Toxicity prediction and analysis of flavonoid apigenin as a histone deacetylase inhibitor: an in-silico approach.

Occurrence of cancer is driving up on a global scale that exerts greater implications on the physical, psychological and economic stability of the human population. In the present context, numerous research studies are being conducted to explore and discover the drug molecule as an anticancer agent. Diverse scales of flavonoids entail the human diet, and they displayed prospective curative effects against an array of ailments. Among different categories of flavonoids, apigenin a trihydroxy flavone has been proven to have various pharmacological effects. Molecular docking is a key tool in structural molecular biology and computer assisted drug design. In this study, HDAC inhibitory action of apigenin and its probable toxicity was assessed by docking study using Auto dock platform. Molecular dynamics simulation was done by using iMODS server for elucidating the stability of the receptor-ligand complex. Toxicity predictions were evaluated by using tools such as CarcinoPred for carcinogenicity study, pkCSM for ADMET analysis, ProTox-II for rodent oral toxicity, lazar for estimating mutagenicity, BOILED Egg plot analysis for examining the gastrointestinal absorption and blood brain permeability, PASS prediction to identify the various biological functions and DruLiTo program to compute the drug likeness property.

Antineoplastic activity of plant-derived compounds mediated through inhibition of histone deacetylase: a review.

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated.

Epidemics and local governments in struggling nations: COVID-19 in Lebanon.

Municipalities in Lebanon represent local governments at the basic community level. The proximity of the municipality to the local community and its knowledge of available resources, can be crucial in easing the impact of any disaster. This study aimed to document the range of preparedness/reactivity of municipalities as COVID-19 swept through Lebanon. A qualitative case study was implemented to explore municipal response to control the epidemic, using in-depth semi-structured interviews with twenty-seven stakeholders from nine municipalities across all governorates in Lebanon. In each municipality, participants included mayors/deputy mayors, available members of municipal councils, prominent community leaders, health care professionals, and managers of local NGOs. The collected data were analyzed using the comparative thematic analysis. The socioecological model was adopted to illustrate the dynamic interplay between the barriers and facilitators at all ecological levels. The response to the pandemic differed significantly in volume and nature among different municipalities across regions, with rural areas clearly disadvantaged in terms of adequacy and completeness of response. Barriers consistently mentioned by most municipalities included economic collapse and poverty, shortage in resources, lack of support from the central government, stigma, lack of awareness, underreporting, flaws in the MOPH surveillance system, impeded accessibility to healthcare services, limited number and weak role of municipal police, increased mental illnesses, and political patronage, favoritism, and interference. On the other hand, increased donations, community engagement, social support and empathy, sufficient human resources, the effective role of healthcare systems, and good governance were identified as key facilitators. The socioecological model identified several multi-level facilitators and loopholes which can be addressed through a suggested strategic "roadmap" providing evidence-based interventions for future epidemics. It is crucial meanwhile that the central government strengthens the administrative and financial resources of municipalities in preparing and rapidly deploying the expected optimal response.

Rapid construction of substituted 3-amino-1,5-benzothiazepin-4(5H)-one dipeptide scaffolds through an Ugi-4CR - Ullmann cross-coupling sequence.

A 3-step methodology for the synthesis of 1,5-benzothiazepin-4(5H)-one dipeptidomimetics has been elaborated via an Ugi-4CR followed by a S-trityl deprotection and an intramolecular Cu(i)-catalyzed Ullmann condensation with moderate to good yields. In silico and NMR conformational studies showed that the lowest energy conformers stabilize γ- and ß-turn structures.

Efficient one-pot synthesis of amino-benzotriazolodiazocinone scaffolds via catalyst-free tandem Ugi-Huisgen reactions.

Herein we describe a catalyst-free, one-pot procedure employing an Ugi-4CR between propargyl glycine, functionalised 2-azidoanilines, different isocyanides and aldehydes, followed by a thermal azide-alkyne Huisgen cycloaddition to generate a 14-member set of amino-benzotriazolodiazocine-bearing dipeptides with multiple points of diversification and high atom economy. These structures were derivatized by means of Suzuki-Miyaura cross-coupling reactions at two positions with good to excellent yields, leading to conformationally constrained tricyclic structures. In silico and NMR conformational analysis studies demonstrated that turn conformations are adopted by these structures.

Efficient synthesis of conformationally constrained, amino-triazoloazepinone-containing di- and tripeptides via a one-pot Ugi-Huisgen tandem reaction.

Herein we describe a catalyst-free procedure employing an Ugi-4CR between a ß-azido-α-amino acid, propargylamine, an isocyanide and an aldehyde, followed by a thermal azide-alkyne Huisgen cycloaddition to generate a 16-member library of amino-triazoloazepinone-bearing di- and tripeptides with up to four points of diversification and high atom economy.

[Extra-anatomical bypass for an atypical coarctation of aorta associated with hypertensive heart failure; report of a case].

A 60-year-old woman with hypertension for 40 years had presented the hypertensive heart failure due to an atypical coarctation of the aorta. The difference of blood pressure between upper and lower limbs reached 110 mmHg with taking 6 kinds of antihypertensive drugs. Her blood pressure declined without antihypertensive medication and heart failure got subsided after the extra-anatomical bypass of axillobilateral external iliac artery bypass. Extra-anatomical bypass for Takayasu's arteritis had enough effects to improve the hypertension and was supposed to have the advantages of decreasing the operative risk, and preventing the aneurysmal formation of anastomotic site rather than the thoracoabdominal aortic bypass.

[Bilateral coronary-pulmonary artery fistulae without cardiopulmonary bypass].

A 68-year-old female with heart failure was admitted on the probable diagnosis of patent ductus arteriosus. Coronary arteriography revealed the coronary-pulmonary artery fistulae which originated the bilateral coronary arteries. Excision of coronary artery fistulae was performed without cardiopulmonary bypass. The symptom of heart failure has been improved for postoperative 6 years. Coronary pulmonary artery fistula is commonly a meanders long and flowing into the pulmonary artery as one influx artery. We presume the surgical intervention without cardiopulmonary bypass would be adopted for the treatment of this type. Multidetector-row computed tomography (MD CT) is useful in verification to detect the perioperative fistulae.