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Background: Liver fibrosis is a chronic pathological condition with a leading cause of liver-related mortality worldwide. In the present study, we have evaluated the antifibrotic effect of crocin, a carotenoid present in the stigma of Crocus sativus, and also explored its putative mechanism of action. Methods: Liver fibrosis was induced by intraperitoneal administration of 30% carbon tetrachloride (CCl4). The crocin was administered orally at 20, 40 and 80 mg/kg body weight along with CCl4 up to 8 weeks. Results: Chronic exposure to CCl4 resulted in elevated levels of liver enzymes and reduced cytochrome P450 2E1 (CYP2E1) activity in the liver. The liver tissue showed cellular swelling, vacuolization, necrosis, infiltration of inflammatory cells and fibrotic changes. The crocin treatment significantly lowered the levels of liver enzymes in serum and improved the liver CYP2E1 mRNA levels. The pathological changes in the liver were also lowered by crocin treatment. The level of pro-inflammatory cytokines, nuclear factor-kappa B, interleukin-6 and tumor necrosis factor α and fibrogenic factor, transforming growth factor β, and α-smooth muscle actin were elevated by the CCl4 in the liver tissue. However, crocin treatment at different doses significantly reduced the expression of these factors. The increased caspase 3/7 activity was also lowered by crocin. CCl4 administration decreased the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) in liver tissue. The improved PPAR-γ expression in the liver by crocin treatment indicates its role in the therapeutic effect of crocin. Conclusions: Crocin attenuated the various events in the progression of liver fibrosis via PPAR-γ mediated modulation of inflammatory and fibrogenic pathways. [ABSTRACT FROM AUTHOR]

The potential of thidiazuron (1-phenyl-3-(1, 2, 3-thiadiazol-5-yl) urea (TDZ) in the micropropagation ofPicrorhiza kurroa, a western Himalayan herb was studied. The roots and rhizomes of this plant are rich in medicinally important glycosides i.e., picroside I, picroside II and kutkoside. Nodal segments (2.0–2.5 cm) from plants were pretreated with 0, 0.25, 0.50, 0.75, 1.0 μM TDZ for 7, 15 and 30 days. Maximum shoot multiplication was recorded after 60 days, provided, the nodal segments pretreated with 0.5 μM TDZ for 15 days were transferred to 0.8% agar gelled MS medium containing 3.0% sucrose. The shoots also showed profuse rooting having maximum length. When these plantlets were incubated at 15°C for 10 days and transferred to sand under polyhouse conditions, 100% survival was recorded after one month. In contrast, when the plantlets were not incubated at 15°C, only 86% survival was recorded. While the stomata and chlorophyll content of the tissue culture-raised plantlets treated at 15°C were comparable to that of plants growing in the field, the ones that were not treated at 15°C showed lower number of stomata and chlorophyll content. [ABSTRACT FROM PUBLISHER]

The Himalayan plant Inula racemosa has medicinal properties and can be used to prevent or treat cancer. This is because it contains certain chemicals that are known to fight cancer cells with few or no side effects. I. racemosa has been used for this purpose for many years in traditional medicine and has shown promising results. The present study was crafted to explore the suppressive impacts on cellular proliferation of the root extract derived from I. racemosa via in vivo experimentation. I. racemosa (IR) root extract was tested at three different doses (100, 250, and 500 mg/Kg BW) for 18 weeks to assess its anti-neoplastic activity against mammary tumors in female rats. The assessment included various parameters such as hematological and biochemical indices, tumor parameters, oxidative stress analysis, gross and histopathological lesion determination, Masson's trichrome staining, immunohistochemical expression of Ki-67, MMP-9, and VEGF in mammary gland tissues, and molecular docking. The chemopreventive action of IR root extract was demonstrated by the inhibition of tumor parameters (tumor size and tumor volume), minimum changes in the liver (ALT, AST, and ALP) and kidney enzymes (BUN and creatinine), declined lipid peroxidation activity, decline gross, and histological changes in mammary gland tumors, reduced expression of KI-67, MMP-9, and VEGF and maximum binding affinity of isoalantolactone with VEGF through molecular docking. The study suggests that the active constituents (isoalantolactone and alantolactone) of I. racemosa roots have anti-neoplastic activity against mammary tumors, making them a valuable therapeutic regimen for the future., (© 2024 Wiley Periodicals LLC.)

Malnutrition is a public health epidemic mainly targeting poverty-stricken people, young ones, older people, pregnant women, and individuals with metabolic disorders. Severe malnutrition is linked with several metabolic defects, such as hepatic dysfunction, hypertension, cardiovascular disease, and osteoarthritis. The proper functioning of the liver plays a crucial role in ensuring the supply of nutrients to the body. Consequently, inadequate nutrition can lead to severe periportal hepatic steatosis due to compromised mitochondrial and peroxisome functions. Reduced protein intake disrupts essential metabolic processes like the TCA cycle, oxidative phosphorylation, and β-oxidation, ultimately affecting ATP production. Furthermore, this can trigger a cascade of events, including disturbances in amino acid metabolism, iron metabolism, and gut microbiota, which activate genes involved in de novo lipogenesis, leading to the accumulation of lipids in the liver. The condition, in prolonged cases, progresses to steatohepatitis and liver fibrosis. Limited therapeutic solutions are available; however, few dietary supplements and drugs have demonstrated positive effects on the growth and health of malnourished individuals. These supplements improve parameters such as inflammatory and oxidative status, reduce triglyceride accumulation, enhance insulin sensitivity, and downregulate gene expression in hepatic lipid metabolism. This review elucidates the various mechanisms involved in malnutrition-associated steatohepatitis and provides an overview of the available approaches for treating this condition., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Ethnopharmacological Relevance: Gentiana kurroo Royle is a medicinal plant mentioned as Traymana in Ayurveda. In the folklore, it is used to cure fever, stomach ache, skin diseases and liver disorders. However, limited reports are available on the therapeutic potential of Gentiana kurroo Royle against alcohol-induced liver damage., Aim of the Study: To assess the effectiveness of the hydroethanolic extract of Gentiana kurroo Royle rhizome (GKRE) against alcohol-induced liver injury and explore the mechanism of action., Materials and Methods: GKRE was characterized using UHPLC-QTOF-MS/MS. The binding affinity of the identified compound was studied in silico. In vitro studies were performed in the Huh-7 cell line. An acute oral toxicity study (2 g/kg BW) of GKRE was done in rats following OECD 420 guidelines. In the efficacy study, rats were treated with 50% ethanol (5 mL/kg BW, orally) for 4 weeks, followed by a single intraperitoneal dose of CCl 4 (30%; 1 mL/kg BW) to induce liver injury. After 4th week, the rats were treated with GKRE at 100, 200 and 400 mg/kg BW doses for the next fifteen days. The biochemical and antioxidant parameters were analyzed using commercial kits and a biochemistry analyzer. Histopathology, gene and protein expressions were studied using qRT PCR and western blotting., Results: Thirteen compounds were detected in GKRE. Few compounds showed a strong interaction with the fibrotic and inflammatory proteins in silico. GKRE reduced (p < 0.05) the ethanol-induced ROS production and inflammation in Huh-7 cells. The acute oral toxicity study revealed no adverse effect of GKRE in rats at 2 g/kg BW. GKRE improved (p < 0.05) the body and liver weights in ethanol-treated rats. GKRE improved (p < 0.05) the mRNA levels of ADH, SREBP1c and mitochondrial biogenesis genes in the liver tissues. GKRE also improved (p < 0.05) the liver damage markers, lipid peroxidation and levels of antioxidant enzymes in the liver. A reduced severity (p < 0.05) of pathological changes, fibrotic tissue deposition and caspase 3/7 activity were observed in the liver tissues of GKRE-treated rats. Further, GKRE downregulated (p < 0.05) the expression of fibrotic (TGFβ, αSMA and SMADs) and inflammatory markers (TNFα, IL6, IL1β and NFκB) in the liver., Conclusion: GKRE showed efficacy against alcohol-induced liver damage by inhibiting oxidative stress, apoptosis, inflammation and fibrogenesis in the liver., 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 © 2024 Elsevier B.V. All rights reserved.)

