actin (α-SMA), collagen I, collagen III, and fibronectin, and interfered with the TGF-β1/Smad2/3 signaling axis. Further studies revealed that TAC-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and the protein levels of Bax/Bcl2 ratio and cleaved caspase 3 were substantially decreased by Daph treatment. We further characterized the effect of Daph on angiotensin II (Ang-II)-stimulated H9c2 cardiomyoblast cells and observed that Daph markedly decreased the Ang-II induced increase in cell size, production of ROS, and proteins associated with apoptosis and fibrosis. Mechanistically, Daph alone treatment enhanced the protein levels of Nrf2, NQO1, and HO-1 in H9c2 cells. The inhibition of this axis by Si-Nrf2 transfection abolished the protective effect of Daph in H9c2 cells. Taken together, Daph effectively counteracted the TAC-induced cardiac hypertrophy and fibrosis by improving the Nrf2/HO-1 axis and inhibiting the TGF-β1/Smad2/3 signaling axis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Tubulointerstitial fibrosis, a frequent complication of chronic kidney disease (CKD) is a major public health issue. Biochanin A (BCA), an isoflavone, has numerous pharmacological activities. However, its effect on renal fibrosis and underlying molecular mechanism has not yet been clarified. This study explored the effect of BCA on renal tubulointerstitial fibrosis and inflammation in mice., Main Methods: The mouse model of unilateral ureteral obstruction (UUO) in vivo and transforming growth factor (TGF)-β1 activated renal fibroblast (NRK 49F) cells in vitro model were used to assess the antifibrotic effect of BCA. Biochemical analysis, histopathology, western blotting, and immunofluorescent staining methods were performed to elucidate the mechanism of BCA., Key Findings: In vitro, BCA suppressed the expression of fibrogenic proteins in TGF-β1-activated renal fibroblasts. The treatment with BCA displayed less tubular injury, prevented the aberrant accumulation of extracellular matrix (ECM) components, and inhibited the TGF-β1/Smad2/3 signaling axis in the kidneys. Furthermore, BCA impeded the phosphorylation of NF-kB(p65) and blunted the expression of inflammatory genes in the obstructed kidneys. The UUO induced expressions of nod-like receptor protein 3 (NLRP3), active caspase 1, interleukin(IL)-18, and IL-1β proteins were decreased in the BCA treated groups. We also found the increased expression of redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) proteins in BCA treated groups compared to the UUO control., Significance: These findings indicate that BCA has a therapeutic benefit against renal fibrosis, and the ameliorative effect is mediated via inhibiting the TGF-β1/Smad2/3 and NF-kB/NLRP3 signaling axis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

NLRP3 activation plays a key role in the initiation and progression of a variety of neurodegenerative diseases. However, understanding the molecular mechanisms involved in the bidirectional signaling required to activate the NLRP3 inflammasomes is the key to treating several diseases. Hence, the present study aimed to investigate the role of lipopolysaccharide (LPS) and hydrogen peroxide (H 2 O 2 ) in activating NLRP3 inflammasome-driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in in vitro and in vivo models of Parkinson's disease (PD). Initial priming of microglial cells with LPS following treatment with H 2 O 2 induced NF-κB translocation to the nucleus with a robust generation of free radicals that act as signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses the nuclear translocation of NF-κB, enhances PARKIN translocation into the mitochondria, and maintains cellular redox homeostasis in both mouse and human microglial cells that limit NLRP3 inflammasome activation along with processing of active caspase-1, IL-1β, and IL-18. To further correlate the in vitro study with the in vivo MPTP model, treatment with PA also inhibited the nuclear translocation of NF-κB and downregulated the NLRP3 inflammasome activation. PA administration upregulated various antioxidant enzymes' levels and restored the level of dopamine and other neurotransmitters in the striatum of the mouse brain, subsequently improving the behavioral activities. Therefore, we conclude that NLRP3 inflammasome activation required a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting the NLRP3 inflammasome pathway in PD.

