Early coronary angioplasty fails to lower all-cause mortality in patients with out-of-hospital cardiac arrest without ST-segment elevation: A systematic review and meta-analysis.

Introduction: Out-of-hospital cardiac arrest (OHCA) is defined as the loss of functional mechanical activity of the heart in association with an absence of systemic circulation, occurring outside of a hospital. Immediate coronary angiography (CAG) with percutaneous coronary intervention is recommended for OHCA with ST-elevation. We aimed to evaluate the effect of early CAG on mortality and neurological outcomes in OHCA patients without ST-elevation. Methods: This meta-analysis and systemic review was conducted as per principles of Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) group. A protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO, Ref No. = CRD42022327833). A total of 674 studies were retrieved after scanning several databases (PubMed Central, EMBASE, Medline, and Cochrane Central Register of Controlled Trials). Results: A total of 18 studies were selected for the final analysis, including 6 randomized control trials and 12 observational studies. Statistically, there was no significant difference in primary outcome, i.e., mortality, between early and delayed CAG. In terms of the grade of neurological recovery as a secondary outcome, early and delayed CAG groups also showed no statistically significant difference. Conclusion: Early CAG has no survival benefits in patients with no ST elevations on ECG after OHCA.

2-Oxoquinoline-based-thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors.

Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long-term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2-oxoquinoline-based thiosemicarbazones 9a-r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO-A and MAO-B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO-A, MAO-B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 µM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

Synthesis, biological evaluation and molecular modelling of 3-Formyl-6-isopropylchromone derived thiosemicarbazones as α-glucosidase inhibitors.

Type-2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders in the world and over the past three decades its incidence has increased drastically. α-Glucosidase inhibitors are used to control the hyperglycemic affect of T2DM. Herein, we report the synthesis, α-glucosidase inhibition, structure activity relationship, pharmacokinetics and docking analysis of various novel chromone based thiosemicarbazones 3(a-r). The derivatives displayed potent activity against α-glucosidase with IC50 in range of 0.11 ± 0.01-79.37 ± 0.71 µM. Among all the synthesized compounds, 3a (IC50 = 0.17 ± 0.026 µM), 3 g (IC50 = 0.11 ± 0.01 µM), 3n (IC50 = 0.55 ± 0.02 µM), and 3p (IC50 = 0.43 ± 0.025 µM) displayed higher inhibitory activity as compared to the standard, acarbose. Moreover, we have developed a statistically significant 2D-QSAR model (R2tr:0.9693; F: 50.4647 and Q2LOO:0.9190), which can be used in future to further design potent thiosemicarbazones as inhibitors of α-glucosidase.

Synthesis, biological evaluation, and molecular docking study of chromen-linked hydrazine carbothioamides as potent α-glucosidase inhibitors.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen-linked hydrazine carbothioamide (3a-r) were designed and synthesized by condensation of chromone-3-carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques (1 H NMR, 13 C NMR, and ESI-MS). The resulted compounds were screened for α-glucosidase inhibitory potential and all the compounds (3a-r) exhibited potent inhibition of α-glucosidase with IC50 values ranging 0.29-53.70 µM. Among them compounds 3c, 3f, 3h, and 3r displayed the highest α-glucosidase inhibitor capability with IC50 values of 1.50, 1.28, 1.08, and 0.29 µM, respectively. Structure-activity relationship showed that different substituted groups are responsible for the variation in the α-glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 ± 0.31 µM. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H-bonding, or π-π stacking, with the key residues of α-glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of α-glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a-r reflects that these molecules have acceptable range of these properties.

Endothelial-Specific Expression of CIDEC Improves High-Fat Diet-Induced Vascular and Metabolic Dysfunction.

Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), originally identified to be a lipid droplet-associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells and regulates vascular function. The current study was designed to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg mice exhibited protection against high-fat diet-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, these mice displayed improved insulin signaling and endothelial nitric oxide synthase activation, enhanced endothelium-dependent vascular relaxation, and improved vascularization of adipose tissue, skeletal muscle, and heart. Mechanistically, we identified a novel interplay of CIDEC-vascular endothelial growth factor A (VEGFA)-vascular endothelial growth factor receptor 2 (VEGFR2) that reduced VEGFA and VEGFR2 degradation, thereby increasing VEGFR2 activation. Overall, our results demonstrate a protective role of endothelial CIDEC against obesity-induced metabolic and vascular dysfunction, in part, by modulation of VEGF signaling. These data suggest that CIDEC may be investigated as a potential future therapeutic target for mitigating obesity-related cardiometabolic disease.

