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Neonatal anoxia is linked to long-lasting neurodevelopmental deficits. Due to the lack of pharmacological intervention to treat neonatal anoxia, there is interest in finding new molecules for its treatment. Indole-3-carbinol (I3C) has shown neuroprotective effects in some disease conditions. However, the neuroprotective role of I3C in neonatal anoxia has not been explored. Consequently, we have investigated the effect of I3C on neonatal anoxia-induced brain injury and neurodevelopmental deficits. Rat pups after 30 h of birth were subjected to two episodes of anoxia (10 min in each) at a time interval of 24 h by flowing 100% nitrogen. I3C was administered within 30 min of the second episode of anoxia on a postnatal day (PND) 3 and continued for PND 9. Neurodevelopmental deficits, cortical mitochondrial membrane potential (MMP), opening of mitochondrial permeability transition pore (MPTP), electron transport chain (ETC) enzyme activities, oxidative stress, hypoxia-inducible factor-1α (HIF-1α) levels, histopathological changes, and apoptosis were measured. I3C treatment dose-dependently ameliorated the neurodevelopmental deficits and somatic growth in anoxic pups. I3C improved mitochondrial function by enhancing the MMP, mitochondrial ETC enzymes, and antioxidants. It blocked the MPTP opening and release of cytochrome C in anoxic pups. Further, I3C reduced the elevated cortical HIF-1α in neonatal anoxic pups. Furthermore, I3C ameliorated histopathological abnormalities and mitochondrial-mediated apoptotic indicators Cyt C, caspase-9, and caspase-3. Our study concludes that I3C improved neuronal development in anoxic pups by enhancing mitochondrial function, reducing HIF-1α, and mitigating apoptosis.

Dimethyl fumarate (DMF) is an enoate ester approved for treating autoimmune diseases like relapsing-remitting multiple sclerosis (RRMS) and psoriasis. Although its efficacy is attributed to its immunomodulatory properties but the exact mechanism of action is undeciphered. DMF tends to make Michael-adduct with cysteine residues of enzymes. The current study focuses on in-vitro experiments to find out the time-dependent enzyme inhibition of cathepsin C, which is an essential upstream target for immune cells controlling apoptosis. An in-vivo study was also performed by inducing experimental autoimmune encephalitis (EAE) on the day-1 of the experiment, and clinical scoring was done after 4 hours onwards up to day-33. Oral drug treatment was done from day-7 onwards with DMF-50 mg/kg. A significant improvement in the clinical score with DMF treatment compared to the EAE group has been observed. DMF has been shown to ameliorate demyelination in the spinal cord and reduce CD8+ and CD4+ T lymphocyte infiltration in the CNS. Moreover, a significant reduction in the cathepsin C activity and its downstream granzyme B activity in the CNS on day-33 has been noticed. The irreversible inhibition of cathepsin C indicates the efficacy of DMF on mononuclear cells.

Molecular near-infrared (NIR) imaging is an emerging pre-clinical tool for labeling Alzheimer's disease (AD) pathogenic biomarkers, especially cerebral amyloid-beta (Aβ) plaques. Herein, we present a series of acceptor-π-donor based molecular NIR probes, composed of rhodanine (acceptor fragment) in conjugation with coumarin or carbostyril (donor fragment) nucleus. The most promising probe 19 has a desirable binding affinity (Kd = 0.143 μM) against Aβ aggregates with little or no nonspecific interaction with BSA, minimal cytotoxicity, good brain permeability, desirable plasma stability, and fluorescence sustainability profile across a comprehensive physiological pH range. Histological fluorescence imaging revealed that probe 19 had good selectivity and affinity for Aβ plaques, confirmed with immunofluorescence and ThT (aggregated Aβ specific dye), and a high signal-to-noise ratio. It was also successfully applied for fluorescence labeling of Aβ in the eye imaginal disc of AD Drosophila larvae. Collectively, these probes can be finetuned due to their versatile structural scaffold to evolve as promising NIR imaging probes for the detection of AD biomarkers.

