Network pharmacology and experimental insights into STAT3 inhibition by novel isoxazole derivatives of piperic acid in triple negative breast cancer.

STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.

Compatibility Effects of Waste Cooking Oil Biodiesel Blend on Fuel System Elastomers in Compression Ignition Engines.

Alternative energy sources, such as biodiesel, play a vital role in environmental protection. Waste cooking oil (WCO) biodiesel has promising applications in compression ignition engines. A major problem regarding biodiesel implementation is the deterioration and materials incompatibility of existing fuel system components with biodiesel. Variations in the composition of fuel prompted by the inclusion of biodiesel cause a variety of issues in diesel engine fuel systems where the elastomer is generally utilized as the fuel hose material and sealings. In this experimental work, the effects of the diesel and WCO biodiesel blends (B8, B16, B24, and B100) on Buna-N, ethylene propylene rubber (EPR), and polystyrene (PS) were examined by the immersion test, which was conducted for 160 h at various immersion temperatures of 30, 60, and 80 °C, respectively. The study also showed that the use of elastomer materials like Buna-N, EPR, and PS in diesel engines fueled up to 20% WCO biodiesel blends is advantageous; the overall compatibility improves by 100% compared to that obtained using neat diesel. The outcome revealed remarkable behavior changes, including a minor increase in volume and a slight loss in tensile strength and hardness compared to that observed using neat diesel fuel. The expansion of rubber materials increases over 60 °C, although the rate of this process decreases above 80 °C. It has been found that the expansion of rubber materials is unaffected by the acid concentration of the WCO biodiesel blends but significantly affected by the moisture content.

Experimental Investigation and Characterization of Friction Stir Spot-Welded Dissimilar Aluminum Copper Metallic Lap Joints.

Due to their contrasting physical properties, joining materials like copper and aluminum has always proven difficult. The disadvantages of traditional joining methods include additional weight, solidification problems, and energy waste. Friction stir spot-welding (FSSW) was utilized for joining copper and aluminum in order to get around these difficulties. This study illustrates that friction stir spot-welding (FSSW) produces joints between incompatible copper and aluminum alloys with better mechanical and electrical properties. The numerous FSSW parameters play an important role in deciding how well the welded joint performs. Tool rotational speed (TRS), plunge rate (PR), and dwell duration (DT) are the study parameters. During manufacture, a case-hardened H13 tool was used to lap-joint AA 6061 T6 hot-rolled aluminum flat strips with C11000 copper strips while operating at three different levels of TRS, PR and DT. SEM analysis was utilized to investigate the interface region and bimetallic interface of the joints. In order to demonstrate modifications in the grain-related characteristics, the joints were examined for electrical conductivity, mechanical strength (lap shear, bending, and microhardness test), and analysis of the microstructure at the weld zones. The outcome demonstrates that other factors, such as plunge rate, dwell time, and tool rotation speed, had the greatest impact on the joints' electrical conductivity, mechanical strength, and microstructure.

Diverse Pharmacological Potential of different Substituted Pyrazole Derivatives.

The chemistry of heterocyclic compounds has been a topic of research interest. Some five-membered heterocyclic compounds have been the subject of extensive research due to their different types of pharmacological effects. The five-membered nitrogen-containing heterocyclic compounds pyrazole, pyrazoline, and pyrazolone derivatives have a lot of interest in the fields of medical and agricultural chemistry due to their diverse spectrum of therapeutic activities. Various substituted pyrazole, pyrazoline, and pyrazolone compounds exhibited diverse pharmacological effects like Anti-microbial, anti-inflammatory, anti-tubercular, anti-fungal, anti-malarial, anti-di-abetic, diuretic, anti-depressant, anticonvulsant, antioxidant, anti-leishmanial, antidiabetic, and antiviral, etc. In recent decades, the synthesis of numerous pyrazole, pyrazoline, and pyrazolone derivatives by different synthetic methods as well as research into their chemical and biological behavior have become more important. This review focuses on synthetic methods of the pyrazole, pyrazoline, and pyrazolone derivatives, which have significant biological properties and a variety of applications.