Neuroprotective Effects of Shogaol in Metals (Al, As and Pb) and High-fat diet-induced Neuroinflammation and Behavior in Mice.

BACKGROUND: Increased exposure of humans to toxic metals and high-fat diet (HFD) consumption severely damages brain health. Natural plant extracts have shown huge potential to treat multiple human diseases. OBJECTIVE: The present study was designed to evaluate the protective effects of Shogaol (an active component of ginger) in neuroinflammation and behavioral paradigms in mice treated with metals and HFD. METHODS: 8-11 weeks old male mice model was developed by giving a combination of metals, i.e., Arsenic (As), Lead (Pb) and Aluminum (Al), 25mg/kg each mixed in drinking water with laboratory prepared HFD (40% fat) for a total duration of 72 days. Shogaol treated groups received two doses (2mg/kg & 12mg/kg) of Shogaol along with metals and HFD. The biochemical parameters, including body weights, blood glucose, and kidney and liver functions, were assessed along with the integrity of the blood-brain barrier (BBB). The expression analysis of neuroinflammatory genes (TNF-α, IL-1ß & GFAP) was performed using q-PCR in the hippocampus and cortex. The exploratory and anxiety-like behavior was assessed using an open field test, and depressive behavior was assessed through the forced swim test, while learning and memory were assessed using the Morris water maze test and y-maze test. RESULTS: Shogaol (2mg/kg & 12mg/kg) treatment improved metabolic profile and reduced expression of neuroinflammatory genes in the cortex and the hippocampus. Shogaol treatment improved BBB integrity. Results of the behavioral analysis showed that Shogaol treatment (2mg/kg & 12mg/kg) rescued behavioral impairment and improved anxiety and depression. CONCLUSION: Shogaol treatment showed strong therapeutic potential in metals & HFD induced neuroinflammation and improved cognitive functions; thus, can be considered a potential drug candidate in the future.

Role of anticoagulation in lowering the mortality in hospitalized covid-19 patients: Meta-analysis of available literature.

OBJECTIVES: To reducing the risk of venous thromboembolic (VTE) events and subsequent mortality in covid-19 patients is still a matter of research. This systematic review and meta-analysis serve the purpose of comparing the mortality associated with the intensity of anticoagulation in patients admitted with covid-19. METHODS: A total of 7120 patients were recruited in 11 studies comparing using prophylactic anticoagulants against therapeutic anticoagulants. RESULTS: Our study showed that using prophylactic anticoagulants was associated with a 42% reduction in mortality compared to therapeutic anticoagulants (OR 0.58 (95% CI:0.676-0.499), p=0.000). Also, we assessed mortality in patients using no anticoagulants against using prophylactic anticoagulants. A total of 6069 patients were recruited in 4 studies in which 2 studies significantly favored prophylactic anticoagulants in terms of reducing mortality. Cumulatively, the meta-analysis showed that using prophylactic anticoagulants was associated with a 5% reduction in mortality but without any statistical significance: (OR 1.049 [95% CI 1.237 - 0.865]) (p=0.626). CONCLUSION: Our meta-analysis favors using prophylactic anticoagulation in covid-19 patients reduces all-cause mortality in comparison to therapeutic anticoagulation however the impact on mortality when compared with no anticoagulation was not significant.PROSPERO Number: CRD42021257320.

Quinoline based thiosemicarbazones as colorimetric chemosensors for fluoride and cyanide ions and DFT studies.

High toxicity and extensive accessibility of fluoride and cyanide ions in diverse environmental media encouraged attention for scheming well-organized probes for their detection. Keeping in mind we have designed and synthesized thiosemicarbazone-based chemosensors RB-1, RB-2 and RB-3 for the detection of fluoride and cyanide ions. The structural elucidation of the synthesized chemosensors is done by employing different analytical techniques including nuclear magnetic resonance and electronic absorption specrtoscopies. Admirable detection limit, binding constant and fast response time (2 s) to F- and CN- ions enlarged the applications of these chemosensors. Additional confirmation of the sensing ability of these chemosensors is derived from DFT and TDDFT calculations with M06/6-311G(d,p) method by performing FMO, UV-Vis, QTAIM and global reactivity parameters elucidation. Overall results point out that investigated chemosensors are suitable candidates for sensing the F- ions. These chemosensors were successfully applied to detect F- ions in a commercial toothpaste sample.

Acquired methemoglobinemia: A systematic review of reported cases.