L-asparaginase having low glutaminase activity is important in clinical and food applications. Herein, glutaminase-free L-asparaginase (type I) coding genes from Pseudomonas sp. PCH182 (Ps-ASNase I) and Rahnella sp. PCH162 (Rs-ASNase I) was amplified using gene-specific primers, cloned into a pET-47b(+) vector, and plasmids were transformed into Escherichia coli (E. coli). Further, affinity chromatography purified recombinant proteins to homogeneity with monomer sizes of ~37.0 kDa. Purified Ps-ASNase I and Rs-ASNase I were active at wide pHs and temperatures with optimum activity at 50 °C (492 ± 5 U/mg) and 37 °C (308 ± 4 U/mg), respectively. Kinetic constant K m and V max for L-asparagine (Asn) were 2.7 ± 0.06 mM and 526.31 ± 4.0 U/mg for Ps-ASNase I, and 4.43 ± 1.06 mM and 434.78 ± 4.0 U/mg for Rs-ASNase I. Circular dichroism study revealed 29.3 % and 24.12 % α-helix structures in Ps-ASNase I and Rs-ASNase I, respectively. Upon their evaluation to mitigate acrylamide formation, 43 % and 34 % acrylamide (AA) reduction were achieved after pre-treatment of raw potato slices, consistent with 65 % and 59 % Asn reduction for Ps-ASNase I and Rs-ASNase I, respectively. Current findings suggested the potential of less explored intracellular L-asparaginase in AA mitigation for food safety., Competing Interests: Declaration of competing interest The authors declare no conflict of personal or financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Breast cancer is a major cause of death among human females across the globe. The anti-neoplastic agents or therapies used for the treatment of cancers can enhance longevity but are subsequently observed to deteriorate the quality of life due to the extensive side effects produced. Saussurea costus is a potential medicinal plant of the Himalayas with noticeable ethnopharmacological properties. The phytochemicals present in Saussurea costus are responsible for anti-carcinogenic potential and warranted nil or minimal side effects of Saussurea costus and directed to use this plant as a preventive or therapeutic drug candidate against cancers., Aim of the Study: The present study was planned to evaluate the anti-neoplastic activity of Saussurea costus root extract (SL) in rat mammary tumour model., Materials and Methods: The anti-neoplastic activity of SL root extract at 3 different doses (100, 250 and 500 mg/kg BW) for 18 weeks against 12-dimethylbenz (a) anthracene (DMBA)-induced mammary tumours in Sprague Dawley (SD) female rats was analyzed through serum biochemistry (ALT, AST, ALP, Total protein, Creatinine and BUN), oxidative stress parameters (Lipid peroxidation, Catalase and Reduced glutathione), pro-inflammatory cytokines (TNF-α and NF-κB), immunohistochemical markers (Ki-67, MMP-9 and VEGF), real-time PCR (PCNA, p53, bax, bcl-2 and caspase-3, genes) and molecular docking., Results: Inhibition of tumour parameters, minimal alteration in the liver (ALT, AST and ALP) and kidney enzymes (Creatinine and BUN), decreased activity of MDA, elevated levels of GSH and catalase, reduction in the levels of pro-inflammatory cytokines i.e. TNF-α and NF-κB, reduced gross and histomorphological changes, declined expression of Ki-67, MMP-9 and VEGF in vivo rat model, mRNA expression of cancer-related genes and docking of dehydrocostus lactone and costunolide with NF-κB and TNF-α demonstrated the chemopreventive action of SL root extract., Conclusions: The in-vivo trial elucidates anti-neoplastic activity of Saussurea costus root extract as demonstrated through the reduction of biochemical indices, oxidative stress parameters, histological changes, pro-inflammatory cytokines (NF-κB and TNF-α), cellular proliferation (Ki-67), metastases (MMP-9) and neovascularization (VEGF) markers with highest anti-neoplastic effect of SL extract at the dose of 500 mg/kg body weight. Therefore, the present study signifies the need to use the active principles present in the root extract of Saussurea costus against breast cancer as a therapeutic regimen., 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.)

The escalating incidences of non-alcoholic fatty liver disease (NAFLD) and associated metabolic disorders are global health concerns. Phloretin (Ph) is a natural phenolic compound, that exhibits a wide array of pharmacological actions including its efficacy towards NAFLD. However, poor solubility and bioavailability of phloretin limits its clinical translation. Here, to address this concern we developed an amorphous solid dispersion of phloretin (Ph-SD) using Soluplus® as a polymer matrix. We further performed solid-state characterization through SEM, P-XRD, FT-IR, and TGA/DSC analysis. Phloretin content, encapsulation efficiency, and dissolution profile of the developed formulation were evaluated through reverse phase HPLC. Finally, the oral bioavailability of Ph-SD and its potential application in the treatment of experimental NAFLD mice was investigated. Results demonstrated that the developed formulation (Ph-PD) augments the dissolution profile and oral bioavailability of the native phloretin (Ph). In NAFLD mice, histopathological studies revealed the preventive effect of Ph-SD on degenerative changes, lipid accumulation, and inflammation in the liver. Ph-SD also improved the serum lipid profile, ALT, and AST levels and lowered the interleukin-6 and tumor necrosis factor-α levels in the liver. Further, Ph-SD reduced fibrotic changes in the liver tissues and attenuates NAFLD progression by blocking the mTOR/SREBP-1c pathway. In a nutshell, the results of our study strongly suggest that Ph-SD has the potential to be a therapeutic candidate in the treatment of NAFLD and can be carried forward for further clinical studies., 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.)

The importance of gut-liver axis in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD) is being investigated more closely in recent times. However, the inevitable changes in gut microbiota during progression of the disease merits closer look. The present work intends to assess the time-dependent gut dysbiosis in MAFLD, its implications in disease progression and role of plant-derived prebiotics in its attenuation. Male C57BL/6J mice were given western diet (WD) for up to 16 weeks and phloretin was administered orally. The fecal samples of mice were collected every fourth week for 16 weeks. The animals were sacrificed at the end of the study and biochemical and histological analyses were performed. Further, 16S rRNA amplicon sequencing analysis was performed to investigate longitudinal modification of gut microbiome at different time points. Findings of our study corroborate that phloretin alleviated the metabolic changes and mitigated circulating inflammatory cytokines levels. Phloretin treatment resists WD induced changes in microbial diversity of mice and decreased endotoxin content. Prolonged exposure of WD changed dynamics of gut microbiota abundance and distribution. Increased abundance of pathogenic taxa like Desulfovibrionaceae, Peptostreptococcus, Clostridium , and Terrisporobacter was noted. Phloretin treatment not only reversed this dysbiosis but also modulated taxonomic signatures of beneficial microbes like Ruminococcus , Lactobacillus , and Alloprevotella . Therefore, the potential of phloretin to restore gut eubiosis could be utilized as an intervention strategy for the prevention of MAFLD and related metabolic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chhimwal, Anand, Mehta, Swarnkar, Patial, Pandey and Padwad.)

