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A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer’s disease (AD). The results showed that the target compounds 5a – l and 7e – m exhibited significant anti-Aβ aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced Aβ aggregation (74% and 71.4%, 25 μM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aβ fibrils generated by Cu 2+ -induced Aβ aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC 50 values of 0.056 μM and 0.121 μM, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546–5.86 Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment. [ABSTRACT FROM AUTHOR]

Drug safety for the patients is of paramount importance for a medical professional. Pharmacovigilance attempts to ensure the safety of patients by keeping a close vigil on the pattern of adverse events secondary to drug use. Number of medicolegal cases is at rise since last few years. Forensic sciences and pharmacovigilance need to work hand in hand to unlock the mystery of many criminal and civil proceedings. Pharmacovigilance offers its wide scope in forensic sciences by putting forward its expertise on adverse profile of drugs which may be instrumental in solving the cases and bringing the justice forth. It may range from as simple affairs as defining the adverse drug reaction on one hand to putting expert advice in critical criminal cases on the other one. Pharmacovigilance experts have to abide by the ethics of the practice while executing their duties as expert else it may tarnish the justice and loosen its dependability. As a budding discipline of science, it is confronted with several hurdles and challenges which include reluctance of medical professionals for being involved in court proceedings, extrapolations of facts and data and variations in law across the globe etc. These challenges and hurdles call the medical fraternity come forward to work towards the momentous application of pharmacovigilance in the forensic sciences. Evidence based practice e.g. testing the biological samples for the presence of drugs may prove to be pivotal in the success of this collaboration of sciences. [ABSTRACT FROM AUTHOR]

Ubiquitin, a post-translational protein modifier inside the cell, functions as a CXC chemokine receptor (CXCR) 4 agonist outside the cell. However, the structural determinants of the interaction between extracellular ubiquitin and CXCR4 remain unknown. Utilizing C-terminal truncated ubiquitin and ubiquitin mutants, in which surface residues that are known to interact with ubiquitin binding domains in interacting proteins are mutated (Phe-4, Leu-8, Ile-44, Asp-58, Val-70), we provide evidence that the ubiquitin-CXCR4 interaction follows a two-site binding mechanism in which the hydrophobic surfaces surrounding Phe-4 and Val-70 are important for receptor binding, whereas the flexible C terminus facilitates receptor activation. Based on these findings and the available crystal structures, we then modeled the ubiquitin-CXCR4 interface with the RosettaDock software followed by small manual adjustments, which were guided by charge complementarity and anticipation of a conformational switch of CXCR4 upon activation. This model suggests three residues of CXCR4 (Phe-29, Phe-189, Lys-271) as potential interaction sites. Binding studies with HEK293 cells overexpressing wild type and CXCR4 after site-directed mutagenesis confirm that these residues are important for ubiquitin binding but that they do not contribute to the binding of stromal cell-derived factor 1α. Our findings suggest that the structural determinants of the CXCR4 agonist activity of ubiquitin mimic the typical structure-function relationship of chemokines. Furthermore, we provide evidence for separate and specific ligand binding sites on CXCR4. As exogenous ubiquitin has been shown to possess therapeutic potential, our findings are expected to facilitate the structure-based design of new compounds with ubiquitin-mimetic actions on CXCR4. [ABSTRACT FROM AUTHOR]

Recently, we identified extracellular ubiquitin as an endogenous CXC chemokine receptor (CXCR) 4 agonist. However, the receptor selectivity and molecular basis of the CXCR4 agonist activity of ubiquitin are unknown, and functional consequences of CXCR4 activation with ubiquitin are poorly defined. Here, we provide evidence that ubiquitin and the cognate CXCR4 ligand stromal cell-derived factor (SDF)-la do not share CXCR7 as a receptor. We further demonstrate that ubiquitin does not utilize the typical two-site binding mechanism of chemokine-receptor interactions, in which the receptor N terminus is important for ligand binding. CXCR4 activation with ubiquitin and SDF-la lead to similar Gairesponses and to a comparable magnitude of phosphorylation of ERK-1/2, p90 ribosomal S6 kinase-l and Akt, although phosphorylations occur more transiently after activation with ubiquitin. Despite the similarity of signal transduction events after activation of CXCR4 with both ligands, ubiquitin possesses weaker chemotactic activity than SDF-la in cell migration assays and does not interfere with productive entry of HIV-1 into P4.R5 multinuclear activation of galactosidase indicator cells. Unlike SDF-la, ubiquitin lacks interactions with an N-terminal CXCR4 peptide in NMR spectroscopy experiments. Binding and signaling studies in the presence of antibodies against the N terminus and extracellular loops 2/3 of CXCR4 confirm that the ubiquitin CXCR4 interaction is independent of the N-terminal receptor domain, whereas blockade of extracellular loops 2/3 prevents receptor binding and activation. Our findings define ubiquitin as a CXCR4 agonist, which does not interfere with productive cellular entry of HIV-1, and provide new mechanistic insights into interactions between CXCR4 and its natural ligands. [ABSTRACT FROM AUTHOR]

Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD 184) agonist. Extracellular ubiquitin promotes intracellular Ca2+ flux and reduces cAMP levels through a G protein-coupled receptor that signals via a Gαi/o protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four Gαi/o PCRs as ubiquitin receptor candidates. Overexpression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1α (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identify CXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the major reason for death of women worldwide. As per the International Agency for Research on Cancer (IARC) statistics, the number of cases of breast cancer is increasing year by year in many parts of the world. As per the recent global cancer burden figures, in 2020, there were 2.26 million incidences of breast cancer cases and it is one of the main causes of mortality due to cancer in women in the world. Biomarkers of breast cancer would prove to be very beneficial to screen women who are at higher risk and for detection of disease recurrence. Here, studies carried out on biomarkers of breast cancer and susceptibility to the disease have been reviewed. Various databases like Google Scholar, ScienceDirect and PubMed have been used for searching and majorly literature from the last 10 years have been considered. Potential biomarkers of breast cancer including blood based angiogenic factors, glycoprotein-based biomarkers, hormone receptor biomarkers and other biomarkers that were identified from various studies have been summarized. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihypertensive properties. The present study was designed to evaluate the effect of novel DADS analogs, against L-NAME induced hypertension in Wistar rats. The daily administration of L-NAME (50mg/kg) for six weeks along with DADS analogs (20mg/kg) significantly decreased the elevated systolic blood pressure (SBP) and the activity of angiotensin converting enzyme (ACE) and also inhibited the decline in nitrite/nitrate (NO x ) concentrations and cyclic guanosine monophosphate (cGMP) levels. Adverse changes such as lipid peroxidation, protein damage and a decrease in the levels of antioxidant enzymes, were rectified after the administration of DADS analogs. Oral administration of DADS analogs preserved the expression of endothelial nitric oxide synthase (eNOS). The ability of the DADS analogs to inhibit L-NAME induced hypertension was compared with Enalapril (15mg/kg), which was taken as a standard. The DADS analogs prevented L-NAME-induced cardio toxicity, which was also reflected at the microscopic level indicative of its cardio protective effects. DADS analogs induced vasorelaxation was completely abolished by the removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. DADS analogs inhibited the calcium influx induced by phenylephrine (0.3μM) and high K+ (60mM) and this effect was completely abolished by pretreatment of L-NAME. Taken together, our results show that the DADS analogs induce vasorelaxation and have antihypertensive properties, which may be mediated through activation of eNOS. [Copyright &y& Elsevier]

A novel series of donepezil based multi-functional agents “( E )-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1 H -inden-1-ones” have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9 , IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9 , IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds ( IP-9 , IP-13 and IP-15 ) successfully diminished H 2 O 2 induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H 2 O 2 as well as Aβ induced toxicity in SH-SY5Y cells in a concentration dependent manner. Moreover, these derivatives did not exert any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of the compounds IP-9 , IP-13 and IP-15 , molecular docking studies and molecular dynamics (MD) simulation studies were also performed and the results indicate their significant interactions with the active sites of AChE as well as Aβ 1-42 peptide. Thus, the present study evidently showed that IP-9 , IP-13 and IP-15 are potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development. [ABSTRACT FROM AUTHOR]

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1 H -indene-1,3(2 H )-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27 – 38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC 50 = 0.048 μM: 34 ; 0.036 μM: 38 ), Aβ aggregation (max% inhibition 82.2%, IC 50 = 9.2 μM: 34 ; max% inhibition 80.9%, IC 50 = 10.11 μM: 38 ) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H 2 O 2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H 2 O 2 and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future. [ABSTRACT FROM AUTHOR]

A series of new cyanopyridine–triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer’s agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a – 4h against cholinesterases, Aβ 1–42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ 1–42 -induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC 50 values 0.059 and 0.080 μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H 2 O 2 -mediated oxidative stress and Aβ 1–42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine–triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer’s therapy. [ABSTRACT FROM AUTHOR]