Diverse pharmacological potential of pyridazine analogs against various diseases.

Pyridazinone analogs possess diverse types of pharmacological activities, such as anticancer, antimicrobial, anticonvulsant, analgesic, anti-inflammatory, antioxidant, antihypertensive, antisecretory, antiulcer, and other useful pharmacological activities. They also possess cyclooxygenase (COX) inhibitors, dipeptidyl peptidase inhibitors, phosphodiesterase inhibitors, glutamate transporter activators, adenosine receptor antagonists, serotonin receptors antagonists, lipooxygenase, cholinesterase, vasodilator, and anesthetics. Pyridazine rings are the essential structure for some marketed drugs, such as pimobendan, levosimendan as a cardiotonic drug, and emorfozan as an analgesic and anti-inflammatory (Non-steroidal anti-inflammatory drug) agent. So, researchers all over the world have paid attention to synthesizing various pyridazinone compounds mainly due to the ease of design and synthesis of different analogs and variables in the pharmacological responses. This review article focuses on the pharmacological activities of different pyridazine analogs.

Evaluation of Nootropic Potential of Aerva persica Roots against D-galactose-induced Memory Impairment.

BACKGROUND: The primary phytoconstituents reported to have neuroprotective effects are flavonoids and phenolic compounds. Aerva persica roots are reported to be rich in flavonoids and phenolic compounds. Therefore, this study aimed to explore the nootropic potential of Aerva persica roots. OBJECTIVE: The objective of this study was to evaluate the nootropic potential of Aerva persica roots against D-galactose-induced memory impairment. METHODS: In this study, the roots of Aerva persica were extracted with 70% ethanol. The obtained extract was evaluated for total phenolic content using the Folin-Ciocalteu method and total flavonoid content using the aluminium chloride colorimetric assay. Afterward, the acute oral toxicity of the extract was determined following the Organisation for Economic Co-operation and Development (OECD) guideline 423. Additionally, two doses of Aerva persica (100 and 200 mg/kg body weight (BW)) were evaluated for their nootropic potential against D-galactose-induced memory impairment. The nootropic potential of the crude extract was assessed through a behavioural study and brain neurochemical analysis. Behavioural studies involved the evaluation of spatial reference- working memory using the radial arm maze test and the Y-maze test. Neurochemical analysis was performed to determine the brain's acetylcholine, acetylcholinesterase, glutathione (GSH), and malondialdehyde (MDA) levels. RESULTS: The total phenolic content and total flavonoid content were found to be 179.14 ± 2.08 µg GAE/mg and 273.72 ± 3.94 µg QE/mg, respectively. The Aerva persica extract was found to be safe up to 2000 mg/kg BW. Following the safety assessment, the experimental mice received various treatments for 14 days. The behavioural analysis using the radial maze test showed that the extract at both doses significantly improved spatial reference-working memory and reduced the number of total errors compared to disease control groups. Similarly, in the Y-maze test, both doses significantly increased the alteration percentage and the percentage of novel arm entry (both indicative of intact spatial memory) compared to disease control. In neurochemical analysis, Aerva persica at 200 mg/kg significantly normalised the acetylcholine level (p<0.0001) and GSH level (p<0.01) compared to disease control. However, the same effect was not observed with Aerva persica at 100 mg/kg. Additionally, Aerva persica at 200mg/kg BW significantly decreased the acetylcholinesterase level (p<0.0001) and decreased the brain's MDA level (p<0.01) compared to the disease control, whereas the effect of Aerva persica at 100 mg/kg BW in reducing acetylcholinesterase was non-significant. CONCLUSION: Based on the results, it can be concluded that the nootropic potential of Aerva persica was comparable to that of the standard drug, Donepezil, and the effect might be attributed to the higher content of flavonoids and phenolic compounds.

Potential Effect of Lemon Peel Oil with Novel Eco-Friendly and Biodegradable Emulsion in Un-Modified Diesel Engine.