Aims: The rising prevalence of type 2 diabetes mellitus (T2DM) and accompanying insulin resistance is alarming globally. Natural and synthetic agonists of PPARγ are potentially attractive candidates for diabetics and are known to efficiently reverse adipose and hepatic insulin resistance, but related side effects and escalating costs are the causes of concern. Therefore, targeting PPARγ with natural ligands is advantageous and promising approach for the better management of T2DM. The present research aimed to assess the antidiabetic potential of phenolics Phloretin (PTN) and Phlorizin (PZN) in type 2 diabetic mice., Main Methods: In silico docking was performed to check the effect of PTN and PZN on PPARγ S273-Cdk5 interactions. The docking results were further validated in preclinical settings by utilizing a mice model of high fat diet-induced T2DM., Key Findings: Computational docking and further MD-simulation data revealed that PTN and PZN inhibited the activation of Cdk5, thereby blocking the phosphorylation of PPARγ. Our in vivo results further demonstrated that PTN and PZN administration significantly improved the secretory functions of adipocytes by increasing adiponectin and reducing inflammatory cytokine levels, which ultimately reduced the hyperglycaemic index. Additionally, combined treatment of PTN and PZN decreased in vivo adipocyte expansion and increased Glut4 expression in adipose tissues. Furthermore, PTN and PZN treatment reduced hepatic insulin resistance by modulating lipid metabolism and inflammatory markers., Significance: In summary, our findings strongly imply that PTN and PZN are candidates as nutraceuticals in the management of comorbidities related to diabetes and its complications., 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 Inc. All rights reserved.)

Ethnopharmacological Relevance: Nardostachys jatamansi (D.Don) DC. is a perennial herbaceous medicinal plant widely used for the ethnomedical treatment of various ailments. The underground parts of the plants are used in traditional medicine to manage epilepsy and other cardiovascular conditions., Aim of the Study: The present study was undertaken to investigate the efficacy of a characterized hydroalcoholic extract (NJET) of Nardostachys jatamansi in the lithium-pilocarpine rat model of spontaneous recurrent seizures (SRS) and associated cardiac irregularities., Materials and Methods: NJET was prepared by percolation using 80% ethanol. The dried NEJT was subjected to UHPLC-qTOF-MS/MS for chemical characterization. Molecular docking studies were performed using the characterized compounds to understand mTOR interactions. The animals showing SRS following lithium-pilocarpine administration were treated with NJET for 6 weeks. Afterward, seizure severity, cardiac parameters, serum biochemistry, and histopathological parameters were studied. The cardiac tissue was processed for specific protein and gene expression studies., Results: The UHPLC-qTOF-MS/MS characterized 13 compounds in NJET. The identified compounds subjected to molecular docking showed promising binding affinities toward mTOR. There was a dose-dependent decrease in the severity of SRS following the extract administration. A reduction in mean arterial pressure and serum biochemical markers (lactate dehydrogenase and creatine kinase) was also observed following NJET treatment in epileptic animals. Histopathological investigations revealed reduced degenerative changes and decreased fibrosis following the extract treatment. The cardiac mRNA level of Mtor, Rps6, Hif1a, and Tgfb3 was reduced in the extract-treated groups. Further, a similar reduction in the protein expression of p-mTOR and HIF-1α was also observed following NJET treatment in the cardiac tissue., Conclusions: The results concluded that NJET treatment reduces lithium-pilocarpine-induced recurrent seizures and associated cardiac irregularities via downregulation of the mTOR signalling pathway., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Here, we report the first complete genome of a psychrotolerant and yellow-pigmented rhizobacteria Chryseobacterium cucumeris PCH239. It was obtained from the rhizospheric soil of the Himalayan plant Bergenia ciliata. The genome consists of a single contig (5.098 Mb), 36.3% G + C content, and 4899 genes. The cold adaptation, stress response, and DNA repair genes promote survivability in a high-altitude environment. PCH239 grows in temperature (10-37 °C), pH (6.0-8.0), and NaCl (2.0%). The genome derived plant growth-promoting activities of siderophore production (siderophore units 53 ± 0.6), phosphate metabolism (PSI 5.0 ± 0.8), protease, indole acetic acid production (17.3 ± 0.5 µg/ml), and ammonia (2.89 ± 0.4 µmoles) were experimentally validated. Interestingly, PCH239 treatment of Arabidopsis seeds significantly enhances germination, primary, and hairy root growth. In contrast, Vigna radiata and Cicer arietinum seeds had healthy radicle and plumule elongation, suggesting varied plant growth-promotion effects. Our findings suggested the potential of PCH239 as a bio-fertilizer and biocontrol agent in the challenging conditions of cold and hilly regions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Obesity is an epidemic and a growing public health concern worldwide. It is one of the significant risk factors for developing chronic kidney disease. In the present study, we evaluated the preventive effect of green tea catechins (GTC) against obesity-induced kidney damage and revealed the underlying molecular mechanism of action. Various green tea catechins were quantified in the catechins-rich fraction using HPLC. In vitro, the palmitic and oleic acid-treated NRK-52E cells showed reduced fat accumulation and modulated expressions of PPARγ, CD36, and TGFβ after GTC treatment. In vivo, rats were fed with a high-fat diet (HFD), and the effect of GTC was assessed at 150 and 300 mg/kg body weight doses. HFD-fed rats showed a significant reduction in weight gain and improved serum creatinine, urea, and urine microalbumin levels after GTC treatment. The improved adipokines and insulin levels in GTC treated groups indicated the insulin-sensitizing effect. Histopathology revealed reduced degenerative changes, fibrous tissue deposition, and mesangial matrix proliferation in GTC treated groups. GTC treatment also downregulated the gene expressions of lipogenic and inflammatory factors and improved the altered expressions of CD36 and PPARγ in the kidney tissue. Further, GTC prevented gut dysbiosis in rats by promoting healthy microbes like Akkermansia muciniphila and Lactobacillus reuteri. Faecal metabolome revealed reduced saturated fatty acids, and improved amino acid levels in the GTC treated groups, which help to maintain gut health and metabolism. Overall, GTC prevented obesity-induced kidney damage by modulating PPARγ/CD36 signaling and maintaining gut health in rats., 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 Inc. All rights reserved.)

L-asparaginase (L-ASNase) from microbial sources is a commercially vital enzyme to treat acute lymphoblastic leukemia. However, the side effects associated with the commercial formulations of L-ASNases intrigued to explore for efficient and desired pharmacological enzymatic features. Here, we report the biochemical and cytotoxic evaluation of periplasmic L-ASNase of Pseudomonas sp. PCH199 isolated from the soil of Betula utilis, the Himalayan birch. L-ASNase production from wild-type PCH199 was enhanced by 2.2-fold using the Response Surface Methodology (RSM). Increased production of periplasmic L-ASNase was obtained using an optimized osmotic shock method followed by its purification. The purified L-ASNase was a monomer of 37.0 kDa with optimum activity at pH 8.5 and 60 ℃. It also showed thermostability retaining 100.0% (200 min) and 90.0% (70 min) of the activity at 37 and 50 ℃, respectively. The K m  and V max values of the purified enzyme were 0.164 ± 0.009 mM and 54.78 ± 0.4 U/mg, respectively. L-ASNase was cytotoxic to the K562 blood cancer cell line (IC 50 value 0.309 U/mL) within 24 h resulting in apoptotic nuclear morphological changes as examined by DAPI staining. Therefore, the dynamic functionality in a wide range of pH and temperature and stability of PCH199 L-ASNase at 37 ℃ with cytotoxic potential proves to be pharmaceutically important for therapeutic application., (© 2023. The Author(s).)