INTRODUCTION: Acquired methemoglobinemia may cause cyanosis and tissue ischemia unresponsive to oxygen supplementation. METHODS: We performed a literature search to identify cases of acquired methemoglobinemia published between 1980 and 2020. Clinical, diagnostic, and treatment details were extracted from eligible cases. RESULTS: A total of 76 reports involving 87 cases were analyzed. The median age at presentation was 32.5 with male to female ratio of 1.6. Cyanosis and SpO2 <90 % were reported in 82 % and 60 % of cases, respectively. Dapsone or cocaine-based anesthetics were causative in 52 % of cases; most anesthetic-related cases occurred in the peri-procedural setting. Methylene blue (MB) and red cell transfusion were given in 71 % and 10 % of cases, respectively. Compared to MB untreated patients, MB treated patients were more likely to be cyanotic (91.9 % vs 54.2 %), had higher proportions (%) and levels (g/dL) of methemoglobin (MetHb) - 33.2 % vs 15.3 % and 3.1 g/dL vs 1.2 g/dL, respectively. We found that among cyanotic cases, the median MetHb level was 3.0 g/dL (0.4-12.3 g/dL) with 74 % of values ≥ 1.5 g/dL. An SaO2:SpO2 ratio of >1 was not universally present, but always coincided with an [SaO2-SpO2] delta value greater than zero. CONCLUSIONS: Cyanosis and hypoxemia were not universal findings of acquired methemoglobinemia in our series. In addition, not all patients had cyanosis at MetHb ≥ 1.5 g/dL or an SaO2:SpO2 ratio of >1. All those with an SaO2:SpO2 >1 did, however, have a delta value greater than zero - a finding not previously reported which we feel holds diagnostic value.

Therapeutic potential of N4-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach.

Urease enzyme plays a key role in pathogenesis of gastritis and peptic ulcers. Its inhibition averts our bodies from many disorders including formation of urinary calculi. In agriculture, the high urease content causes severe environmental and hence economic problems. Due to deficiency of effective and safer drugs to tackle the aforementioned disorders, the quest for new scaffolds becomes mandatory in the field of medicinal chemistry. In this regard, we herein report a new series of N4-substituted thiosemicarbazones 3a-v as potential candidates for urease inhibition. These new N4-substituted thiosemicarbazones 3a-v of distant chemical scaffolds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR, ESI-MS and in the case of compound 3g by single crystal X-ray analysis. The compounds were evaluated for their urease inhibitory potential. All newly synthesized compounds showed significant urease inhibitions with IC50 values in range of 2.7 ± 0.320-109.2 ± 3.217 µM. Molecular docking studies were used for interactions pattern and structure-activity relationship for all compounds, which demonstrated excellent binding interactions with the active site residues, such as hydrogen bonding, π-π interactions, π-H and nickel atom coordination.

Exploration of Chromone-Based Thiosemicarbazone Derivatives: SC-XRD/DFT, Spectral (IR, UV-Vis) Characterization, and Quantum Chemical Analysis.

By the condensation of thiosemicarbazide with coumarin aldehyde, two novel substituted thiosemicarbazones with chemical formulae C24H25N3O3S (3a) and C26H23N3O3S (3b) have been synthesized. The synthesized compounds were resolved using SC-XRD, and structure elucidation was carried out using 1H NMR, 13C NMR, UV-visible, and FT-IR spectroscopic analyses. Computational calculations at the B3LYP/6-311+G(d,p) level of theory were performed to countercheck the experimental (UV-vis, FT-IR) findings and explore the electronic (FMO, NBO, MEP) properties of 3a-b. The nonlinear optical (NLO) properties of 3a-b were estimated using B3LYP, HF, LC-BLYP, CAM-B3LYP, M062X, and M06 functionals in combination with the 6-311+G(d,p) basis set. The crystallographic data revealed that compounds were crystallized as an orthorhombic crystal lattice with the Pbcn space group and the triclinic crystal lattice with the P̅1 space group. A good concurrence among experimental SC-XRD-generated bond lengths, bond angles, FT-IR, UV-vis, and corresponding DFT results was found, which confirms the purity of both compounds. The NBO analysis confirmed the presence of intramolecular hydrogen bonding and hyperconjugative interactions, which not only were the pivotal cause of stability of the investigated compounds but also led to an overwhelming NLO response. The energy differences calculated for HOMO/LUMO are 3.053 and 3.118 eV in 3a and 3b, respectively. The crystal 3b showed a higher value of first-order polarizability at all levels of theory than 3a. Overall results show that the crystals under investigation are polarized in nature with a good dipole moment. A comparative analysis with urea molecules clearly indicates that the studied compounds are acceptable NLO candidates and they can be used for future technological applications.