ε-Poly-l-lysine: A Naturally Occurring Biodegradable Polypeptide for Selective Detection of 5-Nitroimidazole Antibiotics in Animal Products and Living Cells via Fluorescence.

The 5-nitroimidazole (5-NI) class of antibiotics, such as metronidazole, ornidazole, secnidazole, and tinidazole, are widely used to prevent bacterial infection in humans and livestock industries. However, their overuse contaminates the farmed animal products and water bodies. Hence, a selective, sensitive, and cost-effective method to detect 5-NI antibiotics is the need of the hour. Herein, we report a rapid, inexpensive, and efficient sensing system to detect 5-NI drugs using an as-prepared solution of ε-poly-l-lysine (ε-PL), a naturally occurring and biodegradable homopolypeptide that has an intrinsic fluorescence via clustering-triggered emission. The low nanomolar detection limit (3.25-3.97 nM) for the aforementioned representative 5-NI drugs highlights the sensitivity of the system, outperforming most of the reported sensors alike. The resulting fluorescence quenching was found to be static in nature. Importantly, excellent recovery (100.26-104.41%) was obtained for all real samples and animal products tested. Visual detection was demonstrated by using paper strips and silica gel for practical applications. Furthermore, ε-PL could detect 5-NI antibiotics in living 3T3-L1 mouse fibroblast cells via cellular imaging. Taken together, the present work demonstrates the detection of 5-NI antibiotics using a biocompatible natural polypeptide, ε-PL, and represents a simple and inexpensive analytical tool for practical application.

A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation.

Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres, and the silent mating type locus in Schizosaccharomyces pombe. Using quantitative measures, iterative genetic screening, and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. However, most other mutants exhibited distinct qualitative and quantitative profiles that indicate domain-specific functions. For example, decreased mating type silencing was linked to mutations in heterochromatin maintenance genes, while compromised subtelomere silencing was associated with metabolic pathways. Furthermore, similar phenotypic profiles revealed shared functions for subunits within complexes. We also discovered that the uncharacterized protein Dhm2 plays a crucial role in maintaining constitutive and facultative heterochromatin, while its absence caused phenotypes akin to DNA replication-deficient mutants. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity.

Persistent respiratory symptoms and lung function abnormalities in recovered patients of COVID-19.

Background and Objectives: COVID-19 is a disease caused by SARS-CoV-2 which belongs to a family of coronaviruses. After the acute phase of illness, the majority of the patients recover quickly but, in some cases, symptoms can persist for a variable duration, bringing into light another entity known as post-COVID syndrome. The objective was to estimate the burden of various persistent respiratory symptoms and lung function abnormalities among recovered patients of COVID-19 and also to correlate them with initial disease severity, demographic factors and comorbidities. Methods: Eighty-five post-COVID patients were recruited as per inclusion/exclusion criteria. Detailed history taking, physical examination and spirometry were done in all patients and data were correlated with baseline disease severity. Results: Fatigue and breathlessness were the most common symptoms followed by cough, chest pain and fever. Persistent symptoms and their severity were significantly higher in severe/moderate cases. Spirometry was abnormal in 45.88% of subjects and the most common pattern was restrictive type. It was seen that the likelihood of persistent symptoms and abnormal lung function increased significantly with the severity of COVID-19, age, comorbidities, hospital stay duration and steroid/oxygen therapy. Conclusion: The current study estimated the burden and array of various pulmonary sequelae encountered by post-COVID patients and elicited various risk factors associated with their occurrence after recovery from active infection. Awareness of these symptoms/sequelae and their risk factors is necessary for their follow-up and timely management, as the threat of this relatively new virus has still not abated.

Heat-assisted detection and ranging.