Transcriptome analysis of head and neck squamous cell carcinoma (HNSCC) has been pivotal to comprehending the convoluted biology of HNSCC tumors. MAPKAPK2 or MK2 is a critical modulator of the mRNA turnover of crucial genes involved in HNSCC progression. However, MK2-centric transcriptome profiles of tumors are not well known. This study delves into HNSCC progression with MK2 at the nexus to delineate the biological relevance and intricate crosstalk of MK2 in the tumor milieu. We performed next-generation sequencing-based transcriptome profiling of HNSCC cells and xenograft tumors to ascertain mRNA expression profiles in MK2-wild type and MK2-knockdown conditions. The findings were validated using gene expression assays, immunohistochemistry, and transcript turnover studies. Here, we identified a pool of crucial MK2-regulated candidate genes by annotation and differential gene expression analyses. Regulatory network and pathway enrichment revealed their significance and involvement in the HNSCC pathogenesis. Additionally, 3'-UTR-based filtering recognized important MK2-regulated downstream target genes and validated them by nCounter gene expression assays. Finally, immunohistochemistry and transcript stability studies revealed the putative role of MK2 in regulating the transcript turnover of IGFBP2, MUC4, and PRKAR2B in HNSCC. Conclusively, MK2-regulated candidate genes were identified in this study, and their plausible involvement in HNSCC pathogenesis was elucidated. These genes possess investigative values as targets for diagnosis and therapeutic interventions for HNSCC., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors.)

The present study was aimed at developing Arthrospira platensis ( Spirulina ) fortified traditional foods of the Indian subcontinent, namely sattu (multigrain beverage mix) and chikki (peanut bar) and evaluating their ability to promote recovery from protein and iron deficiency anaemia (IDA) using albino Wistar rats. Addition of Spirulina (at 4% w/w Spirulina inclusion levels) enriched the protein content by 20.33% in sattu and 15.65% in chikki while the iron content was enhanced by 45% in sattu and 29.6% in chikki. In addition, the total carotenoid and polyphenol content and antioxidant capacity of the food products improved after Spirulina incorporation. Supplementation of 100 g of Spirulina fortified food products meets more than 50% of recommended dietary allowances (RDA) of protein, dietary fiber, iron and zinc for the age group 3 to 10 years of children. Spirulina contributed between 11% and 22% of RDA for protein and iron, respectively; however it contributed very negligibly to RDA of dietary fibre with respect to the nutrient requirements for the target age group. Supplementation of Spirulina fortified foods individually promoted bodyweight gain in malnourished rats and restored haemoglobin, serum protein, albumin, serum iron, and hepcidin levels and reduced the iron binding capacity indicating recovery from IDA. Spirulina supplementation ameliorated malnutrition induced oxidative stress in the liver, spleen and kidneys by reducing the lipid peroxidation and enhancing superoxide dismutase and glutathione activities. Histopathological analysis revealed that supplementation of Spirulina fortified foods reversed pathological changes such as fatty changes in the liver cells, thinning of cardiac muscle fibers and degeneration of intestinal villi. Fe-protein deficiency significantly altered the gut microflora by reducing the abundance of beneficial microbes. However, supplementation of Spirulina fortified foods improved the levels of beneficial gut microbes such as Lactobacillus reuteri and Akkermansia muciniphila while reducing the abundance of Helicobacteraceae , Enterobacteria and Clostridia . In summary, supplementation of Spirulina fortified foods promoted recovery from protein and iron deficiency indicating the bioavailability of nutrients (iron and protein) from Spirulina at par with casein and ferrous ascorbate.

Acrylamide has received worldwide attention due to its existence in commonly consumed foods. L-asparaginase reduces acrylamide formation in foods by hydrolyzing available L-asparagine. Herein, L-asparaginase (Ps-ASNase II) of Pseudomonas sp. PCH182 was expressed in Escherichia coli (E. coli), purified, and evaluated for acrylamide reduction in food samples. The monomeric 37 kDa Ps-ASNase II protein was purified to homogeneity with a 70 % yield. The enzyme was active at a wide pH range (5.0-11.0) and temperature (10-80 °C) with optimum activity at 45 °C in 50 mM Tris-HCl (pH 8.5) after 10 min. The K m and V max for L-asparagine were 0.52 ± 0.06 mM and 42.55 ± 4.0 U/mg, respectively. Also, the half-life and K d value of the enzyme at 37 °C was 458 min and 1.51 × 10 -3 /min, suggesting its higher stability. Consistently, the enzyme retained 62 % residual activity after 60 days of storage at 4 °C. The Ps-ASNase II enzyme (5 U/mL) treatment of raw potato chips resulted in 90 % asparagine hydrolysis exhibiting high efficiency. Ps-ASNase II (5 U/mL) treated potato chips significantly reduced acrylamide content by 73 % at 37 °C within 24 min compared to untreated controls. Collectively, these findings verified Ps-ASNase's effectiveness and capability to lower acrylamide formation in fried potato chips without altering the food product's nutritional profile., 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 Ltd. All rights reserved.)

Kidney disease is one of the leading non-communicable diseases related to tremendous health and economic burden globally. Diabetes, hypertension, obesity and cardiovascular conditions are the major risk factors for kidney disease, followed by infections, toxicity and autoimmune causes. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that plays an essential role in kidney physiology and disease. The synthetic agonists of PPAR-γ shows a therapeutic effect in various kidney conditions; however, the associated side effect restricts their use. Therefore, there is an increasing interest in exploring natural products with PPARγ-activating potential, which can be a promising solution to developing effective and safe treatment of kidney diseases. In this review, we have discussed the role of PPAR-γ in the pathophysiology of kidney disease and the potential of natural PPAR-γ agonists in treating various kidney diseases, including acute kidney injury, diabetic kidney disease, obesity-induced nephropathy, hypertension nephropathy and IgA nephropathy. PPAR-γ is a potential target for the natural PPAR-γ agonists against kidney disease; however, more studies are required in this direction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sharma and Patial.)

Nonalcoholic fatty liver disease (NAFLD) with growing incidences is a major health concern worldwide. Alteration in cellular redox homeostasis and autophagy plays a critical role in the progression of NAFLD to more severe outcomes. The lack of safe and effective therapy for the disease necessitates the exploration of new therapeutic compounds. Therefore, in the present study, we investigated the potential of phloretin to maintain redox equilibrium and prevent disease progression via modulation of autophagy in NAFLD. Free fatty acid exposed Huh7 cells were used to evaluate the efficacy of phloretin in vitro. Further, phloretin was administered orally to western diet induced NAFLD in C57BL/6J mice at different doses. The chronic exposure to fatty acids and the western diet triggered lipid accumulation in the Huh7 cells and western diet-fed mice liver, respectively. In addition, mitochondrial dysfunction, oxidative stress, inflammation and decreased hepatic autophagy were observed in disease condition. Phloretin encouraged autophagy mediated hepatic lipid clearance and restored mitochondrial membrane potential and redox homeostasis. It also reduced histological injury by reducing hepatic lipogenesis and facilitating fatty acid oxidation. Moreover, findings of the study also revealed the mitigatory effect of phloretin on inflammatory and fibrogenic markers. Altogether, the study suggested that phloretin effectively attenuates NAFLD progression via upregulating autophagy-mediated lipid breakdown and inhibits oxidative damage, hepatic inflammation and fibrosis., (Copyright © 2022. Published by Elsevier Inc.)