The current research work is based on exploring a novel biological fuel source and renewable fuel offered by waste lemon fruit skin. Furthermore, bio-based multi-wall carbon nanotubes (BMWCNTs), emulsion, fossil diesel, and raw lemon peel oil were procured. The single-cylinder diesel engine was evaluated using these potential ingredients in terms of performance, combustion, and emission. Test engine results reveal that the presence of BMWCNT emulsion in the bio-fuel + blend + emulsion blend produced a lower (4.7%) brake thermal efficiency (BTE) and a higher (13.6%) brake-specific energy consumption (BSEC) at peak engine load conditions with diesel. The same test fuel blend possesses an equivalent heat release rate (HRR) and cylinder pressure trends to the diesel fuel blend due to an optimized air/fuel mixture and oxygen supply. Bio-fuel + blend + emulsion achieved step-down reductions of 7.83% carbon monoxide (CO) and 20.68% hydrocarbon (HC) emissions, as well as reductions of 27.7% nitrogen oxide (NOx) and 37.3% smoke emissions at peak engine load with diesel.

Sulfide (H2S) Corrosion Modeling of Cr-Doped Iron (Fe) Using a Molecular Modeling Approach.

This work presents the use of density functional theory to study the adsorption/dissociation mechanism of the H2S molecule at the Cr-doped iron (Fe(100)) surface. It is observed that H2S is weakly adsorbed on Cr-doped Fe; however, the dissociated products are strongly chemisorbed. The most feasible path for disassociation of HS is favorable at Fe compared to Cr-doped Fe. This study also shows that H2S dissociation is a kinetically facile process, and the hydrogen diffusion follows the tortuous path. This study helps better understand the sulfide corrosion mechanism and its impact, which would help design effective corrosion prevention coatings.

CONGENITAL SCAPHOID MEGALOURETHRA: REVISITING A RARE ANOMALY.

Megalourethra is an infrequent malformation of the anterior urethra that is caused by the lack of corpus sponigosum and in severe cases is accompanied by the lack of corpora cavernosa as well. We report a five-year-old boy presented to us with scaphoid variety of megalourethra having complaints of ballooning of urethra during voiding. He was investigated with urethrogram and cystoscopy and subsequently repaired with Nesbitt Longitudinal Reduction Urethroplasty. He had smooth recovery postoperatively with normal voiding stream on follow up.

Enhancement in Cathodic Redox Reactions of Single-Chambered Microbial Fuel Cells with Castor Oil-Emitted Powder as Cathode Material.

Microbial fuel cell (MFC) would be a standalone solution for clean, sustainable energy and rural electrification. It can be used in addition to wastewater treatment for bioelectricity generation. Materials chosen for the membrane and electrodes are of low cost with suitable conducting ions and electrical properties. The prime objective of the present work is to enhance redox reactions by using novel and low-cost cathode catalysts synthesized from waste castor oil. Synthesized graphene has been used as an anode, castor oil-emitted carbon powder serves as a cathode, and clay material acts as a membrane. Three single-chambered MFC modules developed were used in the current study, and continuous readings were recorded. The maximum voltage achieved was 0.36 V for a 100 mL mixture of domestic wastewater and cow dung for an anodic chamber of 200 mL. The maximum power density obtained was 7280 mW/m2. In addition, a performance test was evaluated for another MFC with inoculums slurry, and a maximum voltage of 0.78 V and power density of 34.4093 mW/m2 with an anodic chamber of 50 mL was reported. The present study's findings show that such cathode catalysts can be a suitable option for practical applications of microbial fuel cells.

Association between Palliative Care Consultation and Advance Palliative Care Rates: A Descriptive Cohort Study in Patients at Various Stages in the Continuum of Chronic Kidney Disease.