Machine perception uses advanced sensors to collect information about the surrounding scene for situational awareness1-7. State-of-the-art machine perception8 using active sonar, radar and LiDAR to enhance camera vision9 faces difficulties when the number of intelligent agents scales up10,11. Exploiting omnipresent heat signal could be a new frontier for scalable perception. However, objects and their environment constantly emit and scatter thermal radiation, leading to textureless images famously known as the 'ghosting effect'12. Thermal vision thus has no specificity limited by information loss, whereas thermal ranging-crucial for navigation-has been elusive even when combined with artificial intelligence (AI)13. Here we propose and experimentally demonstrate heat-assisted detection and ranging (HADAR) overcoming this open challenge of ghosting and benchmark it against AI-enhanced thermal sensing. HADAR not only sees texture and depth through the darkness as if it were day but also perceives decluttered physical attributes beyond RGB or thermal vision, paving the way to fully passive and physics-aware machine perception. We develop HADAR estimation theory and address its photonic shot-noise limits depicting information-theoretic bounds to HADAR-based AI performance. HADAR ranging at night beats thermal ranging and shows an accuracy comparable with RGB stereovision in daylight. Our automated HADAR thermography reaches the Cramér-Rao bound on temperature accuracy, beating existing thermography techniques. Our work leads to a disruptive technology that can accelerate the Fourth Industrial Revolution (Industry 4.0)14 with HADAR-based autonomous navigation and human-robot social interactions.

The inner nuclear membrane protein Lem2 coordinates RNA degradation at the nuclear periphery.

Transcriptionally silent chromatin often localizes to the nuclear periphery. However, whether the nuclear envelope (NE) is a site for post-transcriptional gene repression is not well understood. Here we demonstrate that Schizosaccharomyces pombe Lem2, an NE protein, regulates nuclear-exosome-mediated RNA degradation. Lem2 deletion causes accumulation of RNA precursors and meiotic transcripts and de-localization of an engineered exosome substrate from the nuclear periphery. Lem2 does not directly bind RNA but instead interacts with the exosome-targeting MTREC complex and its human homolog PAXT to promote RNA recruitment. This pathway acts largely independently of nuclear bodies where exosome factors assemble. Nutrient availability modulates Lem2 regulation of meiotic transcripts, implying that this pathway is environmentally responsive. Our work reveals that multiple spatially distinct degradation pathways exist. Among these, Lem2 coordinates RNA surveillance of meiotic transcripts and non-coding RNAs by recruiting exosome co-factors to the nuclear periphery.

Variability of particulate organic carbon and assessment of satellite retrieval algorithms over the eastern Arabian Sea.

Particulate organic carbon (POC) and its variability were studied to assess the accuracy of ocean colour retrieval algorithms over the eastern Arabian Sea (EAS) as it controls the carbon sequestration, oxygen minimum zone and biogeochemical (C, N and P) cycles. The seasonality in the physical and biological processes strongly influenced the distribution of POC along the EAS. Higher POC and chlorophyll a (chl a) during the spring inter monsoon (SIM) in the north EAS were due to detrainment bloom. The lower POC:chl a ratios during the winter monsoon (WM) (299.8 ± 190.8) than the SIM (482.1 ± 438.3) were due to the influence of freshly derived organic matter with high nutrient levels. The moderate coefficient of regression values of POC with chl a (R2 = 0.49, N = 59) suggests the importance of dead organic materials in controlling the POC distribution in the EAS. Validation between satellite and in situ POC using the four ocean colour retrieval algorithms showed that the algorithm based on the ratio of remote sensing reflectance (Rrs) performed better (R2 = 0.6, N = 17). It also showed a linear trend of POC with absorption coefficients suggesting it as an optical proxy for the POC retrieval.

Prevalence of Dysnatremia in Pulmonary Tuberculosis.