Aims: Pathological cardiac hypertrophy is a characteristic feature in many cardiovascular diseases (CVDs). Aloin is an anthraquinone glycoside from Aloe species, and the effect of aloin on cardiac hypertrophy and associated fibrotic changes have not been elucidated. This study investigated the effect of aloin against the isoproterenol (ISO)-induced cardiac hypertrophy in rats., Main Methods: Cardiac hypertrophy experimental model was induced in rats by subcutaneous injection of ISO for 14 days. Meanwhile, the animals were administered orally with aloin at doses of 25 and 50 mg/kg/day. On the 15th day, cardiac echocardiography was performed, the heart was collected and subjected for histopathological, gene expression, and immunoblot studies. Additionally, the effect of aloin on ISO-induced hypertrophic changes in H9c2 cells was investigated., Key Findings: Aloin markedly alleviated ISO-induced heart injury, reduced cardiac hypertrophy, improved cardiac function, and histological alterations in the heart. Mechanistically, aloin attenuated ISO-induced fibrosis via inhibition of the levels of collagen I, α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor-β (TGF-β) and pSmad2/3 proteins in the heart. Aloin alleviated ISO-induced myocardial oxidative damage and up-regulated the levels of antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Moreover, aloin treatment attenuated ISO-induced hypertrophic changes and the generation of reactive oxygen species (ROS) in H9c2 cells in vitro., Significance: Our findings demonstrated that aloin alleviated ISO-induced cardiac hypertrophy and fibrosis via inhibiting TGF-β/pSmad2/3 signaling and restoring myocardial antioxidants, and therefore has promising therapeutic potential against cardiac hypertrophy and fibrosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Plant-based drugs have a significant impact on modern therapeutics due to their vast array of pharmacological activities. The integration of herbal plants in the current healthcare system has emerged as a new field of research. It can be used for the identification of novel lead compound candidates for future drug development. Nootkatone is a sesquiterpene derivative and an isolate of grapefruit. Shreds of evidence illustrate that nootkatone targets few molecular mechanisms to exhibit its pharmacological activity and yet needs more exploration. The current review is related to nootkatone, drafted through a literature search using research articles and books from different sources, including Science Direct, Google Scholar, Elsevier, PubMed, and Scopus. It has been reported to possess a wide range of pharmacological activities such as anti-inflammatory, anticancer, antibacterial, hepatoprotective, neuroprotective, and cardioprotective. Although preclinical studies in experimental animal models suggest that nootkatone has therapeutic potential, it is further warranted to evaluate its toxicity and pharmacokinetic parameters before being applied to humans. Hence, in the present review, we have summarized the scientific knowledge on nootkatone with a particular emphasis on its pharmacological properties to encourage researchers for further exploration in preclinical and clinical settings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chronic kidney disease (CKD) with underlying interstitial fibrosis is often associated with end-stage renal disease (ESRD). In the present study, we investigated the renoprotective and antifibrotic potential of nootkatone (NTK), a bioactive sesquiterpene, in an experimental model of renal fibrosis. Unilateral ureteral obstruction (UUO) model was performed to induce renal fibrosis in Balb/C mice. The animals were randomly assigned into 5 groups: sham, NTK control, UUO control, UUO and NTK 5 mg/kg, and UUO and NTK 10 mg/kg. Animals received NTK at a dose of 5 mg/kg and 10 mg/kg orally for the next 14 consecutive days. UUO induced histological alterations, accumulation of extracellular matrix (ECM) components including collagens, fibronectin, and alpha-smooth muscle actin (α-SMA), activation of the transforming growth factor-β (TGF-β)/Smad signaling and oxidative damage in the obstructed kidneys. Our study revealed that NTK (10 mg/kg) inhibits UUO mediated kidney fibrosis in vivo. Administration of NTK (10 mg/kg) prevented the activation of the TGF-β/Smad signaling, expression of ECM components, markedly attenuated the renal tubular injury and fibrosis area (% area: 6.66 ± 1.45% vs UUO: 26.33 ± 2.90%). Administration of NTK at 10 mg/kg significantly restored the endogenous antioxidants and prevented the reactive oxygen species generation (25.31 ± 1.65% vs UUO: 45.01 ± 4.85%) and reduced the level of tumor necrosis factor (TNF)-α (95.22 ± 12.39 vs UUO: 215.57 ± 60.45 pg/mg protein) in the kidneys. Altogether, our findings suggest that NTK might be a budding therapeutic candidate for renal fibrosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Zanthoxylum alatum (ZA) Roxb (family: Rutaceae) plant has been traditionally used for multiple indications by local healers among different communities of South Asian countries mainly in India and Bangladesh. The extracts of ZA have reported strong anti-inflammatory and anti-oxidant