Background: Despite evidence that advance care planning (ACP) benefits patients with serious illnesses, there is a dearth of information about "who" is referred for palliative care (PC) consultation, the rate of PC consultation, and the outcomes of referrals in patients with advanced chronic kidney disease/end-stage kidney disease (aCKD/ESKD). Objectives: (1) To describe patient characteristics associated with PC consultations and (2) to determine the frequency and outcome of PC consultation on documented ACP discussions for patients with aCKD/ESKD. Methodology/Design: This is retrospective observational electronic health record cohort review. Settings: University of Virginia (UVA) hospital, clinics, and dialysis units. Participants: Patients were studied along two time intervals. Time period January 1, 2015 to June 30, 2017 included all patients admitted to UVA during that time period with estimated glomerular filtration rate (eGFR) <60 mL/minute. Time period January 1, 2018 to March 31, 2019 included two cohorts: patients with eGFR <15 mL/minute who had died during study period excluding those who withdrew from dialysis and those who were dialysis dependent and withdrew from dialysis. Results: Aside from higher rates of PC consultation in patients with heart failure, none of the demographic and comorbidity data studied affected whether or not a patient is referred to PC in patients with aCKD/ESKD. PC consultation rates were low among all patients studied: 14.7% in patients with eGFR <60 mL/minute, 28.9% in dialysis patients withdrawing from dialysis, and 57.1% in terminally ill patients with eGFR <15 mL/minute. In all cohorts, PC consultations were associated with improved ACP. Conclusion: PC consultation is significantly associated with better end-of-life outcomes with more completion of ACP and hospice referral in patients with aCKD/ESKD. PC consultation rates remain low. Even in terminally ill patients with more aCKD, >40% were never seen by PC. Until policies and curricula better prepare nephrologists to independently address ACP, collaboration between nephrologists and PC specialists is recommended.

Expression of Ki-67 and Βeta-Catenin in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma in Oral Mucosal Biopsies : An Immunohistochemical Study.

OBJECTIVE: To examine the immunohistochemical expression of Ki-67 and beta-catenin in pseudoepitheliomatous hyperplasia and squamous cell carcinoma (SCC) in oral mucosal biopsies. METHODS: In this comparative cross sectional study, 70 cases of each PEH and OSCC were taken from the patients of both genders and in all age groups. Study was conducted at Armed Forces Institute of Pathology (AFIP), Rawalpindi from Dec 2017 to March 2019. Statistical analysis was done with the help of SPSS Version 24.0. We used Chi-Squared test with p value of < 0.05 which was considered as statistically significant. RESULTS: In the current study, 80 (57.1%) male and 60 (42.8%) female patients with the mean age of 51.69 ± 16.121 (mean ± SD) years were included. It was found that 6-25% Ki-67 labeling index was observed in all (70) PEH cases, which involved only basal layer of the epithelium. Whereas, Ki-67 labeling index was highly expressed in tumor of high grade malignancy than tumor of low grade malignancy. On the other hand, expression of membranous beta-catenin was higher in PEH and cytoplasmic beta-catenin expression was higher in OSCC. CONCLUSION: It is concluded that Ki-67 and beta-catenin showed significant expression in PEH and OSCC in oral mucosal biopsies especially those with intense inflammation or unoriented tissue, helping the clinicians to arrive at a final diagnosis before planning any surgical intervention.

Direct physical interaction of active Ras with mSIN1 regulates mTORC2 signaling.

BACKGROUND: The mechanistic (or mammalian) target of rapamycin (mTOR), a Ser/Thr kinase, associates with different subunits forming two functionally distinct complexes, mTORC1 and mTORC2, regulating a diverse set of cellular functions in response to growth factors, cellular energy levels, and nutrients. The mechanisms regulating mTORC1 activity are well characterized; regulation of mTORC2 activity, however, remains obscure. While studies conducted in Dictyostelium suggest a possible role of Ras protein as a potential upstream regulator of mTORC2, definitive studies delineating the underlying molecular mechanisms, particularly in mammalian cells, are still lacking. METHODS: Protein levels were measured by Western blotting and kinase activity of mTORC2 was analyzed by in vitro kinase assay. In situ Proximity ligation assay (PLA) and co-immunoprecipitation assay was performed to detect protein-protein interaction. Protein localization was investigated by immunofluorescence and subcellular fractionation while cellular function of mTORC2 was assessed by assaying extent of cell migration and invasion. RESULTS: Here, we present experimental evidence in support of the role of Ras activation as an upstream regulatory switch governing mTORC2 signaling in mammalian cancer cells. We report that active Ras through its interaction with mSIN1 accounts for mTORC2 activation, while disruption of this interaction by genetic means or via peptide-based competitive hindrance, impedes mTORC2 signaling. CONCLUSIONS: Our study defines the regulatory role played by Ras during mTORC2 signaling in mammalian cells and highlights the importance of Ras-mSIN1 interaction in the assembly of functionally intact mTORC2.