Pulmonary tuberculosis is one of the common diseases with high prevalence of mortality and morbidity in developing countries. It is one of the rare pulmonary infections which can induce hyponatremia and it is important to recognise hyponatremia because of its potential hazards. OBJECTIVES: To assess the serum sodium levels in patients with pulmonary tuberculosis and to establish a relation between the serum sodium levels and its effect on illness in these patients. MATERIAL: This is a single-center prospective observational Study conducted on patients with Pulmonary Tuberculosis, irrespective of treatment, in the department of General Medicine, B. R. Ambedkar Medical College, Bangalore from August 2019 to June 2021after obtaining ethical clearance. A total of 100 patients were enrolled in the study who met the predefined inclusion criteria of age more than 18 years and having been diagnosed with active tuberculosis. The collected data was analysed using student's T test and Chi-Square Test and the analysis was done using SPSS software version 24.0. OBSERVATION: The mean age was 46.46+/- 15.69, with majority of participants in the age group 46-60 years. Gender wise there was male preponderance in our study with 60%. The average serum sodium concentration in our study was 134.20 +/- 5.59 mmol/l, with 44% prevalence of hyponatremia and 4% SIADH Conclusion: Although mild hyponatremia was seen in more than 50% of patients, we found out that hyponatremia in pulmonary tuberculosis is detected in 44% of our patients with male preponderance. The predominant mechanism of hyponatremia was syndrome of inappropriate anti- diuretic hormone secretion (SIADH), which was present in 65% of cases with hyponatremia. Early detection and treatment of underlying electrolyte abnormality can potentially reduce mortality and morbidity associated with tuberculosis and reduce duration of hospitalization. Further research into the prevalence of potassium, magnesium and chloride abnormalities can add to the lacunae of knowledge.

Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion.

OBJECTIVE: Transport of Ca2+ into pancreatic ß cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mitochondrial Ca2+ transport in intact cells. We examined the consequences of deficiency of the accessory protein MICU2 in rat and human insulin-secreting cells and mouse islets. METHODS: siRNA silencing of Micu2 in the INS-1 832/13 and EndoC-ßH1 cell lines was performed; Micu2-/- mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca2+ dynamics were performed. RESULTS: Silencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-ßH1 cells. The Micu2-/- mice also displayed attenuated GSIS. Mitochondrial Ca2+ uptake declined in MICU2-deficient INS-1 832/13 and EndoC-ßH1 cells in response to high glucose and high K+. MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca2+ uptake, perturbed mitochondrial function illustrated by absent mitochondrial membrane hyperpolarization and lowering of the ATP/ADP ratio in response to elevated glucose. Despite the loss of mitochondrial Ca2+ uptake, cytosolic Ca2+ was lower in siMICU2-treated INS-1 832/13 cells in response to high K+. It was hypothesized that Ca2+ accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca2+ channels, lowering total cytosolic Ca2+. Upon high K+ stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca2+ levels. CONCLUSIONS: MICU2 plays a critical role in ß cell mitochondrial Ca2+ uptake. ß cell mitochondria sequestered Ca2+ from the submembrane compartment, preventing desensitization of voltage-dependent Ca2+ channels and facilitating GSIS.

Protocatechuic acid attenuates chronic unpredictable mild stress induced-behavioral and biochemical alterations in mice.

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice.

Computational Studies of bis-2-Oxoindoline Succinohydrazides and their In Vitro Cytotoxicity.