Pigments are an essential part of life on earth, ranging from microbes to plants and humans. The physiological and environmental cues induce microbes to produce a broad spectrum of pigments, giving them adaptation and survival advantages. Microbial pigments are of great interest due to their natural origin, diverse biological activities, and wide applications in the food, pharmaceutical, cosmetics, and textile industries. Despite noticeable research on pigment-producing microbes, commercial successes are scarce, primarily from higher, remote, and inaccessible Himalayan niches. Therefore, substantial bioprospection integrated with advanced biotechnological strategies is required to commercialize microbial pigments successfully. The current review elaborates on pigment-producing microbes from a Himalayan perspective, offering tremendous opportunities for industrial applications. Additionally, it illustrates the ecological significance of microbial pigments and emphasizes the current status and prospects of microbial pigments production above the test tube scale., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society of Industrial Microbiology and Biotechnology.)

l-Asparaginase (l-ASNase) is a key enzyme used to treat acute lymphoblastic leukemia, a childhood blood cancer. Here, we report on the characterization of a recombinant l-ASNase ( Ps 44- asn II) from Pseudomonas sp. PCH44. The gene was identified from its genome, cloned, and overexpressed in the host Escherichia coli ( E. coli ). The recombinant l-ASNase ( Ps 44-ASNase II) was purified with a monomer size of 37.0 kDa and a homotetrameric size of 148.0 kDa. The purified Ps 44-ASNase II exhibited optimum activity of 40.84 U/mg in Tris-HCl buffer (50 mM, pH 8.5) at 45 °C for 15 min. It retained 76.53% of enzyme activity at 45 °C after 120 min of incubation. The half-life and K d values were 600 min and 1.10 × 10 -3  min -1 , respectively, at 45 °C. The kinetic constants values K m and V max were 0.56, 0.728 mM, and 29.41, 50.12 U/mg for l-asparagine and l-glutamine, respectively. However, k cat for l-glutamine is more (30.91 s -1 ) than l-asparagine (18.06 s -1 ), suggesting that enzymes act more efficiently on l-glutamine than l-asparagine. The docking analysis of l-asparagine and l-glutamine with active site residues of the enzyme revealed a molecular basis for high l-glutaminase (L-GLNase) activity and provided insights into the role of key amino acid residues in the preferential enzymatic activities., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03224-0., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© King Abdulaziz City for Science and Technology 2022.)

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interests to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins. Here, we show how a statistical and machine learning (ML) based approach can be used to discriminate between SARS-CoV-2 infection and immune response to an inactivated whole virion vaccine (BBV152, Covaxin). For this, we assessed serial data on antibodies against Spike and Nucleocapsid antigens, along with age, sex, number of doses taken, and days since last dose, for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, our ensemble ML model classified 724 to be infected. For method validation, we determined the relative ability of a random subset of samples to neutralize Delta versus wild-type strain using a surrogate neutralization assay. We worked on the premise that antibodies generated by a whole virion vaccine would neutralize wild type more efficiently than delta strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, neutralization against Delta strain was more effective, indicating infection. We found 71.8% subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period. Our approach will help in real-world vaccine effectiveness assessments where whole virion vaccines are commonly used., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Oestrogen deprivation as a consequence of menopause alters the brain neuronal circuit and results in the development of neurobehavioural symptoms later. Hormone replacement therapy to some extent helps to overcome these abnormalities but is associated with various adverse events. Lithium therapy is being used to manage multiple neuropsychiatric disorders and is reported to maintain structural synaptic plasticity, suppress neuroinflammation, and promote adult neurogenesis. The present study examined the effect of lithium treatment on the neurobehavioural impairments in ovariectomized rat model mimicking clinical postmenopausal condition. A protective effect of lithium treatment was observed on the reconsolidation of spatial and recognition memory along with depression-like behaviour in ovariectomized rats. The Golgi-Cox staining revealed increased dendritic length and spine density in the pyramidal neurons of the CA1 region of the hippocampus, layer V of the somatosensory cortex, and layer II/III of the prefrontal cortex in the treated group. A significant reduction in pro-inflammatory markers, Il2, II6, and Il1b, was observed in the hippocampus, somatosensory cortex, and prefrontal cortex following lithium treatment. mRNA expression studies of Gfap and Pparg, along with histopathological analysis, suggested reactive astrogliosis to be a major contributor of neuroinflammation in ovariectomized rats that was normalized following lithium treatment. Further, the treatment inhibited Gsk-3β activity and maintained the normal level of β-catenin, CREB, and BDNF. The results revealed a defensive role of lithium against ovariectomy-induced neurobehavioural impairments, thus suggesting it to be a potential therapeutic agent for managing postmenopausal neurological symptoms., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Swertia purpurascens Wall belongs to a well-known genus in traditional systems of medicine worldwide. In folklore, it is used to treat various ailments, including hepatic disorders, as an alternative to the endangered species Swertia chirayita. However, the therapeutic potential of Swertia purpurascens Wall against hepatic fibrosis has not been validated yet., Aim of the Study: The present study was planned to evaluate the efficacy of the Swertia purpurascens Wall extract (SPE) against hepatic fibrosis and elucidate the underlying mechanism of action., Materials and Methods: The metabolite profiling of the SPE was done using UHPLC-QTOF-MS/MS. The acute oral toxicity study of SPE at 2 g/kg BW dose was done in rats. Further, the liver fibrosis was induced by the CCl 4 intoxication, and the efficacy of SPE at three doses (100, 200 and 400 mg/kg BW) was evaluated by studying biochemical parameters, histopathology, immunohistochemistry, qRT-PCR, western blotting and in silico analysis., Results: UHPLC-QTOF-MS/MS analysis revealed the presence of a total of 23 compounds in SPE. Acute oral toxicity study of SPE at 2 g/kg BW showed no harmful effects in rats. Further, the liver fibrosis was induced by the CCl 4 administration, and the efficacy of SPE was evaluated at three doses (100, 200 and 400 mg/kg BW). SPE treatment significantly improved the body weight gain, the relative liver weight, serum liver injury markers and endogenous antioxidant enzyme levels in the CCl 4 -treated rats. SPE also recovered the altered liver histology and effectively reduced the fibrotic tissue deposition in the hepatic parenchyma. Further, SPE significantly inhibited the fibrotic (TGFβ, αSMA, SMADs and Col1A), proinflammatory markers (NFκB, TNFα and IL1β) and apoptosis in the liver tissue. Interestingly, SPE treatment also restored the altered hepcidin levels in the liver tissue. In silico study revealed the potential of various metabolites as drug candidates and their interaction with target proteins., Conclusion: Altogether, SPE showed its therapeutic potential against CCl 4 -induced hepatic fibrosis by restoring the hepatic hepcidin levels and inhibiting TGFβ/SMAD/NFκB signaling in rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anthocyanins are good alternative to synthetic dyes for food, pharmaceutical and nutraceutical industries. Owing to their wide occurrence in plant kingdom, an UPLC-ESI-MS/MS method was used to identify and quantify the constituents in flowers of Ipomoea nil . The qualitative evaluation of I. nil results in the characterisation of acylated and non-acylated anthocyanins. Besides characterisation, the total phenolic contents in different fractions of I. nil were found to be 49.69 ± 1.74 and 331.54 ± 1.14 mg GAE/g, respectively. The total anthocyanins content was also determined by spectrophotometer and found to be 5.89 mg/100g of cyanidin-3- O -glucoside equivalent. The antioxidant activity of different fraction of I. nil was evaluated by different assays (DPPH ● , ABTS ●+ and FRAP). In the direction of natural colour stability, we had studied different stabilising agents/copigments and were found to provide stability up to 140 °C. The extracted anthocyanins were evaluated for acute oral toxicity studies and observed to be non-toxic and may direct the use of I. nil for human consumption.