activities, but no scientific report is available on its efficacy in intestinal inflammatory disorders like ulcerative colitis., Aim of the Study: The overall objective of our study was to evaluate the anti-inflammatory potency of hydro-ethanolic extract of Zanthoxylum alatum seed (ZAHA) using both in-vitro NF-κB-luciferase translocation assay and in-vivo stress aggravated dextran sodium sulfate (DSS)-induced ulcerative colitis model., Materials and Methods: The in-vitro anti-inflammatory effect of ZAHA extract was evaluated by luciferase assay in HEK293 cells. Parameters such as body weights, behavioural, colonoscopy, colon lengths and spleen weights were measured and recorded in stress aggravated DSS-induced colitis model in C57BL/6 mice. Biochemical, histological and immunoblot analysis in the colon tissues were determined to prove its anti-inflammatory and anti-oxidant activities. Characterization of the extract was done by LC-MS/MS study., Results: Initial in vitro NF-κB-luciferase translocation assay showed that the hydroalcoholic extract of ZA (ZAHA) showed potent inhibitory activity for NF-κB translocation by TNF-α stimulation and hence this particular extract was further evaluated in stress aggravated DSS-induced ulcerative colitis model in C57BL/6 mice. Treatment of ZAHA for two weeks at a dose of 200 mg/kg significantly ameliorated the stress aggravated DSS-induced colitis in mice. Histological alterations, infiltration of inflammatory cells, and the levels of IL-1β, IL-6, TNF-α in colon tissue and serum samples were significantly decreased in ZAHA treatment groups compared to the stress aggravated DSS induced colitis animals. Moreover, the protein expressions of p-NF-κB, p-IκBα, p-STAT3, COX-2, and TNF-α were significantly reduced in colon tissues of ZAHA treated groups and also increased anti-oxidant markers like SOD-1, Nrf2 significantly when compared with disease control group. Characterization of the extract further by LC-MS/MS revealed the presence of several active compounds which could be responsible for its anti-inflammatory activity., Conclusions: Thus from the above findings it can be concluded that ZAHA ameliorates stress aggravated DSS-induced ulcerative colitis due to its anti-inflammatory and anti-oxidant activity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cardiovascular diseases (CVDs) are an ever-growing problem and are the most common cause of death worldwide. The uncontrolled production of reactive oxygen species (ROS) and the activation of ROS associated with various cell signaling pathways with oxidative cellular damage are the most common pathological conditions connected with CVDs including endothelial dysfunction, hypercontractility of vascular smooth muscle, cardiac hypertrophy and heart failure. The nuclear factor E2-related factor 2 (Nrf2) is a basic leucine zipper redox transcription factor, together with its negative regulator, kelch-like ECH-associated protein 1 (Keap1), which serves as a key regulator of cellular defense mechanisms to combat oxidative stress and associated diseases. Multiple lines of evidence described here support the cardiac protective property of Nrf2 in various experimental models of cardiac related disease conditions. In this review, we emphasized the molecular mechanisms of Nrf2 and described the detailed outline of current findings on the therapeutic possibilities of the Nrf2 activators specifically from herbal origin in various CVDs. Based on evidence from various preclinical experimental models, we have highlighted the activation of Nrf2 pathway as a budding therapeutic option for the prevention and treatment of CVDs, which needs further investigation and validation in the clinical settings., (© 2021 John Wiley & Sons Ltd.)

A growing body of literature has recognized the non-thermal effect of pulsed microwave radiation (PMR) on bacterial systems. However, its mode of action in deactivating bacteria has not yet been extensively investigated. Nevertheless, it is highly important to advance the applications of PMR from simple to complex biological systems. In this study, we first optimized the conditions of the PMR device and we assessed the results by simulations, using ANSYS HFSS (High Frequency Structure Simulator) and a 3D particle-in-cell code for the electron behavior, to provide a better overview of the bacterial cell exposure to microwave radiation. To determine the sensitivity of PMR, Escherichia coli and Staphylococcus aureus cultures were exposed to PMR (pulse duration: 60 ns, peak frequency: 3.5 GHz) with power density of 17 kW/cm 2 at the free space of sample position, which would induce electric field of 8.0 kV/cm inside the PBS solution of falcon tube in this experiment at 25 °C. At various discharges (D) of microwaves, the colony forming unit curves were analyzed. The highest ratios of viable count reductions were observed when the doses were increased from 20D to 80D, which resulted in an approximate 6 log reduction in E. coli and 4 log reduction in S. aureus. Moreover, scanning electron microscopy also revealed surface damage in both bacterial strains after PMR exposure. The bacterial inactivation was attributed to the deactivation of oxidation-regulating genes and DNA damage.