Perinatal asphyxia (PA)-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and long-term sequelae such as spastic motor deficits, intellectual disability, seizure disorders and learning disabilities. The brain injury is secondary to both the hypoxic-ischemic event and oxygenation-reperfusion following resuscitation. Following PA, a time-dependent progression of neuronal insult takes place in terms of transition of cell death from necrosis to apoptosis. This transition is the result of time-dependent progression of pathomechanisms which involve excitotoxicity, oxidative stress, and ultimately mitochondrial dysfunction in developing brain. More precisely mitochondrial respiration is suppressed and calcium signalling is dysregulated. Consequently, Bax-dependent mitochondrial permeabilization occurs leading to release of cytochrome c and activation of caspases leading to transition of cell death in developing brain. The therapeutic window lies within this transition process. At present, therapeutic hypothermia (TH) is the only clinical treatment available for treating moderate as well as severe asphyxia in new-born as it attenuates secondary loss of high-energy phosphates (ATP) (Solevåg et al. in Free Radic Biol Med 142:113-122, 2019; Gunn et al. in Pediatr Res 81:202-209, 2017), improving both short- and long-term outcomes. Mitoprotective therapies can offer a new avenue of intervention alone or in combination with therapeutic hypothermia for babies with birth asphyxia. This review will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after PA, as a means of identifying new avenues of therapeutic intervention.

In this work, for the first time, zinc substituted baghdadite (Ca3-xZnxZrSi2O9; x = 0, 0.1, 0.25 and, 0.5) ceramic was successfully prepared. A solid-state ceramic synthesis route was utilized to prepare a composite for biomedical applications. The incorporation of zinc oxide reduces the synthesis temperature. The properties of composites were presented in terms of Zinc oxide amount. In-vitro bioactivity and degradation results indicated lower degradation in comparison with pure baghdadite. The hemolysis rate was observed

Introduction: Diindolylmethane (DIM), a major acid condensation product of Indole-3-carbinol, is known to inhibit platelet aggregation and thrombosis. The drugs with antiplatelet and antithrombotic activities are used to treat ischemic stroke. Objective: The present study investigated the role of DIM on platelet aggregation inhibitory properties in middle cerebral artery occluded (MCAO) rats. Methods: DIM (12.5, 25, and 50 mg/kg) was orally administered to MCAO rats for 3 days. Platelet aggregation, platelet cyclic adenosine monophosphate (cAMP), reactive oxygen species (ROS), hydrogen peroxide (H2O2), and serum cyclooxygenase (COX-1), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2), and inflammatory markers were estimated. Further brain structural and functional recovery was evaluated by measuring cerebral blood flow, neurological deficits, brain infarction, blood-brain barrier (BBB) leakage, brain water content, and histological abnormalities. Results: DIM significantly ameliorated adenosine diphosphate (ADP), collagen, thrombin, and arachidonic acid-induced platelet aggregation by inhibiting COX-1, TXB2, and PGE2 and elevating cAMP. Further, DIM also alleviated platelet-mediated oxidative stress (ROS and H2O2) and reduced the serum inflammatory markers, tumor necrosis factor-α (TNF-α) and interleukin -6 (IL-6), and increased anti-inflammatory cytokine, IL-10, in MCAO rats Conclusion: DIM treatment confers neuroprotection in MCAO rats by inhibition of platelet aggregation, platelet-mediated oxidative stress, and inflammation. Correspondingly, DIM improved cerebral blood flow and reduced neurological deficits, brain infarction, BBB leakage, brain water content, and histopathological abnormalities indicating the preservation of brain structural integrity. Thus, the present study provided preclinical evidence of DIM neuroprotection against ischemic stroke.