Background: Diabetic Kidney Disease (DKD) is a common complication of diabetes and a leading cause of end-stage renal disease progression. Therefore, therapeutic strategies are desirable to mitigate the progression of disease into more severe consequences. Hypothesis/Purpose:Tinospora cordifolia is a traditionally known antidiabetic plant; however, its effect against DKD remains unexplored. Therefore, in the present study, we assessed the efficacy and mechanism of action of Tinospora cordifolia extract (TC) against DKD., Methods: The molecular interaction of the various phytoconstituents of TC with PPARγ were analyzed in silico. The effect of TC was studied on the viability, cell cycle, and gene expressions (PPARγ, TGFβ, and αSMA) in high glucose treated NRK-52E and SV40 MES13 cells. Further, streptozotocin-induced diabetic rats were treated with TC for eight weeks, and the effects on different biochemical, histological and molecular parameters were studied., Results: In silico analysis revealed the integration of various phytoconstituents of TC with PPARγ. It further increased PPARγ and decreased TGFβ and αSMA expressions in NRK-52E and SV40 MES13 cells. In diabetic rats, TC improved the fasting blood glucose, serum urea, and creatinine levels. It also lowered the urine microalbumin and advanced glycation end products (AGEs) levels. Histopathological studies revealed the preventive effect of TC on degenerative changes, mesangial proliferation and glomerular hypertrophy. Further, it reduced the inflammation and fibrotic changes in the kidney tissue estimated by various markers. The kidney tissue and gene expression analysis revealed the augmented levels of PPARγ after TC treatment., Conclusion: In conclusion, TC exerted the protective effect against DKD by inhibiting inflammation and fibrogenesis through the activation of PPARγ dependent pathways., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Background & Aims: Beverages and Non-alcoholic fatty liver disease (NAFLD) both the terms are associated with westernized diet and sedentary lifestyle. Throughout recent decades, dietary changes have boosted demand of beverages to meet the liquid consumption needs, among which rising consumption of several calorie-rich beverages have increased the risk of fatty liver disease. Meanwhile, certain beverages have capacity to deliver many unanticipated health benefits thereby reducing the burden of NAFLD and metabolic diseases. The present review therefore addresses the increasing interconnections between beverages intake among population, dietary patterns and the overall effect of these beverage on the development and prevention of NAFLD. Methods In the present review, some frequently consumed beverage groups have been analyzed in light of their role in the advancement and prevention of NAFLD, including sugar sweetened, hot and alcoholic beverages. The nutritional composition of different beverages makes the progression of NAFLD distinctive., Results: The ingestion of sugar-rich beverages has demonstrated the metabolic burden and in all cases, raises the risk of NAFLD, while intake of coffee and tea has decreased this risk without any significant adverse effects. In some cases, low to moderate alcohol intake has been shown to minimize the risk of advanced fibrosis and NAFLD-mortality., Conclusion: Together, this review discusses and supports work on new dietary approaches and clinical studies to accomplish nutrition-oriented NAFLD care by improving the drinking habits., Competing Interests: Conflicts of interest None., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India) conducted a serosurvey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS-CoV2 anti-nucleocapsid (anti-NC) antibodies, 95% of which had surrogate neutralization activity. Three-fourth of these recalled no symptoms. Repeat serology tests at 3 (n = 607) and 6 (n = 175) months showed stable anti-NC antibodies but declining neutralization activity. Local seropositivity was higher in densely populated cities and was inversely correlated with a 30-day change in regional test positivity rates (TPRs). Regional seropositivity above 10% was associated with declining TPR. Personal factors associated with higher odds of seropositivity were high-exposure work (odds ratio, 95% confidence interval, p value: 2.23, 1.92-2.59, <0.0001), use of public transport (1.79, 1.43-2.24, <0.0001), not smoking (1.52, 1.16-1.99, 0.0257), non-vegetarian diet (1.67, 1.41-1.99, <0.0001), and B blood group (1.36, 1.15-1.61, 0.001)., Competing Interests: SN, VS, RU, NB, RK, AB, SP, SP, RK, BR, KT, MA, GC, AL, SK, SM, MM, MS, SK, AS, BT, MV, GV, SV, AA, DG, PH, MP, GS, RV, AP, VA, AM, RS, AR, SA, PK, SV, HS, AK, RJ, AT, DP, AS, JK, VK, AM, IG, GR, PS, RC, GC, PK, RY, SS, DS, SS, PB, SA, VS, SV, DS, SS, SV, ST, FF, AS, AS, BS, MS, YP, VH, VP, DS, NT, PC, SM, DG, JS, SR, BK, KK, SG, PJ, RC, VJ, NK, DG, GT, US, PS, SC, RK, PG, AT, DS, RR, AD, MK, DS, MD, SD, RJ, AP, SM, AK, VW, RY, AK, MB, AC, SK, KK, SP, JK, NS, TP, PM, WR, PB, DO, RS, EB, RS, AN, PV, AP, AV, KC, SD, YM, VA, SD, AA, DD, SS No competing interests declared, (© 2021, Naushin et al.)

Theileriosis is an important tick borne disease of cattle caused by a haemoprotozoan of genus Theileria. Clinical bovine theileriosis is mainly caused by T. annulata or T. parva but the clinical disease due to T. orientalis is rare. T. orientalis mainly infect RBCs and causes "Oriental theileriosis" or Theileria-associated bovine anaemia in cattle and other livestock species. Two genotypes of T. orientalis (Chitose and Ikeda) are reported to cause severe disease in some countries. In this report, a spontaneous outbreak of Oriental theileriosis was studied in an organized Holstein-Friesian cattle breeding farm situated in the south-eastern Himalayan ranges of Himachal Pradesh State of India. Animal blood and tick samples were tested using cytological and PCR techniques. The disease episode occurred in a protracted manner spanning over 10 to 12 months and association of T. orientalis was confirmed in 93.3% of the blood and 21.7% of Rhipicephalus microplus (tick) samples. No other tick borne pathogen was detected except Anaplasma marginale in two blood samples. Haematological profiling of infected cattle showed characteristic indicators of anaemia like haemoblobin, RBC count, haematocrit value and mean corpuscular volume at either lower than normal or near the lower normal range. The prevailing persistent anaemic changes led to more severe clinical manifestations like abortion and joint inflammation. The detected T. orientalis strains and ticks species were further confirmed by nucleotide sequence analysis of 18S rRNA and 16S rRNA genes. Phylogenetically, T. orientalis strains showed clustering with other reported strains of T. orientalis from the surrounding regions. This first report of clinical Oriental theileriosis from India emphasises the importance of T. orientalis as an emerging tick borne pathogen and role of widely prevalent ticks species in disease transmission and their impact on livestock production., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The zebrafish has emerged as a powerful vertebrate model for studying liver-associated disorders. Liver damage is a crucial problem in the process of drug development and zebrafish have proven to be an important tool for the high-throughput screening of drugs for hepatotoxicity. Although the structure of the zebrafish liver differs to that of mammals, the fundamental physiologic processes, genetic mutations and manifestations of pathogenic responses to environmental insults exhibit much similarity. The larval transparency of the zebrafish is a great advantage for real-time imaging in hepatic studies. The zebrafish has a broad spectrum of cytochrome P450 enzymes, which enable the biotransformation of drugs via similar pathways as mammals, including oxidation, reduction and hydrolysis reactions. In the present review, we appraise the various drugs, chemicals and toxins used to study liver toxicity in zebrafish and their similarities to the rodent models for liver-related studies. Interestingly, the zebrafish has also been effectively used to study the pathophysiology of nonalcoholic and alcoholic fatty liver disease. The genetic models of liver disorders and their easy manipulation provide great opportunity in the area of drug development. The zebrafish has proven to be an influential model for the hepatic system due to its invertebrate-like advantages coupled with its vertebrate biology. The present review highlights the pivotal role of zebrafish in bridging the gap between cell-based and mammalian models., (© 2020 John Wiley & Sons, Ltd.)