Acute kidney injury (AKI) is a progressive renal complication which significantly affects the patient's life with huge economic burden. Untreated acute kidney injury eventually progresses to a chronic form and end-stage renal disease. Although significant breakthroughs have been made in recent years, there are still no effective pharmacological therapies for the treatment of acute kidney injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response plays a pivotal role in the pathogenesis of acute kidney injury. The expression of TLR4 has been seen in resident renal cells, including podocytes, mesangial cells, tubular epithelial cells and endothelial cells. Activation of TLR4 signaling regulates the transcription of numerous pro-inflammatory cytokines and chemokines, resulting in renal inflammation. Therefore, targeting TLR4 and its downstream effectors could serve as an effective therapeutic intervention to prevent renal inflammation and subsequent kidney damage. For the first time, this review summarizes the literature on acute kidney injury from the perspective of TLR4 from year 2010 to 2020. In the current review, the role of TLR4 signaling pathway in AKI with preclinical evidence is discussed. Furthermore, we have highlighted several compounds of natural and synthetic origin, which have the potential to avert the renal TLR4 signaling in preclinical AKI models and have shown protection against AKI. This scientific review provides new ideas for targeting TLR4 in the treatment of AKI and provides strategies for the drug development against AKI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diabetes mellitus is an increasingly prevalent disease around the globe. The epidemic of diabetes mellitus and its complications pretenses the foremost health threat globally. Diabetic nephropathy is the notable complication in diabetes, leading to end-stage renal disease (ESRD) and premature death. Abundant experimental evidence indicates that oxidative stress and inflammation are the important mediators in diabetic kidney diseases and interlinked with various signal transduction molecular mechanisms. Inflammasomes are the critical components of innate immunity and are recognized as a critical mediator of inflammation and autoimmune disorders. NOD-like receptor protein 3 (NLRP3) inflammasome is the well-characterized protein and it exhibits the sterile inflammation through the regulation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 production in tissues. In recent years, the role of NLRP3 inflammasome in the pathophysiology of diabetic kidney diseases in both clinical and experimental studies has generated great interest. In the current review, we focused on and discussed the role of NLRP3 inflammasome in diabetic nephropathy. A literature review was performed using online databases namely, PubMed, Scopus, Google Scholar and Web of science to explore the possible pharmacological interventions that blunt the NLRP3 inflammasome-caspase-1-IL-1β/IL-18 axis and shown to have a beneficial effect in diabetic kidney diseases. This review describes the inhibition of NLRP3 inflammasome activation as a promising therapeutic target for drug discovery in future., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Inflammatory bowel disease is an umbrella-term used to describe a set of chronic inflammatory conditions that affect the gastro-intestinal tract. Since most of the inflammatory medications in current use have several undesirable side-effects, stevioside, a naturally occurring, high-intensity sweetener was assessed in our study for its anti-inflammatory properties by in-vitro and in-vivo experiments. Stevioside was observed to significantly inhibit the levels of LPS induced elevation of cytokines, TNF-α (P < 0.05) and IL-6 (P < 0.001) as well as the production of reactive oxygen species (P < 0.01) and nitrites (P < 0.001) in RAW264.7 cells. Stevioside has also been evaluated for its anti-inflammatory effect by using dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice. Stevioside significantly reduced the disease activity index (DAI) score, ameliorated the inflammatory symptoms induced by DSS in mice and exhibited intact colon histo-architecture. Stevioside treatment significantly inhibited the levels of pro-inflammatory cytokines, TNF-α and IL-6, and the protein expressions of pro-inflammatory mediators, COX-2 (P < 0.01) and iNOS (P < 0.01) and restored the levels of endogenous anti-oxidants such as superoxide dismutase (P < 0.01), catalase (P < 0.001), glutathione s-transferase (P < 0.001) and reduced glutathione (P < 0.001) level in colon tissues. It was also observed that stevioside significantly suppressed NF-κB (p65) activation by abrogating IκB phosphorylation and attenuated the phosphorylation of p38, ERK and JNK proteins in colon tissues. The findings of the present study suggest that stevioside exhibits anti-inflammatory property by inhibiting NF-κB (p65) and MAPK pathways and can be employed as an adjunct in nutraceuticals to treat IBD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dietary supplementation of oats has been associated with reduced risk of cardiovascular disease, diabetes, and gastrointestinal disorders. The role of oat extract as prophylactic in treating acute liver injury is not thoroughly established. We, therefore, hypothesized that oat extract would exert protective effect against alcohol-induced acute liver injury in a mouse model. To test this hypothesis, male C57BL/6 mice were pretreated with phenolic-enriched ethyl acetate (EA) fraction of oats (prepared by fractionating aqueous ethanolic extract with solvents of increasing polarity) at dosages of 125 and 250 mg kg -1 d -1 for 12 consecutive days. Acute liver injury was induced by administering 5 doses of 50% ethanol intragastrically (10 g/kg body weight) to mice at an interval of 12 hours. The alcohol-induced liver injury was evaluated by measuring serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, antioxidant parameters, mitochondrial function, and histology of liver tissue. Our results demonstrated that pretreatment with EA fraction at 250 mg kg -1 d -1 significantly (P < .001 for aspartate aminotransferase, alanine aminotransferase, and thiobarbituric acid-reactive species and P < .01 for lactate dehydrogenase and nitrites) reduced the levels of liver injury markers and significantly (P < .001 for glutathione reductase and glutathione S-transferase; P < .01 for catalase, superoxide dismustase, and vitamin C; P < .05 for reduced glutathione and NAD(P)H quinone dehydrogenase 1) increased the levels of antioxidant defenses. Furthermore, EA-pretreated mice showed mechanistic inhibition of nuclear factor κB signaling pathway through decreased phosphorylation and degradation of IκBα. We conclude that phenolic-enriched EA fraction of oats has immense potential to serve as dietary intervention against alcohol-induced liver damage., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alcohol, the most common cause for hepatic injury, may further deteriorate the hepatic tissue when left unattended. Capsaicin, the pungent principle of chilli peppers, possesses antioxidant and anti-inflammatory properties and is a proven dietary antioxidant in various ailments. However, its role in alcohol-induced hepatic injury is unclear. In this study, we investigated the effects of capsaicin on the hepatic tissue of mice treated with alcohol. Acute liver injury was induced in mice by oral gavage of 5 doses of 10 mL/kg of 50% ethyl alcohol at an interval of 12 h. The tissue antioxidant levels along with the mitochondrial functional parameters and matrix metalloproteinase levels were evaluated in the hepatic tissues of mice following alcohol challenge. The results showed that alcohol intake significantly attenuated the hepatic antioxidant levels and mitochondrial function. These changes were accompanied by enhanced serum hepatic injury markers and matrix metalloproteinases. However, capsaicin treatment (10 and 20 mg/kg, oral) throughout the experimental period caused a drastic improvement in the hepatic tissue of the alcohol-treated mice, reflected by the normalization of hepatic enzyme and protein levels along with restored histological alterations. These results indicate that capsaicin, as a dietary intervention, may prevent alcohol-induced acute liver injury.