BACKGROUND: The discovery of clinically relevant EGFR inhibitors for cancer therapy has proven to be a challenging task. To identify novel and potent EGFR inhibitors, the quantitative structure-activity relationship (QSAR) and molecular docking approach became a very useful and largely widespread technique for drug design. METHODS: We performed the in vitro cytotoxic activity on HEPG-2 cell line and earlier on MCF-7 and A 549 by using MTT assay method. The development of 3D QSAR model of N1,N4-bis(2-oxoindolin-3- ylidene) succinohydrazides using the stepwise-backward variable methods to generate Multiple Linear Regression method elucidates the structural properties required for EGFR inhibitory activity and also perform the Molecular Docking studies on EGFR (PDB ID:1M17). Further, we analysed for Lipinski's rule of five to evaluate the drug-likeness and established in silico ADMET properties. RESULTS: The resulting cytotoxicity (IC50) values ranged from 9.34 to 100 µM and compared with cisplatin as a standard. Among the series of compounds, 6j showed good cytotoxic activity on HEPG-2 cell line with 9.34 µM, IC50 value. Most of the evaluated compounds showed good antitumor activity on HEPG-2 than MCF-7and A549. The developed 3D QSAR Multiple Linear Regression models are statistically significant with non-cross-validated correlation coefficient r2 = 0.9977, cross-validated correlation coefficient q2 = 0.902 and predicted_r2 = 0.9205. Molecular docking studies on EGFR (PDB ID: 1M17) results, compounds 6d, 6j and 6l showed good dock/PLP scores i.e. -81.28, -73.98 and -75.37, respectively, by interacting with Leu-694, Val-702 and Gly-772 amino acids via hydrophobic and hydrogen bonds with Asn818 and Met- 769. Further, we analysed drug-likeness and established in silico ADMET properties. CONCLUSION: The results of 3D QSAR studies suggest that the electrostatic and steric descriptors influence the cytotoxic activity of succinohydrazides. From the molecular docking studies, it is evident that hydrophobic, hydrogen and Van Der Waal's interactions determine binding affinities. In addition to this, druglikeness and ADMET properties were analysed. It is evident that there is a correlation between the QSAR and docking results. Compound 6j was found to be too lipophilic due to its dihalo substitution on isatin nucleus, and can act as a lead molecule for further and useful future development of new EGFR Inhibitors.

Protocatechuic acid attenuate depressive-like behavior in olfactory bulbectomized rat model: behavioral and neurobiochemical investigations.

The main objective of the present study is to investigate potential effects of PCA in OBX induced depressive-like behavior in rat model. PCA was administered at a dose of 100 mg/kg and 200 mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) expression], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Experimental findings reveals that OBX subjected rats showed alteration in behaviors like, increase in immobility time, ambulatory and rearing behaviors significantly, reduced BDNF level, 5-HT, DA,NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of PCA significantly attenuated behavioral and neurobiochemical alterations, thus, its antidepressant-like activity is largely mediated through modulation of neurotransmitter, endocrine and immunologic systems, mainly by improvements of BDNF, 5-HT, DA, NE, reduced MDA, IL-6, and TNF-α in hippocampus and cerebral cortex.

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response.

Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-α significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex as well as serum corticosterone.

Attenuation of acute restraint stress-induced depressive like behavior and hippocampal alterations with protocatechuic acid treatment in mice.

Protocatechuic acid ethyl ester (PCA), a phenolic compound, exhibits neuroprotective effects through improving endogenous antioxidant enzymatic and nonezymatic system. Based on the role of oxidative stress in modulating depressive disorders and the relationship between neuroprotective and antioxidant potential of PCA, we studied if its antidepressant like effect is associated by modulation of cerebral cortex and hippocampal antioxidant alterations. Acute restraint stress (ARS) is known to induce depressive like behavior by neuronal oxidative damage in mice. Swiss albino mice subjected to ARS exhibited an increased immobility time in forced swim test, elevated serum corticosterone and produced oxidative stress dependent alterations in cerebral cortex and hippocampus mainly increased thiobarbituric acid reactive substances and reduced catalase (CAT), superoxide dismutase (SOD) activity. Treatment with PCA was able to prevent stress induced immobility time in forced swim test without altering locomotor activity in mice. Further, PCA treatment attenuated the elevation of serum corticosterone, lipid peroxidation and restored enzymatic antioxidants in cerebral cortex and hippocampus in ARS mice. Altogether, the experimental findings demonstrate the notion that PCA exhibit antidepressant like activity might be related, at least in part, to its capability of modulating antioxidant defense system and oxidative damage induced by ARS in cerebral cortex and hippocampus in mice and thus maintain the pro-/anti-oxidative homeostasis.

Complementary and alternative medicine use by diabetes patients in Kerala, India.

