Cellular and functional exhaustion of bone marrow mesenchymal stem cells (BM-MSC) is significantly associated with the loss of HSCs and hepatic osteodystrophy in cirrhosis. The molecular mechanisms ...underlying the dysfunction of BM-MSCs are not well understood. We investigated the underlying mechanisms of cellular and functional exhaustion of BM-MSCs in cirrhosis.
The MSCs were isolated retrospectively from bone marrow of decompensated alcoholic cirrhosis patients {(Trial registration: ClinicalTrials.gov NCT01902511) (n=10; MELD=16.2±2.3; CTP=8.7±2.3)} and age and gender-matched healthy controls (n=8). Global gene expression profile of healthy bone marrow MSCs (hBM-MSCs) and cirrhosis patients BM-MSCs (cBM-MSCs) were done by mRNA sequencing. XFe24-bioanalyzer analyzed the bioenergetic potential of cells. Level of different cytokines and growth factors in BM-plasma and MSCs secretome were analyzed by Luminex-based bead array.
Analysis of differentially expressed genes showed significant (P<0.01) up-regulation of genes associated with ubiquitination and catabolism of proteins; TNF signaling, insulin resistance, and down-regulation of genes associated with DNA repair, protein processing, cell cycle, and mitochondrial respiration in cBM-MSCs in comparison to hBM-MSCs. Compared to hBM-MSCs, cBM-MSCs showed a significant defect in glycolysis due to insulin resistance and poor glucose uptake (P=0.002). This led to compromised self-renewal capacity and cellular loss of MSCs in cirrhosis. cBM-MSCs also showed a significant impairment in Oxidative phosphorylation (OXPHOS) due to mitochondrial dysfunction leading to defects in the osteogenic differentiation with early aging and senescence.
Compromised energy metabolism due to inflammatory and metabolic stress-induced insulin resistance underlies the cellular and functional exhaustion of BM-MSCs in cirrhosis.
The present study was conducted to evaluate the effect of
Cochlospermum religiosum (CSR)
in animal models of depression and anxiety. The CSR leaves are well known for their sedative, antibacterial, ...antifungal antioxidant, memory enhancing, anxiolytic and antidepressant potential. In present study, the extract of the leaves is used to relieve the anxiolytic and antidepressant potential. The leaves of
CSR
were investigated for antidepressant and anxiolytic activities in mice behavioural models namely, spontaneous locomotor activity (SLA), forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM) and marble burying behaviour (MBB). The mechanism was supported by reserpine-induced hypothermia (RIH). Further, the in vivo synergistic evaluation of the CSR leaf extract was evaluated with imipramine and fluoxetine. The treatment of mice with ethanolic extract of CSR leaves for 7 days resulted significant antidepressant and anxiolytic effects (
p
< 0.05 for 50 mg/Kg p.o /
p
< 0.01 for 100 mg/kg p.o) with null impact on baseline locomotor activity. Further, the study on rat RIH model revealed that the CSR (50 mg/kg p.o) predominantly antagonized the effect (
p
< 0.05) of reserpine. Furthermore, synergic action was screened by co-administration of leaf extracts of
CSR
with fluoxetine (10 mg/Kg, i.p.) and imipramine (10 mg/Kg, i.p.) at below therapeutic dose levels using FST, TST, EPM and MBB. The synergistic effect was significant (
p
< 0.05) for both antidepressant and anxiolytic activities as compared to therapeutic doses of extract, imipramine and fluoxetine.
Targeting natural products against SARS-CoV-2 Al-Harrasi, Ahmed; Behl, Tapan; Upadhyay, Tanuj ...
Environmental science and pollution research international,
06/2022, Letnik:
29, Številka:
28
Journal Article
Recenzirano
Odprti dostop
The human coronavirus disease (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Natural products, secondary metabolites show ...positive leads with antiviral and immunotherapy treatments using genomic studies in silico docking. In addition, it includes the action of a mechanism targeting the SARS-CoV-2. In this literature, we aimed to evaluate the antiviral movement of the NT-VRL-1 unique terpene definition to Human coronavirus (HCoV-229E). The effects of 19 hydrolysable tannins on the SARS-CoV-2 were therefore theoretically reviewed and analyzed utilising the molecular operating surroundings for their C-Like protease 3CLpro catalytic dyad residues Angiotensin converting enzyme-2 (MOE 09). Pedunculagin, tercatan, and castalin were detected as interacting strongly with SARS-receptor Cov-2’s binding site and catalytic dyad (Cys145 and His41). SARS-CoV-2 methods of subunit S1 (ACE2) inhibit the interaction of the receiver with the s-protein once a drug molecule is coupled to the s-protein and prevent it from infecting the target cells in alkaloids. Our review strongly demonstrates the evidence that natural compounds and their derivatives can be used against the human coronavirus and serves as an area of research for future perspective.
