Rapid Synthesis of Benzimidazole-Fused Isoindoles by Rh(III)/Ru(II)-Catalyzed [4 + 1] Cascade C-H/N-H Annulation of 2-Arylbenzimidazoles with Alkynoates and Alkynamide.

A Rh(III)-catalyzed [4 + 1] cyclization of 2-arylbenzimidazoles with alkynoates through C-H activation/ortho-alkenylation/intramolecular annulation cascade to obtain benzimidazole-fused isoindoles is reported. The reaction of the Rh catalyst and internal alkyne ester provides benzo[4,5]imidazo[2,1-a]isoindole acetate exclusively. Conversely, internal alkyne amide participates in the annulation process in the presence of a Ru catalyst to provide benzo[4,5]imidazo[2,1-a]isoindole acetamide. The alkyne acts as a C1 synthon and undergoes [4 + 1] cyclization rather than traditional [4 + 2] annulation.

Diversity in the ligand binding pocket of HapR attributes to its uniqueness towards several inhibitors with respect to other homologues - A structural and molecular perspective.

Vibrio cholerae is a prolific bacterium. Cumulative studies clearly demonstrate the key role of quorum sensing on the lifecycle of this bacterium. Of the sensory network components, HapR is known as high cell density master regulator. Until now, no information is available on native HapR ligand despite the protein having a ligand binding pocket. Interestingly, function of SmcR, a HapR homologue of Vibrio vulnificus is inhibited by a small molecule Qstatin. Structural analysis of SmcR with Qstatin identifies key interacting residues in SmcR ligand binding domain. Despite bearing significant homology with SmcR, HapR function remained unabated by Qstatin. Sequence alignment indicates divergence in the key residues of ligand binding pocket between these two regulators. A series of ligand binding domain mutants of HapR was constructed where only HapR quadruple mutant responded to Qstatin and newly synthesized IMT-VC-212. Crystal structure analysis revealed four key residues are responsible for changes in the volume of ligand binding pocket of HapR quadruple mutant compared to the wild type counterpart, thereby increasing the accessibility of Qstatin and its derivative in case of the former. The mechanistic insights exuberating from this study will remain instrumental in designing inhibitors against wild type HapR.

One-Pot Domino Reaction: Direct Access to Polysubstituted 1,4-Benzothiazine 1,1-Dioxide via Water-Gas Shift Reaction Utilizing DMF/H2O.

Benzothiazine 1,1-dioxide (BTDO) is a privileged chemical motif, and its metal-free domino access is in high demand. Current BTDO production methods require costly metal catalysts or harsh reaction conditions. A facile domino approach to BTDO via a water-gas shift reaction (WGSR) employing sodium 2-nitrobenzenesulfinates and α-bromo ketones is presented. This strategy is cost-effective and environmentally beneficial. The optimized reaction conditions demonstrated remarkable chemical tolerance to a wide range of electrically and sterically varied substituents on both coupling partners.

Ghrelin alleviates depression-like behaviour in rats subjected to high-fat diet and diurnal rhythm disturbance.

OBJECTIVES: In the era of globalization, a sedentary lifestyle is highly linked with obesity and neurobehavioral complications such as depression. While depression is associated with dopamine dysfunction in the ventral tegmental area (VTA), ghrelin enhances the dopaminergic activity in the VTA. Therefore, the present study aimed to assess the effect of ghrelin on depression-like behaviour in rats subjected to a high-fat diet (HFD) and disturbed diurnal rhythm (DDR) for 45 days. METHODS: The neurobehavioral deficits resulting from HFD and DDR in rats, and the behaviour modulation by intra-VTA administration of ghrelin, alone or in combination with ghrelin receptor antagonist were confirmed by evaluation of behavioural parameters in the elevated plus-maze, forced swim test, open field test, and rotarod assessment. Further, the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6, oxidative stress marker malondialdehyde (MDA), and antioxidants enzymes like superoxide dismutase (SOD), reduced glutathione (GSH), and catalase (CAT) were measured. RESULTS: The levels of TNF-α, IL-1ß, IL-6, and MDA were increased in the brain of HFD and DDR exposed rats, while that of SOD, GSH, and CAT were reduced. Intra-VTA ghrelin administration from day 41-45 to the HFD and DDR exposed rats improved cognitive behaviour and physical activity confirming the antidepressant effect. Moreover, ghrelin restored the levels of SOD, GSH and CAT efficiently, and reduced that of MDA, TNF-α, IL-1ß and IL-6, which signifies its protective effect. CONCLUSION: Overall, this study confirmed the ameliorative effect of ghrelin in HFD- and DDR-induced depression-like behaviour.

Comprehensive Review on the Degradation Chemistry and Toxicity Studies of Functional Materials.