The study assessed: (1) the prevalence of exclusive use of complementary and alternative medicine (CAM), exclusive use of modern medicine and combined use; (2) the factors associated with exclusive CAM use; and (3) the expenditure for CAM use among type-2 diabetes patients in rural Kerala. We surveyed 400 diabetes patients selected by multi-stage cluster sampling. Exclusive CAM use was reported by 9%, exclusive modern medicine by 61% and combined use by 30%. Patients without any co-morbidity were four times, those having regular income were three times and those who reported regular exercise were three times more likely to use exclusive CAM compared with their counterparts. Expense for medicines was not significantly different for CAM compared with modern medicine both in government and private sector. Patients with any co-morbidity were less likely to use CAM indicating that CAM use was limited to milder cases of diabetes.

Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus.

BACKGROUND: Silymarin is a polyphenolic flavanoid of Silybum marianum, elicited neuroprotection and antidepressant like activity in stressed model. It was found to increase 5-hydroxytryptamine (5-HT) levels in the cortex and dopamine (DA) and norepinephrine (NE) in the cerebellum in normal mice. The aim of the present study was to investigate the potential antidepressant-like activity of silymarin in the acute restraint stress (ARS) in mice. METHODS: The ARS was induced by immobilizing the mice for a period of 7h using rodent restraint device preventing them for any physical movement. One hour prior to ARS, silymarin was administered at doses of 100mg/kg and 200mg/kg per oral to non stressed and ARS mice. Various behavioral parameters like immobility time in force swim test, locomotor activity in open field test, and biochemical alterations, serum corticosterone, 5-HT, DA, NE level, malondialdehyde (MDA), and antioxidant enzymes (GSH, CAT and SOD) in hippocampus and cerebral cortex in non stressed and ARS subjected mice were investigated. RESULTS: Experimental findings reveals mice subjected to ARS exhibited significant increase immobility time, serum corticosterone, MDA formation and impaired SOD and CAT activities in hippocampus and cerebral cortex as compared to non stressed mice. Silymarin treatment (100mg/kg and 200mg/kg) significantly attenuated immobility time, corticosterone and restored the antioxidant enzymes after ARS. CONCLUSION: The present experimental findings indicate that silymarin exhibits antidepressant like activity probably either through alleviating oxidative stress by modulation of corticosterone response, and antioxidant defense system in hippocampus and cerebral cortex in ARS mice.

Preparation and Pharmacological Evaluation of Novel Orally Active Ester Prodrugs of Ketoprofen with Non-Ulcerogenic Property.

This study investigates anti-inflammatory activity with improved pharmacokinetic and non-ulcerogenic properties of various novel synthesized prodrugs of ketoprofen in experimental animals. Prodrugs 3a, 3f and 3k were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ketoprofen (1) in both normal and inflammation-induced rats. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent drug ketoprofen. These prodrugs are found to have no gastric ulceration with retained anti-inflammatory activity. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with non-ulcerogenic potential of ester prodrugs of ketoprofen.

Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis.

Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of 6k, we carried out a molecular docking simulation study.

Design, synthesis, characterization and in vitro and in vivo anti-inflammatory evaluation of novel pyrazole-based chalcones.

Abstract A series of novel pyrazole-based chalcones have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxyphenyl)-1H-pyrazole (6). The structures of regioisomers 6 and 7 were determined by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their inhibitory activity against COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Moreover, they were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model for acute inflammation and cotton pellet-induced granuloma model for chronic inflammation. All the synthesized compounds showed potential to demonstrate anti-inflammatory activities, of particular interest compounds 10i, 10e, 10f, and 10h were found to be potent anti-inflammatory agents.

Potential targets for the development of novel antidepressants: future perspectives.

Depression is an affective disorder characterized by hallucination, delusion and increased social risk and is estimated to affect approximately 20 % of the population at some point during the lifetime. As per World Health Organization (WHO) it is predicted to be the leading cause of burden of disease by 2030. Effects of currently available antidepressants have explained the monoamine hypothesis of depression, which proposes that impaired release of serotonin, noradrenaline and dopamine, are thought to be responsible for the development of depressive symptoms. However, these drugs are not specific for their action, as they also inhibit other enzymes; this explains the side effects/drug interactions associated with these agents. The present review will familiarize the readers with novel targets being identified for depression which will be certainly beneficial for researcher, academician for the development of drugs for the management of depression and related behavior.