Background: Alcohol, a most commonly consumed beverage, is the foremost cause of liver injury throughout the world. Polydatin, a stilbenoid glucoside, was known to possess antioxidant and anti-inflammatory properties and is being investigated for use in various disorders., Purpose: The present study was intended at investigating the hepatoprotective efficacy of polydatin against acute-alcohol induced liver injury model in mice., Study Design: C57BL/6 mice were fed with five doses of 50% ethyl alcohol (10ml/kg body weight) to induce acute liver injury. Effect of polydatin against alcohol induced hepatic injury was investigated by giving 50 or 100mg/kg polydatin, orally, for 8 days., Methods: Serum markers of liver injury, morphology, histology and fibrosis of liver tissue, levels of enzymatic and non-enzymatic antioxidants and the mitochondrial respiratory enzyme activities in liver tissue were investigated. The activities and the protein expression of matrix metalloproteinases (MMP-2 and -9), the expression of NF-κB in the liver tissue were also studied., Results: Polydatin pre-treatment significantly alleviated the alcohol induced hepatic injury by reducing the serum liver injury markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), attenuating oxidative stress and restoring antioxidant balance in the hepatic tissue. Simultaneously, polydatin pre-treatment also prevented alcohol induced mitochondrial damage and refurbished the matrix metalloproteinases levels of the hepatic tissue., Conclusion: The findings of the present study suggest that polydatin may have a potential benefit in preventing alcohol-induced acute hepatic injury., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Aim: The study was conducted to evaluate the attribution of antibacterial and antioxidant activity of methanolic extract of Cassia tora toward its growth promoting effect in broiler birds., Materials and Methods: A limit test was conducted for C. tora extract in Wistar albino rats. Phytochemical screening of methanolic extract of leaves of C. tora was carried out. In-vitro antibacterial activity was measured by disc diffusion method. 1-day-old Ven Cobb broiler birds (n=90) were randomly allocated into three groups consisting of three replicates with 10 birds in each group. The birds of group T1 (Control) received basal diet, whereas birds of group T2 (Standard) received an antibiotic (Lincomycin at 0.05% in feed). The birds of group T3 (Test) received Cassia tora extract (CSE) at 0.4 g/L in drinking water in addition to basal diet. The treatment was given to birds of all the groups for 6 weeks. Antioxidant activity of C. tora was determined in blood of broiler birds. Cumulative body weight gain, feed intake, feed conversion ratio (FCR), dressing percent, and organ weight factor were evaluated to determine growth performance in broiler birds., Results: Phytochemicals in C. tora were screened. Sensitivity to Escherichia coli and resistant to Staphylococcus aureus and Pseudomonas aeruginosa was observed in in-vitro antibacterial activity test. At the end of 6 th week, antioxidant activity reflected significantly (p≤0.05) lower level of erythrocyte malondialdehyde and higher levels of reduced glutathione (GSH) and GSH peroxidase in broiler birds of group T2 and T3 as compared to broiler of group T1. Mean cumulative body weight gain of birds of T2 and T3 were significantly (p≤0.05) higher as compared to T1. Mean FCR of birds of group T3 decreased significantly than group T1., Conclusion: Supplementation of C. tora leaves extract at 0.4 g/L in drinking water improved growth performance in broiler birds due to its antimicrobial and antioxidant activity. Therefore, it could be used as an alternative to antibiotic growth promoter in poultry ration.

