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The present study intended to divulge the potential role of garlic-derived organosulfur compounds (OSCs) in targeting PCSK-9 and averting its interaction with the EGF-A portion of LDL-R via in-vitro and in-silico analysis. Our in-silico screening data showed that 3-(Propylsulfinyl)-L-alanine (PSA), S-Ethyl-L-cysteine (SEC), alliin, and S-Allyl-L-cysteine (SAC) exhibited higher binding energy (−7.05, −7.00, −6.65, and −6.31 Kcal/mol, respectively) against PCSK-9, among other selected OSCs. Further, the protein-protein interaction study of PCSK-9-OSCs-complex with EGF-A demonstrated a similar binding pattern with E-total values ranging from −430.01 to −405.6 Kcal/mol. These results were further validated via in-vitro analysis which showed that SEC, SAC, and diallyl trisulphide (DAT) exhibited the lowest IC50 values of 4.70, 5.26, and 5.29 µg/mL, respectively. In conclusion, the presented data illustrated that SEC, SAC, and DAT were the best inhibitors of PCSK-9 activity and may have the potential to improve the LDL-R function and lower the circulatory LDL-C level. [ABSTRACT FROM AUTHOR]

The antioxidant and antiglycation activities of the Ficus leaf extracts were evaluated using in vitro assays. The antioxidant activity was determined using the α, α-diphenyl-β-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assays. In vitro ferric reducing activity was evaluated using the ferric reducing antioxidant power assay. The antiglycation potential of the extract was evaluated using dinitrophenylhydrazine, thiobarbituric acid and protein thiol assays. The inhibition of the formation of advanced glycation end products (AGEs) was detected using AGE-specific fluorescence with a fluorescence spectrophotometer. This study was aimed at investigating the potential of Ficus palmata Forssk. leaf extracts, which have abundant bioactive constituents, including polyphenols and flavonoids, in inhibiting glycation and cancer. The results show that the aqueous and methanolic Ficus leaf extracts are rich in phenolic and flavonoid compounds. Both extracts showed potent antioxidant activities. Furthermore, the methanolic extract showed antiglycation activities, as assessed using an in vitro model of bovine serum albumin glycation with D-ribose. The polyphenol- and flavonoid-rich Ficus leaf extracts exhibit antiglycation, chemopreventive and antioxidant activities and have potential for use in the treatment of diseases, such as cancer, which involve oxidative and glycative impairment of cellular proteins. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type-9 (PCSK-9) is a serine protease with profound effects on plasma LDL-C, the major risk factor for cardiovascular diseases (CVDs). However, plasma PCSK-9 level and its association with the biomarkers of CVDs, diabetes, and associated complications have not yet been reported in the northeastern population of India. Methods: Of the total cohort (n = 233), we analyzed healthy controls (HC; n = 50), freshly diagnosed type-2-diabetes mellitus (T2DM-FD; n = 46), T2DM treated (T2DM-T; n = 49), diabetic nephropathy (T2DM-N; n = 43), and diabetic dyslipidemia (T2DM-DL; n = 45) subjects. Plasma PCSK-9 and other biological determinants associated with T2DM, CVD, and nephrotic dysfunction were assessed. Results: The level of plasma PCSK-9 in HC, T2DM-FD, T2DM-T, T2DM-N, and T2DM-DL groups was found to be 184.1 ± 13.83, 183.1 ± 24.4.3, 241.8 ± 75.42, 403.7 ± 85.94, and 641.3 ± 135.5 ng/mL, respectively, indicating its role in the severity of the here-mentioned complications. Moreover, plasma PCSK-9 levels further showed a significant correlation with the biomarkers of hyperglycemia, particularly HbA1c, as well as LDL-C in T2DM-FD, T2DM-N, and T2DM-DL subjects of the Indian population, while moderate association in T2DM-T subjects. Conclusions: Our first-of-its-kind clinical study aiming to quantify the circulatory PCSK-9 level in the Indian population concluded that elevated PCSK-9 was significantly associated with the severity of diabetes and associated complications. Moreover, such elevation in PCSK-9 might be attributed to the lipid- and glucose-lowering medication-induced SREBP-2-dependent mechanisms. Since our conclusion is based on a pilot study, further cohort studies in larger populations of India are required to get a generalization regarding the role of PCSK-9 in DM and associated complications. [ABSTRACT FROM AUTHOR]