Spectrum of Biopsy Proven Extraocular Muscle Tumours of Non-Thyroid Origin.

OBJECTIVE: To describe different types of primary extraocular muscle (EOM) tumours based on the results of imaging studies, peroperative clinical picture and their histopathological diagnosis. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Al-Shifa Trust Eye Hospital, Rawalpindi, from July 2001 to January 2017. METHODOLOGY: A retrospective analysis of 640 diagnosed orbital tumours was carried out using non-randomised sampling technique, and the prevalence of primary EOM tumours was determined. Based on the results of imaging studies, the clinical picture observed during surgery (orbitotomy) and the histopathological diagnosis, primary EOM tumours were divided into different types, accordingly. RESULTS: Nineteen (n=19) primary EOM tumours (frequency of 2.96%) had 12 types of histopathological diagnoses, and were categorised into inflammatory tumours (n=8, 42%), vascular tumours (n=4, 21%), lymphoproliferative tumours (n=3, 16%), neurogenic tumours (n=2, 10.5%) and myogenic tumours (n=2, 10.5%). The recti were involved more frequently than obliques (n=15, 78.94% and n=4, 21.06%, respectively). All the patients presented with proptosis of varying degree with some degree of globe rotation and had surgical excision/appropriate management. Visual acuity was not affected in any of the patients. Four (n=4, 21.05%) tumours were malignant (NHL, ASPS, myeloid sarcoma and rhabdomyosarcoma) and these patients underwent chemotherapy and/or radiotherapy. CONCLUSION: Biopsy-proven primary EOM tumours were devisable into five broad categories. Patients with primary EOM tumours presented with proptosis and impaired ocular motiliy. The primary EOM tumours involved both the recti and the obliques and were excised surgically with favourable outcomes in most cases.

Insights into the chemistry and therapeutic potential of furanones: A versatile pharmacophore.

Furanone, a five-membered heteroaromatic ring containing oxygen atom, is of immense pharmaceutical importance. Presence of this nucleus in biologically active compounds of natural and synthetic origin has made it an indispensable motif for design and development of new therapeutic agents. In recent years synthesis of furanone derivatives and exploring their therapeutic actions has been the prime interest amongst researchers. Furanone containing compounds cover numerous therapeutic categories viz. Analgesic and anti-inflammatory, anticancer, anticonvulsant, antibacterial and antifungal, antioxidant, antiulcer and anti-TB, etc. There is a need to couple recent work done with previously available information on furanone, a well acknowledged scaffold, to help scientists to develop novel and new furanone based therapeutic agents at a faster pace. This updated review highlights the worth of numerous therapeutically active furanone based compounds developed by the medicinal chemists. SAR studies have also been derived which may be useful for rational designing of furanone derivatives with improved therapeutic index.

M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis.

