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Simple Summary: Pancreatic cancer (PanCa) is one of the deadliest forms of cancer with limited therapeutic options. The available conventional therapies are highly toxic and often show resistance. Accumulating evidence suggests that dysregulated ribosome biogenesis has been linked to the survival and aggressive phenotypes of many tumor types, including PanCa. Thus, targeting ribosome biogenesis could be a novel approach for suppressing the growth of PanCa. The current study aimed to investigate the anti-cancer efficacy and underlying molecular mechanisms of honey against PanCa. Our results demonstrated that honey induces apoptosis and inhibits the growth and invasive potential of PanCa cells by targeting ribosome biogenesis components and c-Myc expression. This study suggests that honey can be used as an adjuvant along with conventional chemo/radiation therapy or immunotherapy for the management of PanCa. Pancreatic cancer (PanCa) is one of the deadliest cancers, with limited therapeutic response. Various molecular oncogenic events, including dysregulation of ribosome biogenesis, are linked to the induction, progression, and metastasis of PanCa. Thus, the discovery of new therapies suppressing these oncogenic events and ribosome biogenesis could be a novel therapeutic approach for the prevention and treatment of PanCa. The current study was designed to investigate the anti-cancer effect of honey against PanCa. Our results indicated that honey markedly inhibited the growth and invasive characteristics of pancreatic cancer cells by suppressing the mRNA expression and protein levels of key components of ribosome biogenesis, including RNA Pol-I subunits (RPA194 and RPA135) along with its transcriptional regulators, i.e., UBTF and c-Myc. Honey also induced nucleolar stress in PanCa cells by reducing the expression of various nucleolar proteins (NCL, FBL, and NPM). Honey-mediated regulation on ribosome biogenesis components and nucleolar organization-associated proteins significantly arrested the cell cycle in the G2M phase and induced apoptosis in PanCa cells. These results, for the first time, demonstrated that honey, being a natural remedy, has the potential to induce apoptosis and inhibit the growth and metastatic phenotypes of PanCa by targeting ribosome biogenesis. [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]

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]

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]

A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a–4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a–4h), 4a has a substantial binding affinity (∆G) −6.65, −6.55, −8.73, and −7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems. [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]

This study initially aimed to depict the molecular rationale evolving the role of lycopene in inhibiting the enzymatic activity of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase viain vitroandin silicoanalysis. Our results illustrated that lycopene exhibited strong HMG-CoA reductase inhibitory activity (IC50value of 36 ng/ml) quite better than pravastatin (IC50 = 42 ng/ml) and strong DPPH free radical scavenging activity (IC50value = 4.57 ± 0.23 μg/ml) as compared to ascorbic acid (IC50value = 9.82 ± 0.42 μg/ml). Moreover, theKivalue of lycopene (36 ng/ml) depicted via Dixon plot was well concurred with an IC50value of 36 ± 1.8 ng/ml. Moreover, molecular informatics study showed that lycopene exhibited binding energy of −5.62 kcal/mol indicating high affinity for HMG-CoA reductase than HMG-CoA (ΔG: −5.34 kcal/mol). Thus,in silicodata clearly demonstrate and support thein vitroresults that lycopene competitively inhibit HMG-CoA reductase activity by binding at the hydrophobic portion of HMG-CoA reductase. [ABSTRACT FROM PUBLISHER]

Metabolic syndrome (MetS) is an ever-evolving set of diseases that poses a serious health risk in many countries worldwide. Existing evidence illustrates that individuals with MetS have a 30%-40% higher chance of acquiring type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or both. This study was undertaken to uncover the regulatory role of natural organosulfur compounds (OSCs), S-allyl-L-cysteine (SAC), and S-ethyl-L-cysteine (SEC), in targeting high carbohydrate high fat (HCHF)-diet-induced MetS-associated risk management. Our findings suggested that SAC and SEC ameliorated HCHF-diet-induced diabetic profiles, plasma lipid and lipoprotein level, liver function, oxidative-stress, inflammatory cytokines, and chemokines including monocyte chemoattractant protein-1 (MCP-1), lipid peroxidation, plasma proprotein convertase subtilisin/kexin type-9 (PCSK-9), and high-sensitivity C-reactive protein (hs-CRP). Moreover, the assessment of the hepatic mRNA expression of the key genes involved in cholesterol homeostasis depicted that SAC and SEC downregulated the PCSK-9 mRNA expression via targeting the expression of HNF-1α, a transcriptional activator of PCSK-9. On the other hand, the LDL-receptor (LDL-R) expression was upregulated through the activation of its transcriptional regulator sterol regulatory element binding protein-2 (SREBP-2). In addition, the activity and the mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme-A reductases (HMG-R) and peroxisome proliferator-activated receptors (PPARs) were also improved by the treatment of SAC and SEC. We concluded that SAC and SEC can protect against MetS via improving the lipid and lipoprotein content, glycemic indices, hepatic function, targeting the inflammatory cascades, and oxidative imbalance, regulation of the mRNA expression of PCSK-9, LDL-R, SREBP-2, HNF-1α, PPARs, and inflammatory biomarkers., (© 2024 John Wiley & Sons Ltd.)