We investigated the anti-inflammatory and anti-colitis effects of Rosmarinus officinalis L. extract (RE) by using both in vitro LPS-activated mouse RAW 264.7 macrophages and in vivo dextran sulfate sodium (DSS)-induced experimental murine colitis and suggested the underlying possible mechanisms. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis was performed to identify the major components present in the RE. The clinical signs, biochemistry, immunoblot, ELISA and histology in colon tissues were assessed in order to elucidate the beneficial effect of RE. RE suppressed the LPS-induced pro-inflammatory cytokine production and the expressions of inflammatory proteins in macrophages. Administration of RE (50 and 100 mg kg(-1)) also significantly reduced the severity of DSS-induced murine colitis, as assessed by the clinical symptoms, colon length and histology. RE administration prevented the DSS-induced activation of p38, ERK and JNK MAPKs, attenuated IκBα phosphorylation and subsequent nuclear translocation and DNA binding of NF-κB (p65). RE also suppressed the COX-2 and iNOS expressions, decreased the levels of TNF-α and IL-6 cytokines and the myeloperoxidase activity in the colon tissue. Histological observation revealed that RE administration alleviated mucosal damage and inflammatory cell infiltration induced by DSS in the colon tissue. Hence, RE could be used as a new preventive and therapeutic food ingredient or as a dietary supplement for inflammatory bowel disease.

Fisetin, a dietary flavonoid, is commonly found in many fruits and vegetables. Although studies indicate that fisetin has an anti-inflammatory property, little is known about its effects on intestinal inflammation. The present study investigated the effects of the fisetin on dextran sulphate sodium (DSS)-induced murine colitis, an animal model that resembles human inflammatory bowel disease. Fisetin treatment to DSS-exposed mice significantly reduced the severity of colitis and alleviated the macroscopic and microscopic signs of the disease. Moreover, fisetin reduced the levels of myeloperoxidase activity, the production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) and the expressions of COX-2 and iNOS in the colon tissues. Further studies revealed that fisetin suppressed the activation of NF-κB (p65) by inhibiting IκBα phosphorylation and NF-κB (p65)-DNA binding activity and attenuated the phosphorylation of Akt and the p38, but not ERK and JNK MAPKs in the colon tissues of DSS-exposed mice. In addition, DSS-induced decline in reduced glutathione (GSH) and the increase in malondialdehyde (MDA) levels were significantly restored by oral fisetin. Furthermore, the results from in vitro studies showed that fisetin significantly reduced the pro-inflammatory cytokine and mediator release and suppressed the degradation and phosphorylation of IκBα with subsequent nuclear translocation of NF-κB (p65) in lipopolysaccharide (LPS)-stimulated mouse primary peritoneal macrophages. These results suggest that fisetin exerts anti-inflammatory activity via inhibition of Akt, p38 MAPK and NF-κB signaling in the colon tissues of DSS-exposed mice. Thus, fisetin may be a promising candidate as pharmaceuticals or nutraceuticals in the treatment of inflammatory bowel disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Doxorubicin is a widely used anthracycline derivative anticancer drug. Unfortunately, the clinical use of doxorubicin has the serious drawback of cardiotoxicity. In this study, we investigated whether baicalein, a bioflavonoid, can prevent doxorubicin-induced cardiotoxicity in vivo and we delineated the possible underlying mechanisms., Main Methods: Male BALB/c mice were treated with either intraperitoneal doxorubicin (15 mg/kg divided into three equal doses for 15 days) and/or oral baicalein (25 and 50 mg/kg for 15 days). Serum markers of cardiac injury, histology of heart, parameters related to myocardial oxidative stress, apoptosis and inflammation were investigated., Key Findings: Treatment with baicalein reduced doxorubicin-induced elevation of serum creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and ameliorated the histopathological damage. Baicalein restored the doxorubicin-induced decrease in both enzymatic and non-enzymatic myocardial antioxidants and increased the myocardial expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Further studies showed that baicalein could inverse the Bax/Bcl-2 ratio, suppress doxorubicin-induced p53, cleaved caspase-3 and PARP expression and prevented doxorubicin-induced DNA damage. Baicalein treatment also interferes with doxorubicin-induced myocardial NF-κB signaling through inhibition of IκBα phosphorylation and nuclear translocation of p65 subunit. Doxorubicin elevated iNOS and nitrites levels were also significantly decreased in baicalein treated mice. However, we did not find any significant change (p>0.05) in the myocardial TNF-α and IL-6 levels in control and treated animals., Significance: Our finding suggests that baicalein might be a promising molecule for the prevention of doxorubicin-induced cardiotoxicity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Ulcerative colitis is associated with a considerable reduction in the quality of life of patients. The use of phyto-ingredients is becoming an increasingly attractive approach for the management of colitis. Geraniol is a monoterpene with anti-inflammatory and antioxidative properties. In this study, we investigated the therapeutic potential of geraniol as a complementary and alternative medicine against dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Disease activity indices (DAI) comprising body weight loss, presence of occult blood and stool consistency were assessed for evaluation of colitis symptoms. Intestinal damage was assessed by evaluating colon length and its histology. Pre-treatment with geraniol significantly reduced the DAI score, improved stool consistency (without occult blood) and increased the colon length. The amount of pro-inflammatory cytokines, specifically TNF-α, IL-1β and IL-6 and the activity of myeloperoxidase in colon tissue were significantly decreased in geraniol pre-treated mice. Western blot analyses revealed that geraniol interfered with NF-κB signaling by inhibiting NF-κB (p65)-DNA binding, and IκBα phosphorylation, degradation and subsequent increase in nuclear translocation. Moreover, the expressions of downstream target pro-inflammatory enzymes such as iNOS and COX-2 were significantly reduced by geraniol. Pre-treatment with geraniol also restored the DSS-induced decline in antioxidant parameters such as reduced glutathione and superoxide dismutase activity and attenuated the increase in lipid peroxidation marker, thiobarbituric acid reactive substances and nitrative stress marker, nitrites in colon tissue. Thus, our results suggest that geraniol is a potential therapeutic agent for inflammatory bowel disease.

Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

Myocardial oxidative stress leading to apoptosis and remodeling is the major consequence of ischemic heart disease. In the present study, we investigated the effect of Lagerstroemia speciosa L. leave (LS) extract containing 1 % corosolic acid in the context of cardiovascular disorder by using isoproterenol (ISO)-induced myocardial injury mouse model. Serum was analyzed for specific cardiac injury biomarkers. Cardiac tissue was examined for lipid peroxidation, protein carbonyl content, antioxidant (GSH, GR, GPx, GST, SOD, CAT, NQO1, and HO-1), and apoptosis (cleaved caspase-3, Bax, Bcl-2, p53, and DNA fragmentation) status. Myocardial protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in different experimental groups was evaluated. Pathological changes in heart tissue and activities of matrix metalloproteinases (MMPs) were also analyzed. Our results demonstrated that LS pretreatment augmented myocardial antioxidant status and attenuated myocardial oxidative stress. Myocardial apoptosis as well as MMPs activities was significantly prevented by LS pretreatment in ISO-induced mice. In addition, the immunoblot of Nrf2 revealed that LS pretreatment enhanced the nuclear protein expression of Nrf2 when compared to ISO control group. Thus, the overall results indicate that LS has cardioprotective effect and may prevent the myocardial stress by suppressing apoptosis through up-regulation of myocardial antioxidant levels.

Nephrotoxicity is a major adverse effect of chromium poisoning. In the present study, we investigated the potential renoprotective effect and underlying mechanisms of carvedilol, a non-specific β-adrenergic blocker using rat model of potassium dichromate-induced nephrotoxicity. Rats were pretreated with carvedilol (10mg/kg) for 21days. A single subcutaneous injection of potassium dichromate (15mg/kg, s.c.) resulted in a significant increase in the levels of blood urea nitrogen and serum creatinine, markers related to oxidative stress, nitrosative stress, apoptosis and inflammation accompanied with histopathological changes in kidney tissues. Exploration of the underlying renoprotective mechanisms of carvedilol revealed that carvedilol attenuated nuclear translocation and DNA binding activity of NF-κB (p65) in kidney tissues. The serum levels of TNF-α and the renal expression of iNOS and tissue nitrites were significantly decreased in carvedilol plus potassium dichromate administered rats. Carvedilol pretreatment significantly attenuated the potassium dichromate-induced DNA damage, decreased the p53, Bax and cleaved caspase-3 expression and increased the Bcl-2 expression. Moreover, pretreatment with carvedilol significantly restored the renal tissue antioxidant and mitochondrial respiratory enzyme activities and decreased the elevated lipid peroxidation biomarkers to normal. These results were further supported and confirmed by histopathological findings. In conclusion, the findings of the present study demonstrated that carvedilol is an effective chemoprotectant against potassium dichromate-induced nephrotoxicity in rats., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

Carnosic acid is a well-known antioxidant. Recently, it has been identified as modulator of nuclear factor erythroid 2-related factor 2 (Nrf2). The effect of carnosic acid in the context of cardiovascular disorders has not been studied. In the present study, we investigated the beneficial effect and the underlying cardioprotective mechanism of carnosic acid by using mouse model of isoproterenol (ISO)-induced myocardial stress. Elevated serum levels of Troponin I, CK-MB, LDH, SGOT and SGPT, and myofibrillar degeneration with necrotic damage, and the presence of epicardial inflammatory infiltrate (H & E staining) confirmed the ISO-induced myocardial stress. Myocardial content of vitamin C, reduced glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase,, Nad(p)h: quinine oxidoreductase 1, superoxide dismutase, catalase, nuclear translocation of Nrf2 and protein expression heme oxygenase-1 were evaluated. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and myocardial expression of cleaved caspase-3, caspase-9, p53, Bax, and Bcl-2 were investigated to assess the apoptotic cell death. Pretreatment with carnosic acid attenuated ISO-induced elevated serum levels of Troponin I, CK-MB, LDH, SGOT and SGPT, and histopathological alterations in heart. Moreover, carnosic acid enhanced the nuclear translocation of Nrf2 and up-regulated the phase II/antioxidant enzyme activities. Furthermore, TUNEL assay and apoptosis-related protein analysis indicated that carnosic acid prevented ISO-induced cardiomyocyte apoptosis. Isoproterenol-induced myocardial lipid peroxidation and protein oxidation were also significantly decreased by carnosic acid pretreatment. The overall results clearly indicate that therapeutic application of carnosic acid might be beneficial in treating cardiovascular disorders.