Green nanotechnology has gained much interest in the development of nanoparticles owing to its reliability, safety and eco-accommodating methods of synthesis, with exceptional properties (physical, ...chemical, and biological), and applications. Silver nanoparticles (Ag-NPs) are one of the most well established nanocarriers that have been explored for pharmaceutical purposes due to their obvious advantages over synthetic approaches. Synthetic methods are associated with hazardous byproducts, instability issues, and are generally time consuming expensive procedures having serious environmental concerns. The present review compiles various sources (fungi, plant, and bacteria), their advantages, therapeutic benefits, risk assessment, challenges, and future perspectives of Ag-NPs. We have emphasized comprehensive details of green Ag-NPs used for various pharmacological properties (antimicrobial, cytotoxicity, antifungal, anti-parasitic, and antioxidant) followed by certain limitations and risk assessments when tailored as drug delivery systems. The comparative assessment and major findings of various reports have been elaborately highlighted and are covered in the review. A summary of key findings deliberating the unique features of natural sources namely, ease of availability, safety concerns, stability, green techniques, various challenges in synthesis (negative consequences of nanomaterials), and technology transfer aspects from laboratory to bed, have been included in this review so that readers can be aware of basic information required for developing green-based nanocarriers as drug delivery platforms. Finally, various recent advances in metal nanoparticle preparations using sonochemical and microwave assisted methods have been covered with prime outcomes and related challenges. The present review also emphasizes on the benefits of various green sources for developing Ag-NPs, their advantages over conventional approaches, pharmaceutical applications, related challenges, future prospects, and recent advancements.
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The study aimed to investigate the acute toxicity, antidiabetic potential (in-vitro and in-vivo) of the
Operculina turpethum
(L.) Silva Manso at fraction level. The plant was fractionated into ...different fractions, i.e., flavonoid fraction (OTFF), tannin fraction (OTTF), saponin fraction (OTSF). In-vitro alpha-amylase inhibition assay revealed that OTFF was found to be more potent than standard Acarbose. The plant fractions were evaluated by MTT assay at different concentrations ranging from 100 to 1000 µg/ml. All the fractions were further evaluated for their safety profile, and the biochemical, hematology and histopathology result exhibits that the OTFF fraction produces mild toxicity at organ level at a concentration of 2000 mg/kg in albino mice. The in-vivo antidiabetic study was carried out on Sprague-Dawley rats using high-fat diet (HFD) feeding streptozotocin (STZ) diabetic model, and the biochemical, histopathology research findings represent that OTFF at a concentration of 500 mg/kg, p.o. was found to be highly significant among all the fractions and found to be more potent than the standard Acarbose. LC–MS characterization of the bioactive fraction OTFF showed the presence of rutin with
m
/
z
610.52 in 50.50% and Apigenin 7-
O
-6'' acetyl-glucoside with
m
/
z
475.42 in 24.10%; from molecular docking study, it is predicted that the fraction primarily acts as an alpha-amylase inhibitor and PPAR gamma agonist. In conclusion, the plant’s OTFF fraction acts as a potential therapeutic agent for Type II diabetes mellitus.
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen that can be activated by thrombin. Activated TAFI (TAFIa) cleaves carboxyl-terminal lysine residues from ...partially degraded fibrin, rendering it resistant to fibrinolysis by endogenous tissue plasminogen activator (tPA). Carboxypeptidase inhibitor (CPI) isolated from potato inhibits TAFIa and reduces clot lysis time in rabbit and mouse plasma. In the present study, we report the effect of CPI on tPA-mediated clot lysis using rat plasma in vitro. CPI at 400, 600 and 800 ng/ml caused a dose-dependent enhancement of tPA-induced clot lysis. In vivo effect of CPI was also investigated using ferric chloride-induced arterial thrombosis model in rat. The results showed that i.v. administration of CPI significantly prolonged the 'time to occlusion' at the dose of 2 and 4 mg/kg. At 2 mg/kg i.v. dose in rat, CPI showed no effect on prothrombin time and activated partial thromboplastin time, indicating noninterference of CPI with other clotting factors in mediating its thrombolytic effect through TAFI inhibition. Furthermore, 2 mg/kg i.v. dose of CPI did not produce significant increase in bleeding time when tested in rat tail-transection bleeding model. These results provide evidence for a role of TAFI in arterial thrombosis in rats and suggest that TAFI inhibition could be explored as an attractive target for the development of new antithrombotic drugs.
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