Background: Liver fibrosis is a chronic pathological condition with a leading cause of liver-related mortality worldwide. In the present study, we have evaluated the antifibrotic effect of crocin, a carotenoid present in the stigma of Crocus sativus , and also explored its putative mechanism of action., Methods: Liver fibrosis was induced by intraperitoneal administration of 30% carbon tetrachloride (CCl 4 ). The crocin was administered orally at 20, 40 and 80 mg/kg body weight along with CCl 4 up to 8 weeks., Results: Chronic exposure to CCl 4 resulted in elevated levels of liver enzymes and reduced cytochrome P450 2E1 (CYP2E1) activity in the liver. The liver tissue showed cellular swelling, vacuolization, necrosis, infiltration of inflammatory cells and fibrotic changes. The crocin treatment significantly lowered the levels of liver enzymes in serum and improved the liver CYP2E1 mRNA levels. The pathological changes in the liver were also lowered by crocin treatment. The level of pro-inflammatory cytokines, nuclear factor-kappa B, interleukin-6 and tumor necrosis factor α and fibrogenic factor, transforming growth factor β, and α-smooth muscle actin were elevated by the CCl 4 in the liver tissue. However, crocin treatment at different doses significantly reduced the expression of these factors. The increased caspase 3/7 activity was also lowered by crocin. CCl 4 administration decreased the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) in liver tissue. The improved PPAR-γ expression in the liver by crocin treatment indicates its role in the therapeutic effect of crocin., Conclusions: Crocin attenuated the various events in the progression of liver fibrosis via PPAR-γ mediated modulation of inflammatory and fibrogenic pathways.

Lumpy skin disease (LSD) is a viral disease caused by lumpy skin disease virus (LSDV), a member of Capripoxvirus genus of Poxviridae family. It is a transboundary disease of the economic importance affecting cattle and water buffaloes. The disease is transmitted by arthropod vectors and causes high morbidity and low mortality. LSD has recently been reported first time in India with 7.1% morbidity among cattle. Generally, fever, anorexia, and characteristic nodules on the skin mucous membrane of mouth, nostrils, udder, genital, rectum, drop in milk production, abortion, infertility and sometimes death are the clinical manifestations of the disease. The disease is endemic in African and Middle East countries but has started spreading to Asian and other countries. It has been recently reported from China and Bangladesh sharing borders with India. We have summarized occurrence of LSD outbreaks in last 10 years in Asian countries for the first time. In India, currently epidemiological status of the disease is unknown. Vaccination along with strict quarantine measures and vector control could be effective for preventing the spread of the disease. This review aims to summarise the latest developments in the epidemiology with the focus on transboundary spread, aetiology and transmission, clinical presentations, diagnostics and management of the disease.

Here, we report on the isolation of bacterial isolates from Himalayan niches, which produced extracellular l-asparaginase with low/no glutaminase activity. From the 235 isolates, 85 asparaginase positive bacterial isolates were identified by qualitative screening using optimized chromogenic dyes assay. Optimized concentration of different dyes revealed maximum color visualization in phenol red (0.003%). The diversity analysis of asparaginase positive isolates revealed that Proteobacteria (83%) are the most dominant, followed by Actinobacteria (12%), Firmicutes (3%), and Bacteriodetes (2%). Eleven isolates, which represented seven Pseudomonas species, one species each of the genus Arthrobacter , Janthinobacterium , Lelliottia , and Rahnella , were selected for further studies based on highest zone ratio and novel aspects for l-asparaginase production. Of these, five isolates, namely, Pseudomonas sp. PCH133, Pseudomonas sp. PCH146, Pseudomonas sp. PCH182, Rahnella sp. PCH162, and Arthrobacter sp. PCH138, produced l-asparaginase without glutaminase activity after 55 h of growth with the former isolate showing the highest l-asparaginase activity (1.67 U/ml). Interestingly, this is the first report of l-asparaginase production by members of the genera Janthinobacterium , Rahnella , and Lelliottia ., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

Podophyllotoxin has been explored as an anticancer, antiviral, and antibacterial agent; however, its low water solubility and toxicity limit its use. In this study, the efficacy of a more soluble and less toxic polyamidoamine (PAMAM) dendrimer-conjugated podophyllotoxin (DPODO) was evaluated against chemically induced hepatocellular carcinoma (HCC) in mice. HCC was induced by giving 0.01% diethylnitrosamine (DENA) in drinking water for 16 weeks. The HCC-induced mice were treated with 10 or 20 mg per kg body weight DPODO. The DENA administration led to HCC development, characterized by anisocytosis, karyomegaly, inflammation and degenerative changes in the liver. The DPODO treatment at 10 mg and 20 mg doses significantly reduced the histopathological changes in liver tissue. The DPODO treatment also significantly lowered the levels of inflammatory markers IL-6 and NF-κB in serum and tissue, respectively. Further, the treatment also significantly reduced fibrous tissue deposition in the liver, which was further confirmed by the reduced mRNA levels and tissue expression of fibrogenic markers TGF-β and α-SMA in the liver. The results of the present study indicate that DPODO treatment suppresses the progression of HCC by modulating the inflammatory and fibrogenic factors, which play important roles in HCC development.

The role of neuroinflammatory mediators has been well established in the pathogenesis of temporal lobe epilepsy (TLE) and associated neurobehavioral comorbidities. Mycophenolate mofetil (MMF) is commonly used as an immunosuppressant in organ transplantations. Its neuroprotective effect is well explored in different preclinical and clinical studies. The present study was designed to investigate the effect of MMF in rat model of lithium pilocarpine (LiPc)-induced spontaneous recurrent seizures and its associated neurobehavioral comorbidities. MMF treatment showed a dose-dependent decrease in seizure severity and reduced aggression in epileptic rats. There was marked improvement in spatial and recognition memory functions, along with substantial decrease in depression-like behavior in MMF treated epileptic rats. There was considerable decrease in mossy fiber sprouting in the dentate gyrus and the cornu ammonis 3 regions of the hippocampus, along with reduction in neuronal death in the treated groups. Furthermore, the hippocampal mRNA level of IL-1β, IL-2, PI3K, AKT, HIF-1α, RAPTOR, mTOR, Rps6kb1 and Rps6 was found to be decreased in MMF treated animals. mTOR, S6, pS6 and GFAP protein expression was decreased, whereas NeuN was increased in the rat hippocampus of the treated animals. The results concluded that MMF suppress recurrent seizures, and improves its associated behavioral impairments and cognitive deficit in rat model of TLE. The observed effects of MMF be correlated with the inhibition of IL-2 and IL-1β linked PI3K/AKT/mTOR signaling pathway hyperactivation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Alteration in electrophysiology, leading to cardiac dysfunction and subsequently a nontraumatic death is a complication of epilepsy known as "SUDEP" (Sudden Unexpected Death in Epilepsy)., Aims: The present study was designed to understand the molecular changes and cardiac parameters during different phases of epileptogenesis in lithium-pilocarpine (Li-pilo) rat model of epilepsy., Methods: The animals were exposed to Li-pilo to induce Spontaneous Recurrent Seizures (SRS). Noninvasive blood pressure and electrocardiography was recorded at 7th, 28th and 75th day following pilocarpine administration, considered as latent, initial and late SRS phases, respectively. The serum biochemistry, cardiac histopathology, protein and mRNA expressions were studied, following electrocardiography on day 75., Results: The mean arterial pressure decreased during the latent phase, thereafter it progressively increased during the initial and the late SRS phases, as compared to the basal and the latent phase. Histopathological analysis of the heart sections indicated hypertrophy, degenerative changes and fibrous tissue deposition in epileptic animals, along with increased levels of lactate dehydrogenase and creatine kinase-MB in the serum. The expression of HIF-1α, phospho-S6, phospho-mTOR, TGF-β, collagen I and Na+/K+-ATPase α1 proteins, and mRNA levels of HIF-1α, mTOR, Rps6, Scn1b, Scn3b, Nav1.5 and TGF-β were increased in the cardiac tissue of epileptic animals, as compared to control., Conclusion: Our results conclusively showed that Li-pilo-induced SRS leads to cardiac dysfunction via mTOR pathway upregulation, thus suggested the regulatory control of mTOR pathway as a potential target for SUDEP management., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Three homoisoflavonoids, including a new compound, 5,7-dihydroxy-3-(4-methoxybenzyl)-8-methyl chroman-4-one (1), together with two known compounds, 5,7-dihydroxy-3-(2-hydroxy-4-methoxybenzyl)-8-methylchroman-4-one (2) and 5,7-dihydroxy-3-(2-hydroxy-4-methoxybenzyl)-chroman-4-one (3), were isolated from the rhizomes of Polygonatum verticillatum (L.) All. (P. verticillatum). Isolated compounds were characterized on the basis of UV, FT-IR, ESI-MS, and 1D-, 2D-NMR data. Further, different extract fractions and pure compounds from Polygonatum verticillatum were screened for their antimicrobial potential. Among three pure compounds, compound 2 was found most potent with good zone of microbial growth inhibition as compared to the standards., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)