In recent decades there has been growing interest of material chemists in the successful development of functional materials for drug delivery, tissue engineering, imaging, diagnosis, theranostic, and other biomedical applications with advanced nanotechnology tools. The efficacy and safety of functional materials are determined by their pharmacological, toxicological, and immunogenic effects. It is essential to consider all degradation pathways of functional materials and to assess plausible intermediates and final products for quality control. This review provides a brief insight into chemical degradation mechanisms of functional materials like oxidation, photodegradation, and physical and enzymatic degradation. The intermediates and products of degradation were confirmed with analytical methods such as proton nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), UV-vis spectroscopy (UV-vis), infrared spectroscopy (IR), differential scanning calorimetry (DSC), mass spectroscopy, and other sophisticated analytical methods. These analytical methods are also used for regulatory, quality control, and stability purposes in industry. The assessment of degradation is important to predetermine the behavior of functional materials in specific storage conditions and can be relevant to their behavior during in vivo applications. Another important aspect is the evaluation of the toxicity of functional materials. Toxicity can be accessed with various methods using in vitro, in vivo, ex vivo, and in silico models. In vitro cell culture methods are used to determine mitochondrial damage, reactive oxygen species, stress responses, and cellular toxicity. In vitro cellular toxicity can be measured by MTT assay, LDH leakage assay, and hemolysis. In vivo studies are performed using various animal models involving zebrafish, rodents (mice and rats), and nonhuman primates. Ex vivo studies are also used for efficacy and toxicity determinations of functional materials like ex vivo potency assay and precision-cut liver slice (PCLS) models. The in silico tools with computational simulations like quantitative structure-activity relationships (QSAR), pharmacokinetics (PK) and pharmacodynamics (PD), dose and time response, and quantitative cationic-activity relationships ((Q)CARs) are used for prediction of the toxicity of functional materials. In this review, we studied the principle methods used for degradation studies, different degradation pathways, and mechanisms of functional material degradation with prototype examples. We discuss toxicity assessments with different toxicity approaches used for estimation of the safety and efficacy of functional materials.

In-vivo and in-vitro evaluation of therapeutic potential of ß- Carotene in diabetes.

The present study was performed to investigate the therapeutic potential of ß- Carotene against STZ induced diabetes by using in vivo and in vitro models. MTT assay was performed to check the cytotoxic effect of ß- Carotene in HepG2 liver cells which were treated with ß- Carotene (10, 20 µM). The anti-diabetic activity was examined by estimating different enzymes in cell lines. Further, we validated activity by using in vitro models. Male Albino Wistar rats were divided into five groups each group contain six animals (n = 6). The diabetes was induced via intraperitoneal injection of STZ and the ß- Carotene was treated with daily doses of 10 and 20 mg/kg for 14 days. After the last dose of ß- Carotene, rats were sacrificed and the biochemical parameters were estimated in liver homogenate. The disease control group showed an elevation in the level of cytokine as well as ROS and ß- Carotene-treated animals showed a reduction in the level of cytokine and normal content of anti-oxidant enzyme in liver tissue homogenate. We found ß- Carotene had no toxic effect on HepG2 liver cells. In the case of the glucose utilization assay, it was found that glucose uptake level was significantly increased with the increasing concentrations of ß-Carotene. In conclusion ß- Carotene improves glucose metabolism along with oxidative status in STZ-induced diabetic rats.

Role of toll-like receptor 7/8 pathways in regulation of interferon response and inflammatory mediators during SARS-CoV2 infection and potential therapeutic options.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is the causative agent of Corona Virus Disease 2019 (COVID-19). Lower production of type I and III interferons and higher levels of inflammatory mediators upon SARS-CoV2 infection contribute to COVID-19 pathogenesis. Optimal interferon production and controlled inflammation are essential to limit COVID-19 pathogenesis. However, the aggravated inflammatory response observed in COVID-19 patients causes severe damage to the host and frequently advances to acute respiratory distress syndrome (ARDS). Toll-like receptor 7 and 8 (TLR7/8) signaling pathways play a central role in regulating induction of interferons (IFNs) and inflammatory mediators in dendritic cells. Controlled inflammation is possible through regulation of TLR mediated response without influencing interferon production to reduce COVID-19 pathogenesis. This review focuses on inflammatory mediators that contribute to pathogenic effects and the role of TLR pathways in the induction of interferon and inflammatory mediators and their contribution to COVID-19 pathogenesis. We conclude that potential TLR7/8 agonists inducing antiviral interferon response and controlling inflammation are important therapeutic options to effectively eliminate SARS-CoV2 induced pathogenesis. Ongoing and future studies may provide additional evidence on their safety and efficacy to treat COVID-19 pathogenesis.

Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

Recently, ATP synthase inhibitor Bedaquiline was approved for the treatment of multi-drug resistant tuberculosis emphasizing the importance of oxidative phosphorylation for the survival of mycobacteria. ATP synthesis is primarily dependent on the generation of proton motive force through the electron transport chain in mycobacteria. The mycobacterial electron transport chain utilizes two terminal oxidases for the reduction of oxygen, namely the bc1-aa3 supercomplex and the cytochrome bd oxidase. The bc1-aa3 supercomplex is an energy-efficient terminal oxidase that pumps out four vectoral protons, besides consuming four scalar protons during the transfer of electrons from menaquinone to molecular oxygen. In the past few years, several inhibitors of bc1-aa3 supercomplex have been developed, out of which, Q203 belonging to the class of imidazopyridine, has moved to clinical trials. Recently, the crystal structure of the mycobacterial cytochrome bc1-aa3 supercomplex was solved, providing details of the route of transfer of electrons from menaquinone to molecular oxygen. Besides providing insights into the molecular functioning, crystal structure is aiding in the targeted drug development. On the other hand, the second respiratory terminal oxidase of the mycobacterial respiratory chain, cytochrome bd oxidase, does not pump out the vectoral protons and is energetically less efficient. However, it can detoxify the reactive oxygen species and facilitate mycobacterial survival during a multitude of stresses. Quinolone derivatives (CK-2-63) and quinone derivative (Aurachin D) inhibit cytochrome bd oxidase. Notably, ablation of both the two terminal oxidases simultaneously through genetic methods or pharmacological inhibition leads to the rapid death of the mycobacterial cells. Thus, terminal oxidases have emerged as important drug targets. In this review, we have described the current understanding of the functioning of these two oxidases, their physiological relevance to mycobacteria, and their inhibitors. Besides these, we also describe the alternative terminal complexes that are used by mycobacteria to maintain energized membrane during hypoxia and anaerobic conditions.

Management of Radicular Cyst Using Platelet-Rich Fibrin & Iliac Bone Graft - A Case Report.

Radicular cyst is one of the most commonly occurring cyst in the oral cavity it is usually preceded by trauma or an infectious condition which is followed by enlargement. In recent times there are several treatment procedures that are being applied in order to improve the postoperative condition and to accelerate the process of healing and regeneration in the affected site. A 22-year-old patient reported to our OPD with the chief complaint of swelling on the left side of the face since 2-3 months, on investigating it was diagnosed as Radicular cyst which was initially treated by endodontic treatment of the involved tooth followed by enucleation of the cyst further an apicoectomy was done. Finally a PRF and iliac crest graft was placed for aesthetic rehabilitation with 21.

Evaluation of the Oral Health Knowledge, Attitude and Behavior of the Preclinical and Clinical Dental Students.

BACKGROUND: Dentists play very important role in the oral health education of the community. Thus it is important to know the status of knowledge, attitude, and behavior toward the maintenance of oral health at the student level. The aim of the present study was to evaluate the oral health knowledge, attitude, and behavior among preclinical and clinical dental students. MATERIALS AND METHODS: A cross-sectional study was conducted on 147 dental students from 1(st) to 4(th) year of Malabar Dental College, Kerala, in the year of March-June 2010 and was carried out with the help of 30 questionnaires. Age, gender and academic year data were recorded. Statistical analysis was performed with the help of SPSS version 20 using the Student's t-test and one-way ANOVA tests. RESULTS: The difference in scores of oral health knowledge, attitude and behavior between preclinical and clinical dental students was found statistically highly significant (Student's t-test, P < 0.001). The variation of scores of knowledge, attitude, and behavior also showed highly significant increase with the year of study (one-way ANOVA, P < 0.001). While the difference in scores between males and females showed that females have better oral health knowledge than males, but the difference was not statistically significant (Student's t-test, P > 0.01). The present study thus showed improvement of knowledge, attitude and behavior with the academic years and there was no bias of gender with reference to oral health. CONCLUSIONS: Although oral health knowledge, attitude and behavior showed improved results from 1(st) to 4(th) year dental students, it should be improved in order to serve better for the community in the future.

Presurgical nasoalveolar remodeling - an experience in the journey of cleft lip and palate.

AIMS AND OBJECTIVES: To assess the effect of presurgical nasoalveolar molding (PNAM) therapy in the management of patients with nonsyndromic unilateral cleft lip and palate (UCLP). MATERIAL AND METHOD: Ten patients with UCLP treated from 2009 to 2012. The initiation for PNAM treatment was 7 days and the average time of the treatment was 175 days. Measurements on patients and of casts were made, and statistical analysis was used to evaluate the changes in pre- and posttreatment measurements. RESULTS: Subsequent to PNAM treatment, there was a statistically considerable rise in cleft nostril height and columellar width. There was reduction in both intraoral cleft width and columellar deviation, which was significant statistically. CONCLUSION: PNAM treatment reduces alveolar cleft width. It enhances symmetry of the nose by changing columellar angulation, preserving alar width bilaterally, gaining height of the nostril on the affected side, and increasing columellar length.