Oncostatin M (OSM), an inflammatory cytokine belonging to the interleukin-6 (IL-6) superfamily, plays a vital role in multitude of physiological and pathological processes. Its role in breast tumor progression and metastasis to distant organs is well documented. Recent reports implicate OSM in macrophage M2 polarization, a key pro-tumoral phenomenon. M2 polarization of macrophages is believed to promote tumor progression by potentiating metastasis and angiogenesis. In the current study, we delineated the mechanism underlying OSM induced macrophage M2 polarization. The findings revealed that OSM skews macrophages towards an M2 polarized phenotype via mTOR signaling complex 2 (mTORC2). mTORC2 relays signals through two effector kinases i.e. PKC-α and Akt. Our results indicated that mTORC2 mediated M2 polarization of macrophages is not dependent on PKC-α and is primarily affected via Akt, particularly Akt1. In vivo studies conducted on 4T1/BALB/c mouse orthotropic model of breast cancer further corroborated these observations wherein i.v. reintroduction of mTORC2 abrogated monocytes into orthotropic mouse model resulted in diminished acquisition of M2 specific attributes by tumor associated macrophages. Metastasis to distant organs like lung, liver and bone was reduced as evident by decrease in formation of focal metastatic lesions in mTORC2 abrogated monocytes mice. Our study pinpoints key role of mTORC2-Akt1 axis in OSM induced macrophage polarization and suggests for possible usage of Oncostatin-M blockade and/or selective mTORC2 inhibition as a potential anti-cancer strategy particularly with reference to metastasis of breast cancer to distant organs such as lung, liver and bone.

Design and development of PEGylated liposomal formulation of HER2 blocker Lapatinib for enhanced anticancer activity and diminished cardiotoxicity.

Breast cancer is most frequently diagnosed cancer and fifth leading cause of death in women. About 20-30% of all breast cancers overexpress HER2/neu receptors. Lapatinib is a dual tyrosin kinase inhibitor of EGFR and HER2. It exhibits its anticancer effect via blocking intracellular domain of HER2 receptor in breast cancer. Lapatinib belongs to class II of BSC classification due to its poor solubility restricting its clinical application. Due to presence of HER2 receptor on cardiomyocytes, it is associated with generation of cardiotoxicity. The present study was aimed to design a PEGylated liposomal formulation of Lapatinib and evaluate its anticancer potential. Lapatinib liposomes were prepared using lipid layer hydration method and its characterization was done by determining its particle size, zeta potential, entrapment efficiency and in vitro release profiling. The anti-tumor activity of PEGylated liposomal formulation was evaluated in xenografted tumor induced by MDA-MB-453 breast cancer cells in chick embryos. The anti-tumor effect of lapatinib was enhanced by its PEGylated liposomal preparation as it led to the reduction in tumor size to a greater extent compared to the embryos treated with free lapatinib. Flowcytometric analysis and immunoflurescence study using cleaved PARP antibody demonstrated the enhanced apoptotic potential of PEGylated liposomes of lapatinib. SGOT levels, marker for cardiotoxicity and hepatotoxicity, significantly decreased in serum of embryos treated with PEGylated liposomes of lapatinib compared to free drug treated embryos. Hence, the PEGylated liposomal formulation of lapatinib can be used as a therapeutic strategy against HER2 positive breast cancer either alone or in combination with conventional anticancer agents and hormonal therapies.

Oncostatin M upregulates HIF-1α in breast tumor associated macrophages independent of intracellular oxygen concentration.

AIMS: HIF is an important transcription-regulator for adaptation to cellular stress in cells of myeloid origin. Classically, expression and activity of HIF1-α is regulated by oxygen-concentration within cell. However, there exists an alternative regulatory mechanism affecting HIF1-α levels independent of oxygen concentration particularly in inflammatory cells like macrophages. Here we report the mechanism of HIF1-α upregulation in TAMs by Oncostatin-M (OSM) independent of cellular oxygen concentration. MAIN METHODS: THP-1 derived macrophages were treated with OSM. HIF1-α levels and interaction with pVHL were evaluated via immunoblot-analysis and Co-immunoprecipitation. Translocation of HIF1-α to nucleus was visualized using confocal-microscopy. Fold change in mRNA levels of ARG-1 and COX-2 was analyzed using RT-PCR. KEY FINDINGS: Current study demonstrates that OSM treatment to TAMs led to an increased expression of HIF1-α under normoxic conditions via activation of mTORC2. This HIF1-α upregulation was dependent on both de novo synthesis of HIF1-α and its enhanced stability due to disruption of its binding to pVHL. Furthermore, we evaluated that OSM not only enhances the expression of HIF1-α but also increases its localization to nucleus where it acts as a transcription factor regulating expression of genes like ARG-1 and COX-2. SIGNIFICANCE: Inflammation is a critical hallmark of cancer as tumor microenvironment is largely infiltrated with macrophages. These tumor associated macrophages (TAMs) display a M2 skewed phenotype. Many target genes of TAMs are HIF1-α responsive. These TAMs are involved in tumor progression, metastasis and angiogenesis. Targeting of HIF1-α/OSM can lead to devising of better therapeutic strategy against cancer.