Background: Human angiotensin-converting enzyme-2 (ACE-2) and severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) main protease (Mpro) have been established as the prime targets to restrict viral invasion and replication inside the host, respectively. Methods: The current study delineated the SARS-CoV-2 Mpro as well as human ACE-2 inhibitory potential of carotenoids and polyphenols from tomato (Solanum lycopersicum L.) via in-silico interaction studies. Results: Our drug-likeness studies showed that the selected carotenoids and polyphenols exhibited acceptable Lipinski’s score and ADME determinants. Further, in-silico molecular modelling studies revealed that β-carotene, among other carotenoids, topped the binding score (ΔG: −6.75 kcal/mol; Ki: 11.32 μM) against SARS-CoV-2 Mpro, whereas, cyanidin was the best inhibitor of SARS-CoV-2 Mpro ( −7.24 kcal/mol; Ki: 4.92 μM) amongst polyphenols. Similarly, α-carotene from carotenoids exhibited strongest human ACE-2 inhibitory activity (ΔG: −8.85 kcal/mol; Ki: 326.13 μM), whereas, cyanidin from polyphenols showed best binding affinity against human ACE-2 (ΔG: −7.24 kcal/mol; Ki: 4.89 μM). In contrast, 6-(ethylamino)-pyridine-3-carbonitrile, standard inhibitor of SARS-CoV-2 Mpro, exhibited comparatively weaker binding (ΔG: −4.78 kcal/mol; Ki: 267.49 μM), whereas, telmisartan (reference ACE-2 inhibitor) also exhibited lesser affinity (ΔG: −6.40 kcal/mol; Ki: 20.40 μM). Further exploration via MDS studies also validated the dynamic behavior and stability of protein-ligand complexes as evident by desirable RMSD, RMSF, Rg, and SASA. Conclusion: The current study established carotenoids and polyphenols from S. lycopersicum L. as finer substitutes of reference standards against SARS-CoV-2 Mpro and human ACE-2 activity in combating SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The current in-vivo study was premeditated to uncover the protective role of ezetimibe (EZ) against advanced glycation endproducts (AGEs)-related pathologies in experimental diabetes. Our results showed that EZ markedly improved the altered biochemical markers of diabetes mellitus (DM) (FBG, HbA1c, insulin, microalbumin, and creatinine) and cardiovascular disease (in-vivo lipid/lipoprotein level and hepatic HMG-CoA reductase activity) along with diminished plasma carboxymethyl-lysine (CML) and renal fluorescent AGEs level. Gene expression study revealed that EZ significantly down-regulated the renal AGEs-receptor (RAGE), nuclear factor-κB (NFκB-2), transforming growth factor-β (TGF-β1), and matrix metalloproteinase-2 (MMP-2) mRNA expression, however, the neuropilin-1 (NRP-1) mRNA expression was up-regulated. In addition, EZ also maintained the redox status via decreasing the lipid peroxidation and protein-bound carbonyl content (CC) and increasing the activity of high-density lipoprotein (HDL)-associated-paraoxonase-1 (PON-1) and renal antioxidant enzymes as well as also protected renal histopathological features. We conclude that EZ exhibits antidiabetic and reno-protective properties in diabetic rats. [ABSTRACT FROM AUTHOR]

Hyperglycemia is a poorly controlled diabetic condition, affects about 70% of people all round the world. In the year 2015, about 41.5 crore people were diabetic and is expected to reach around 64.3 crore by the year 2040. Cardiovascular diseases (CVDs) are considered as one of the major risk factors that cause more than half of the death of diabetic patients and promote related comorbidities. Atherosclerosis and amyloidosis are the prime factors linked with CVDs. Apolipoprotein A-I (ApoA-I) of HDL has protective action against CVDs, participates in reverse cholesterol transport mechanism and lipid metabolism, but gets easily glycated under prolonged hyperglycemic aura, i.e. glycation. ApoA-I has a potent role in maintenance of glucose level, providing a compelling link between diabetes and CVDs. Increased protein glycation in people with diabetes promotes atherosclerosis, which might play possible role in promotion of protein aggregation by altering the protein structure and its conformation. Here, we intend to investigate the mechanistic behavior of ApoA-I under the menace of glycation and its impact on ApoA-I structure and function that possibly link with aggregation or amyloidosis. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) stands amongst the leading causes of mortality worldwide and has attracted the attention of world's leading pharmaceutical companies in order to tackle such mortalities. The low-density lipoprotein-cholesterol (LDL-C) is considered the most prominent biomarker for the assessment of ASCVD risk. Distinct inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-R), the chief hepatic cholesterogenic enzyme, are being used since last seven decades to manage hypercholesterolemia. On the other hand, discovery and the association of proprotein convertase subtilisin/kexin type-9 (PCSK-9) with increased ASCVD risk have established PCSK-9 as a novel therapeutic target in cardiovascular medicine. PCSK-9 is well reckoned to facilitate the LDL-receptor (LDL-R) degradation and compromised LDL-C clearance leading to the arterial atherosclerotic plaque formation. The currently available HMG-R inhibitors (statins) and PCSK-9 inhibitors (siRNA, anti-sense oligonucleotides, and monoclonal antibodies) have shown great promises in achieving LDLC lowering goals, however, their life long prescriptions have raised significant concerns. These deficits associated with the synthetic HMG-R and PCSK-9 inhibitors called for the discovery of alternative therapeutic candidates with potential dual HMG-R and PCSK-9 inhibitory activities from natural origins. Therefore, this report firstly describes the mechanistic insights into the cholesterol homeostasis through HMG-R, PCSK-9, and LDL-R functionality and then compiles the pharmacological effects of natural secondary metabolites with special emphasis on their dual HMG-R and PCSK-9 inhibitory action. In conclusion, various natural products exhibit atheroprotective effects via targeting HMG-R and PCSK-9 activities and lipoprotein metabolism, however, further clinical assessments are still warranted prior their approval for ASCVD risk management in hypercholesterolemic patients. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) induce the production of reactive oxygen species (ROS) and extra cellular matrix (ECM) degradation via suppression of neuropilin-1 (NRP-1) and interaction with AGE-receptors (RAGE). This study aimed to reveal whether modulation of NRP-1 by rosuvastatin (RT) prevents AGE-induced renal injury via targeting RAGE/matrix metalloproteinase-2 (MMP-2) signaling in diabetic rats. Treatment with RT ameliorated the altered level of markers of glycemic control, renal injury, cholesterol, triglyceride (TG) and hepatic HMG-CoA reductase activity; the level of circulatory carboxymethyl-lysine (CML) and the accumulation of fluorogenic-AGEs in renal tissue was reduced; the expression of renal NRP-1, a checkpoint target, was stimulated; the transcription of RAGE, NFκB-2, TGF-β1 and MMP-2 was suppressed; the circulatory carbonyl content (CC) and paraoxonase-1 (PON-1) activity was ameliorated, and renal histopathological features were attenuated as evidenced by improved glomerular appearance, Bowman's space and abundant podocytes in kidneys. In conclusion, RT exhibited the potential to counteract diabetes and AGE-induced renal pathologies via stimulation of NRP-1, suppression of RAGE, and of genes responsible for ECM disintegration (MMP-2) and the inflammatory response (NFκB-2). [ABSTRACT FROM AUTHOR]

Diabetic retinopathy and nephropathy are questionably the most dreaded complications of diabetes; contribute to serious morbidity and mortality. The current study was undertaken with the aim of exploring the anti-lipoperoxidative and antioxidant status including nephroprotective and retinoprotective potential of Phyllanthus virgatus methanolic extract and its partially purified fraction in streptozotocin (STZ)-induced diabetic stressed rats. Diabetes was induced by intraperitoneal injection of Streptozotocin (60mg/kg B. Wt of rat). Among all the treatment groups, P. virgatus methanolic extract and its partially purified fraction at a dose of 50mg/kg (PET-1) and 0.5mg/kg (CT-1), respectively, showed significant protection against STZ-induced diabetic oxidative stress in rats with marked amelioration in lipid peroxidation byproducts level, antioxidant enzymes, nephroprotective and retinoprotective effects and plasma total antioxidant levels after treatment of 28 days. The combined results demonstrated significant protection against STZ-induced oxidative stress, nephropathy and retinopathy condition by P. virgatus methanolic extract and its bioactive compound. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MGO), a reactive dicarbonyl metabolite is a potent arginine directed glycating agent which has implications for diabetes-related complications. Dicarbonyl metabolites are produced endogenously and in a state of misbalance, they contribute to cell and tissue dysfunction through protein and DNA modifications causing dicarbonyl stress. MGO is detoxified by glyoxalase 1 (GLO1) system in the cytoplasm. Reactive oxygen species (ROS) are known to aggravate the glycation process. Both the processes are closely linked, and their combined activity is often referred to as “glycoxidation” process. Glycoxidation of proteins has several consequences such as type 2 diabetes mellitus (T2DM), aging etc. In this study, we have investigated the glycation of low-density lipoprotein (LDL) using different concentrations of MGO for varied incubation time periods. The structural perturbations induced in LDL were analyzed by UV–Vis, fluorescence, circular dichroism spectroscopy, molecular docking studies, polyacrylamide gel electrophoresis, FTIR, thermal denaturation studies, Thioflavin T assay and isothermal titration calorimetry. The ketoamine moieties, carbonyl content and HMF content were quantitated in native and glycated LDL. Simulation studies were also done to see the effect of MGO on the secondary structure of the protein. We report structural perturbations, increased carbonyl content, ketoamine moieties and HMF content in glycated LDL as compared to native analog (native LDL). We report the structural perturbations in LDL upon modification with MGO which could obstruct its normal physiological functions and hence contribute to disease pathogenesis and associated complications. [ABSTRACT FROM AUTHOR]