An unusual cause of hematuria.

Hematuria is a cardinal manifestation of renal disease and forms a cornerstone of nephrologic diagnosis. A systemic approach is required to delineate the source of hematuria to the kidney or urinary tract. We present the case of 14 years old boy who presented to us with history of passing red colour urine since 3 month not associated with pain who was subsequently diagnosed to have of Thin Basement Membrane Disease.

Evaluation of efficacy, safety, and cognitive profile of amisulpride per se and its comparison with olanzapine in newly diagnosed schizophrenic patients in an 8-week, double-blind, single-centre, prospective clinical trial.

Background. Impaired cognitive functions in schizophrenia are the major deciding factors in response to treatment. Conventional antipsychotics have minimal impact on cognitive dysfunctions and are associated with adverse effects. Atypical antipsychotics have shown promise in treatment of cognitive and negative symptoms of schizophrenia. Efforts are underway to find out the best drug amongst atypical antipsychotics. Objective. To compare efficacy, safety, and cognitive profile of amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia. Method. A prospective, randomized, double-blind, single-center, 8-week clinical trial we used. Subjects and Treatments. Seventy four patients were treated for two months with either amisulpride (400-800 mg/d) or olanzapine (10-20 mg/d). Statistics. Mann Whitney U test we used for independent samples with P < 0.05 taken as significant. Results. Brief psychiatric rating scale (BPRS) was used as a primary measure of efficacy. Other measures of efficacy and safety were also evaluated. Both amisulpride and olanzapine groups showed equivalent improvement in psychotic symptoms on BPRS scale. Less than five percent of patients suffered adverse effects only to withdraw from the study. Olanzapine group showed statistically significant (P < 0.05) weight gain compared with amisulpride group. Amisulpride group showed significant improvement (P < 0.05) in various cognitive parameters as compared to olanzapine group.

Prevalence of depressive symptoms in the immediate postpartum period.

PURPOSE: There is currently little information about rates of positive maternal depression screens immediately after delivery; rather, most studies have assessed the prevalence of major depression between 1 and 6 months postpartum. This study investigated the rate of positive 9-item Patient Health Questionnaire (PHQ-9) surveys within 1 to 2 days after delivery. METHODS: A retrospective chart review of PHQ-9 results obtained within 1 to 2 days after childbirth was performed on 441 women who delivered at 3 St. Paul, MN, hospitals during February 2010. RESULTS: Out of 441 deliveries recorded during the study period, PHQ-9 results were available for 361 women (81.9%). A total of 9 women (2.5%) had positive PHQ-9 scores within 1 to 2 days after delivery. CONCLUSION: We found very low rates of depressive symptoms during the immediate postpartum period, which leads us to suggest that this is not an ideal time for postpartum depression screening or evaluation.

Evaluation of antidepressant like property of amisulpride per se and its comparison with fluoxetine and olanzapine using forced swimming test in albino mice.

Amisulpride, an atypical antipsychotic was evaluated for antidepressant like activity in forced swimming test in Swiss albino mice. The effect of amisulpride was compared with that of fluoxetine, the standard antidepressant and olanzapine, another atypical antipsychotic claimed to have antidepressant like activity. Both acute and chronic studies were carried out. In both the studies, animals were divided into four groups (n = 8 each) and subjected to oral drug interventions as follows -- Group 1- control (distilled water, 1 mL/kg); Group 2- fluoxetine in a dose of 10 mg/kg 23.5, 5 and 1 h before the test; Group 3-amisulpride in a dose of 70 mg/kg 23.5, 5 and 1 h before the test; Group 4- olanzapine in a dose of 2 mg/kg 23.5, 5 and 1 h before the study. In the chronic study, the treatment was given daily for 28 days with last dose being given 2 h prior to the test. A time sampling method was used to score the behavioral activity in each group. Results of both the studies indicated that animals given amisulpride displayed significant improvement in swimming behavior (p < 0.01), while markedly reducing immobility as compared to control group (p <0.01). Fluoxetine also showed significant difference in activity as compared to amisulpride and olanzapine (p < 0.01). There was no statistically significant difference between amisulpride and olanzapine in terms of effect on immobility and swimming phases in albino mice (p > 0.05). We conclude that amisulpride per se has an antidepressant like activity comparable to that of olanzapine though the activity was significantly less than that of fluoxetine.