Aims: Preventive and/or therapeutic interventions using natural products for ischemic heart disease have gained considerable attention worldwide. This study investigated the cardioprotective effect and possible mechanism of embelin, a major constituent of Embelia ribes Burm, using isoproterenol (ISO)-induced myocardial infarction model in rats., Materials and Methods: Rats were pretreated for three days with embelin (50mg/kg, p.o) before inducing myocardial injury by administration of ISO (85 mg/kg) subcutaneously at an interval of 24h for 2 consecutive days. Serum was analyzed for cardiac specific injury biomarkers, lipids and lipoprotein content. Heart tissues were isolated and were used for histopathology, antioxidant and mitochondrial respiratory enzyme activity assays and western blot analysis., Key Findings: Results showed that pretreatment with embelin significantly decreased the elevated levels of serum specific cardiac injury biomarkers (CK-MB, LDH and AST), serum levels of lipids and lipoproteins and histopathological changes when compared to ISO-induced controls. Exploration of the underlying mechanisms of embelin action revealed that embelin pretreatment restored the myocardial mitochondrial respiratory enzyme activities (NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity), strengthened antioxidant status and attenuated ISO-induced myocardial lipid peroxidation. Immunoblot analysis revealed that embelin interrupted mitochondria dependent apoptotic damage by increasing the myocardial expression of Bcl-2 and downregulating the expression of Bax, cytochrome c, cleaved-caspase-3 & 9 and PARP. Histopathology findings further strengthened the cardioprotective findings of embelin., Significance: Result suggested that embelin may have a potential benefit in preventing ischemic heart disease like myocardial infarction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The present study was aimed at investigating the effect of curcumin in combination with prednisolone for the effective treatment of arthritis with reduced side effects when glucocorticoids therapy is indicated., Methods: Arthritis was induced in wistar rats by subplantar injection of Freund's complete adjuvant, and animals were observed for the symptoms of arthritis during the period of 21 days. Combined treatment of curcumin with various doses of prednisolone (1.25, 2.5 and 5 mg/kg) was evaluated in order to ascertain the efficacy and toxicity induced by steroid., Key Findings: Arthritic animals showed significant increase in tumour necrosis factor-α and IL-1β levels in paw tissue and IL-1β in serum. Combined therapy of curcumin with low doses of prednisolone showed pronounced beneficial effect on joint swelling, leucocyte count and biochemical parameters compared with prednisolone groups. Among the different doses used in the study, prednisolone at 1.25 mg/kg in combination with curcumin showed beneficial anti-arthritic activity and also reduced the steroid toxicity. This is evidenced by increase in body weight, low toxicity to immune organs, reduction in leucocyte count, increase in spleen anti-oxidant enzymes and potent inhibition of cytokines in combination group., Conclusion: Therefore, combined treatment of curcumin with low doses of prednisolone may find therapeutic use in arthritis., (© 2013 Royal Pharmaceutical Society.)

The aim of the study was to investigate the potential protective effect of ethanolic extract of Boswellia ovalifoliolata (BO) bark and leaf against doxorubicin (DOX)-induced cardiotoxicity in mice. Ethanolic extracts of BO bark (400 mg/kg) and leaves (250 mg/kg) were given orally to mice for 9 consecutive days and DOX (15 mg/kg; i.p.) was administered on the seventh day. Extract protected against DOX-induced ECG changes. It significantly inhibited DOX-provoked glutathione depletion and accumulation of malondialdehyde. The decrease in antioxidant enzyme activities of catalase, superoxide dismutase, glutathione peroxidase in cardiac tissue were significantly (p<0.05) mitigated after treatment with BO bark and leaf extracts. Pretreatment with BO significantly (p<0.05) restored the levels of DOX-induced rise of SGPT, SGOT, serum lactate dehydrogenase and creatine kinase-MB levels. These findings suggest that ethanolic extract of BO has protective effects against DOX-induced cardiotoxicity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy., (Copyright © 2013 Elsevier GmbH. All rights reserved.)