Background: In the field conditions, animals regularly consume small quantities of lantana leaves either while grazing or due to mixing with regular fodder. The hypothesis of this study was that consumption of lantana toxins over a long period of time leads to progression of sub-clinical disease. Toxicopathological effects of sub-chronic (90 days) administration of lantadenes of L. camara were investigated in guinea pigs. For this, a total of 40 animals were divided into 5 groups whereby groups I, II, III and IV were orally administered lantadenes, daily at the dose of 24, 18, 12, and 6 mg/kg bw, respectively while group V was control. The animals were evaluated by weekly body weight changes, haematology, serum liver and kidney markers, tissue oxidative markers and histopathology., Results: The results of significant decrease in weekly body weights, haematology, liver and kidney marker enzymes (alanine aminotransaminase, aspartate aminotransaminase, acid phosphatase and creatinine), oxidation stress markers (lipid peroxidation, reduced glutathione, superoxide dismutase and catalase) in liver and kidneys, histopathology, and confirmation of fibrous collagenous tissue proliferation by Masson's Trichome stain showed that lantadenes led to a dose-dependent toxicity in decreasing order with the highest dose (24 mg/kg bw) producing maximum lesions and the lowest dose (6 mg/kg bw) producing minimum alterations., Conclusions: The study revealed that lantadenes which are considered to be classical hepatotoxicants in acute toxicity produced pronounced nephrotoxicity during sub-chronic exposure. Further studies are needed to quantify the levels of lantadenes in blood or serum of animals exposed to lantana in field conditions which would help to assess the extent of damage to the vital organs.

Background: Picrorhiza kurroa Royle (Scrophulariaceae) is an important medicinal herb being widely used in variety of ailments., Purpose: The present study was envisaged to evaluate the effects of iridoid glycosides enriched fraction (IGs) from Picrorhiza kurroa rhizome against cyclophosphamide (CP) -induced renal toxicity and peripheral neuropathy., Methods: Mice in different groups were pretreated with 25, 50 and 100 mg/kg; p.o. doses of IGs for 21 days, followed by cyclophosphamide intoxication for consecutive two days. Further, to identify the putative role of PPAR-γ receptors for the protective effect of IGs, an additional group of mice were pretreated with PPAR-γ antagonist BADGE (5 mg/kg; i.p.) followed by IGs (100 mg/kg; p.o.) for 21 days before CP intoxication., Results: IGs pretreatment decreased the hyperalgesic responses toward acetone and heat in acetone drop and tail immersion tests. The abolition of intramyelin odema, cytoplasmic vacuolization and axonal degeneration of sciatic nerve were observed in IGs pretreated mice in a dose-dependent manner. IGs treatment also attenuated the altered serum biochemical markers for renal injury. Furthermore, the treatment prevented renal tubular swelling, granular degeneration and glomerular damage. The levels of IL-1β and TNFα in different group revealed the anti-inflammatory effect of IGs, which was further confirmed by improvement in altered expressions of NF-kB in kidney and sciatic serve. Bax/Bcl-2 expressions and caspase 3/9 activity in renal tissues showed the anti-apoptotic effect of IGs. IGs pretreatment also improved the PPAR-γ expression in the kidney tissues. All the observed protective effects of IGs were suppressed after pretreatment with BADGE., Conclusion: Present study concludes that IGs from Picrorhiza kurroa attenuates CP-induced renal toxicity and peripheral neuropathy via PPAR-γ -mediated pathways., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

In diabetes, hyperglycemic state immensely hinders the wound healing. Here, nanobiocomposites (NCs) developed by impregnation of in situ prepared silver nanoparticles in the matrix of bamboo cellulose nanocrystals were investigated for their ability to hasten the progress of healing events in streptozotocin induced diabetic mice model. Wounds treated with topically applied NCs (hydrogels) showed full recovery (98-100%) within 18days post wounding in contrast to the various control groups where incomplete healing (88-92%) was noticed. Biochemical estimations documented a marked decrease in the levels of pro-inflammatory cytokines IL-6 and TNF-α leading to decreased inflammation in NCs treated mice. Significantly increased expression of collagen and growth factors (FGF, PDGF, VEGF) upon NCs treatment resulted in improved re-epithelialization, vasculogenesis and collagen deposition as compared to control groups. Hence, developed nanobiocomposites showcased potential to serve as highly effective and biocompatible wound dressings for diabetic patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Clinically approved anticancer drug estramustine mediates its function by impairing microtubule polymerization. However, the low aqueous solubility and high toxicity limit its anticancer activity via the oral route. Previously, efforts have been made to develop an enhanced water soluble form of estramustine as estramustine phosphate (EM) but acidic gastrointestinal pH breaks the phosphate derivative via oral administration. As an alternative approach, we have made an effort to enhance solubility and minimize toxicity in vivo by conjugating EM to a poly(amidoamine) (PAMAM) dendrimer, which generated the sustained release of dendrimer conjugate (DEM). To the best of our knowledge, for the first time, we report the direct proof of the nano-crystalline 'DenDot' of DEM on TEM image. The toxicity study showed that both EM and DEM were nontoxic up to 20mg/kg. A comparative anti-papilloma study was also performed with EM and dendrimer conjugates (DEM) using a two-stage mouse skin carcinogenesis model. We found that DEM was more effective in inhibiting skin tumor formation than EM. Histopathology and immunohistochemistry studies further indicated that DEM treatment increased cell apoptosis, and reduced epithelial hyperplasia, cell proliferation and inflammation in skin tissues of mice. In addition, the synthetic DEM conjugate inhibited skin tumor progression more effectively than EM., (Copyright © 2017 Elsevier B.V. All rights reserved.)