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Globally, the prevalence of breast cancer (BC) is increasing at an alarming level, despite early detection and technological improvements. Alkaloids are diverse chemical groups, and many within this class have been reported as potential anticancer compounds. Chabamide F (F) and chabamide G (G) are two dimeric amide alkaloids found in a traditional medicinal plant, Piper chaba , and possess significant cytotoxic effects. However, their scientific rationalization in BC remains unknown. Here, we aimed to investigate their potential and molecular mechanisms for BC through in silico approaches. From network pharmacology, we identified 64 BC-related genes as targets. GO and KEGG studies showed that they were involved in various biological processes and mostly expressed in BC-related pathways such as RAS, PI3K-AKT, estrogen, MAPK, and FoxO pathways. However, PPI analysis revealed SRC and AKT1 as hub genes, which play key roles in BC tumorigenesis and metastasis. Molecular docking revealed the strong binding affinity of F (− 10.7 kcal/mol) and G (− 9.4 and − 11.7 kcal/mol) for SRC and AKT1, respectively, as well as the acquisition of vital residues to inhibit them. Their long-term stability was evaluated using 200 ns molecular dynamics simulation. The RMSD, RMSF, Rg, and SASA analyses showed that the G-SRC and G-AKT1 complexes were excellently stable compared to the control, dasatinib, and capivasertib, respectively. Additionally, the PCA and DCCM analyses revealed a significant reduction in the residual correlation and motions. By contrast, the stability of the F-SRC complex was greater than that of the control, whereas it was moderately stable in complex with AKT1. The MMPBSA analysis demonstrated higher binding energies for both compounds than the controls. In particular, the binding energy of G for SRC and AKT1 was − 120.671 ± 16.997 and − 130.437 ± 19.111 kJ/mol, respectively, which was approximately twice as high as the control molecules. Van der Waal and polar solvation energies significantly contributed to this energy. Furthermore, both of them exhibited significant interactions with the binding site residues of both proteins. In summary, this study indicates that these two molecules could be a potential ATP-competitive inhibitor of SRC and an allosteric inhibitor of AKT1.

Dopamine receptor D4 (DRD4) plays a vital role in regulating various physiological functions, including attention, impulse control, and sleep, as well as being associated with various neurological diseases, including attention deficit hyperactivity disorder, novelty seeking, and so on. However, a comprehensive analysis of harmful nonsynonymous single nucleotide polymorphisms (nsSNPs) of the DRD4 gene and their effects remains unexplored. The aim of this study is to uncover novel damaging missense nsSNPs and their structural and functional effects on the DRD4 receptor. From the dbSNP database, we found 677 nsSNPs, and then we analyzed their functional consequences, disease associations, and effects on protein stability with fifteen in silico tools. Five variants, including L65 ICL1 P (rs1459150721), V116 3.33 D (rs761875546), I129 3.46 S (rs751467198), I156 4.46 T (rs757732258), and F201 5.47 S (rs199609858), were identified as the most deleterious mutations that were also present in the conserved region and showed lower interactions with neighboring residues. To comprehensively understand their impact, we docked agonist dopamine and antagonist nemonapride at the binding site of the receptor, followed by 200 ns molecular dynamics simulations. We identified the V116D and I129S mutations as the most damaging, followed by F201S in the dopamine-bound states. Both the V116D and I129S variants demonstrated significantly high RMSD, Rg, and SASA, and low thermodynamic stability. The F201S-dopamine complex exhibited lower compactness and higher motions, along with a significant loss of hydrogen bonds and active site interactions. By contrast, while interacting with nemonapride, the impact of the I156T and L65P mutations was highly deleterious; both showed lower stability, higher flexibility, and higher motions. Additionally, nemonapride significantly lost interactions with the active site, notably in the I156T variant. We also found the V116D-nemonapride complex as structurally damaging; however, the interaction patterns of nemonapride were less altered in the MMPBSA analysis. Overall, this study revealed five novel deleterious variants along with a comprehensive understanding of their effect in the presence of an agonist and antagonist, which could be helpful for understanding disease susceptibility, precision medicine, and developing potential drugs.

Liver diseases are quite prevalant in many densely populated countries, including Bangladesh. The liver and its hepatocytes are targeted by virus and microbes, as well as by chemical environmental toxicants, causing wide-spread disruption of metabolic fuctions of the human body, leading to death from end-stage liver diseases. The aim of this review is to systematically explore and record the potential of Bangladeshi ethnopharmacological plants to treat liver diseases with focus on their sources, constituents, and therapeutic uses, including mechanisms of actions (MoA). A literature survey was carried out using Pubmed, Google Scholar, ScienceDirect, and Scopus databases with articles reported until July, 2020. A total of 88 Bangladeshi hepatoprotective plants (BHPs) belonging to 47 families were listed in this review, including Euphorbiaceae, Cucurbitaceae, and Compositae families contained 20% of plants, while herbs were the most cited (51%) and leaves were the most consumed parts (23%) as surveyed. The effect of BHPs against different hepatotoxins was observed via upregulation of antioxidant systems and inhibition of lipid peroxidation which subsequently reduced the elevated liver biomarkers. Different active constituents, including phenolics, curcuminoids, cucurbitanes, terpenoids, fatty acids, carotenoids, and polysaccharides, have been reported from these plants. The hepatoameliorative effect of these constituents was mainly involved in the reduction of hepatic oxidative stress and inflammation through activation of Nrf2/HO-1 and inhibition of NF-κB signaling pathways. In summary, BHPs represent a valuable resource for hepatoprotective lead therapeutics which may offer new alternatives to treat liver diseases.

Fenugreek (Trigonella foenum‐graecum) is a widely grown dietary herb in Asia, and its seeds are traditionally used for several diseases, including diabetes. The seeds and leaves possess a variety of compounds that play an important role in regulating their hypoglycemic effect. However, so far, no extensive systematic review exists on its antidiabetic effect, highlighting the molecular mechanisms and isolated compounds. The purpose of this review is to summarize the preclinical and clinical antidiabetic properties of fenugreek and its isolated compounds by focusing on underlying mechanisms. PubMed, Google Scholar, Science Direct, and Scopus databases were searched to retrieve articles until June, 2024. Preclinical studies demonstrated that the antidiabetic effect of fenugreek was mostly associated with enhanced glucose transporter type‐4 (GLUT4) translocation and hexokinase activity, decreased glucose‐6‐phosphatase and fructose‐1,6‐bisphosphatase activities, inhibited α‐amylase and maltase activities, protected β cells, and increased insulin release. Furthermore, few studies have reported its role as a glucagon‐like peptide‐1 (GLP‐1) modulator, 5′‐AMP‐activated kinase (AMPK) activator, and dipeptidyl peptidase‐IV (DPP‐IV) inhibitor. Further clinical trials showed that fenugreek seeds improved blood glucose levels, insulin resistance, insulin sensitivity, and lipid profiles. This study highlights significant evidence of the antidiabetic effect of fenugreek and its isolated compounds; therefore, it could be a potential therapy for diabetes. This systematic review has been conducted on 98 preclinical and 24 clinical antidiabetic studies of fenugreek and its isolated compounds. We have found significant antidiabetic effect of fenugreek that is primarily a consequence of activation of the PI3K/Akt pathway, restoration of glucose homeostasis, and protection of the β cells. The clinical studies further revealed that fenugreek reduced blood glucose and insulin resistance and enhanced insulin sensitivity.