Studies on new substituted pyridazinones: synthesis and biological evaluation

We report herein the synthesis and pharmacological evaluation of a new series of 6-aryl-2-(imidazol-1-yl/1,2,4-triazol-1-yl)-2-methyl-4,5-dihydro-(2H)-pyridazin-3-one (3a-j) as potential anticonvulsant and antitubercular agents. The title compounds were prepared by reacting 6-aryl-4,5-dihydro-(2H)-pyridazin-3-one (2a-e) with formaldehyde and secondary cyclic amine imidazole or 1,2,4-triazole as per Mannich reaction. Anticonvulsant activity of pyridazinone derivatives was tested at 50 mg.kg-1 dose level against maximal electroshock (MES), isoniazid (INH, 250 mg.kg-1) and pentylenetetrazole (PTZ at 80 mg.kg-1) induced seizure methods. Phenytoin sodium (25 mg.kg-1) and sodium valproate (100 mg.kg-1) were used as reference drugs for comparison purpose. In-vitro antitubercular activity was tested by Microplate Alamar Blue assay (MABA) method and the results were compared with clinically used antitubercular agents such as INH, Pyrazinamide (PZA) and Streptomycin (STM). None of the screened compounds were found to be neurotoxic at a dose level of 100 mg.kg-1. All the screened compounds (3a-j) significantly reduced the MES, INH and PTZ induced convulsions and thus showed good anticonvulsant activity. The minimum inhibitory concentration (MIC) of the title compounds against M. tuberculosis ranged from 1.6 µg/mL to 6.25 µg/mL in comparison to INH, PZA (3.125 µg/mL) and STM (6.25 µg/mL) which indicated good antitubercular activity.

Acute myocardial infarction in very young adults: A clinical presentation, risk factors, hospital outcome index, and their angiographic characteristics in North India-AMIYA Study.

BACKGROUND: India is currently in the fourth stage of epidemiological transitions where cardiovascular disease is the leading cause of mortality and morbidity. Purpose of the present study was to assess the risk factors, clinical presentation, angiographic profile including severity, and in-hospital outcome of very young adults (aged ≤ 30 years) with first acute myocardial infarction (AMI). METHODS: Total of 1,116 consecutive patients with ST-segment elevation acute myocardial infarction (STEMI) were studied between March 2013 and February 2015 at LPS Institute of Cardiology, Kanpur, Uttar Pradesh, India. RESULTS: Mean age of the patients was 26.3 years. Risk factors were smoking (78.5%), family history of premature coronary artery disease (CAD) (46.8%), obesity (39.1%), physical inactivity (38.7%) and stressful life events (29.6%). The most common symptom and presentation was chest pain and anterior wall myocardial infarction (AWMI) in 94.8% and 58.8%, respectively. About 80.6% of patients had obstructive CAD with single vessel disease (57.6%), double-vessel disease (12.9%) and left main involvement (3.2%). Left anterior descending (LAD) was commonest culprit artery (58.1%) followed by right coronary artery in 28.2%. In-hospital mortality was 2.8%. Percutaneous coronary intervention was performed in 71.6% of patients. Median number and length of stent were 1.18 and 28 ± 16 mm, respectively. CONCLUSION: AMI in very young adult occurred most commonly in male. Smoking was the most common risk factor. AWMI owing to LAD artery involvement was the most common presentation. Mean time of presentation after symptom onset was 16.9 hours. In contrast to western population, it is characterised by earlier onset, delayed presentation, more severity, diffuse disease, and more morbidity but with favourable in-hospital mortality.