Glucocerebrosidase (GCase), a GBA1 gene-encoded lysosomal enzyme, is a risk factor for Parkinson's disease (PD). Chaperones that increase GCase activity can potentially be disease-modifying agents in PD. To date, none of the registered treatments has demonstrated disease-modifying effects. Thus, chaperones for GCase were identified using in-silico virtual screening, molecular property filtering, and molecular dynamics and validated by circular dichroism, FT-IR, and Raman spectroscopies. In-vitro enzyme kinetics, thermal denaturation assay (TDA), and cell-line model were used to test their potential for GCase In-silico investigation revealed four compounds as candidate chaperones with adequate brain penetrability and binding energy (BE). Of them, GC466 showed ideal chaperoning characteristics, including potent BE -8.92 ± 0.68 Kcal/mol and binding affinity (K

Milk proteins serve as nutrition and affect neonate development and immunity through their bioactivity. Post-translational modifications of proteins affect their bioactivity. Glycosylation is the attachment of sugar moieties to proteins, with attachment of glycans to asparagine indicated as N-linked glycosylation. Our objective was to characterize N-linked glycosylated proteins in homogenate swine milk samples collected from sows (n = 5/6) during farrowing to represent colostrum and on days 3 and 14 post-farrowing to represent transitional and mature milk, respectively. Glycopeptides were isolated with lectin-based extraction and treated with Peptide N-glycosidase F (PNGase F) to identify N-linked glycosylation sites. Purified glycopeptides were analyzed by label-free liquid chromatography–tandem mass spectrometry (LC–MS/MS). MaxQuant software was used to align spectra to Sus scrofa Uniport database to identify proteins and measure their relative abundances. Analysis of variance and Welch’s t-test analysis identified glycoproteins differentially abundant between colostrum, transitional, and mature milk (false discovery rate 0.75 for deamidation) sites on 220 glycoproteins in sow milk. Glycoproteins were found across all three phases of swine milk production and varied by number of glycosylation sites (1–14) and in abundance and distribution between colostrum, transitional, and mature milk. Polymeric immunoglobulin receptor was the most glycosylated protein with 14 sites identified. Also highly glycosylated were casein and mucin proteins. These data are described and the relevance of glycosylated milk proteins in neonate development, such as protection against pathogens, is discussed.

Bioactive glasses are mostly utilized as bone and dental implants. However, these biomaterials cause immunogenic response even in absence of immune stimulating signals. Therefore, there is a need to develop a biomaterial that would be immunologically inert and possesses beneficial biological effects depending upon the pathological condition. In this study, barium doped bioactive glass (BaBG) and 45S5 were synthesized in the nanometer range using the sol-gel process and the BET-specific surface area was assessed. The in-vitro bioactivity of BaBG and 45S5 was examined in the simulated body fluid (SBF). Hydroxyapatite crystals formed on the surface were evaluated using FTIR, X-ray diffractometry (XRD), scanning electron microscopy (SEM), energy-dispersive X-Ray spectroscopy (EDX), and pH changes of SBF. The doping of barium in bioactive glasses showed biocompatibility as the hemolytic index was within the permissible limit for biomedical agents. BaBG and 45S5 increased the percentage of cell proliferation without producing any cytotoxic effects on C6 and K562 cells. Moreover, BaBG showed coordinated horizontal cell movement in scratch assay which is a gold standard for the regeneration of injured tissues. Intriguingly, for the first time we reported that the incorporation of barium significantly reduced the LPS-induced elevation of interleukin-6 (IL-6) and tumor necrosis factor- α (TNF-α) in C6 cells. Simultaneously, BaBG also elevated IL-10 and hence showed anti-inflammatory properties. Therefore, based on the biocompatibility, cytocompatibility, and regenerative tendency, BaBG can be used for therapeutic purposes where inflammation restricts the use of biomaterials.

Cognitive inflexibility is one of the major clinical symptoms of post-traumatic stress disorder (PTSD). Studies have examined the impact of traumatic events on anxiety. However, there were limited reports on the effect of traumatic episodes on cognitive flexibility. Therefore, animal models developing cognitive inflexibility would provide new insight of pathophysiology and pharmacotherapy of PTSD. Male Wistar rats were subjected to stress–re-stress (SRS) procedure by restraining them for 2 h followed by foot shock (FS) and halothane exposure on day 2 (D-2). Then, the rats were exposed every week to FS as re-stress cue up to D-32. Donepezil (3 mg/kg; po) and sertraline (10 mg/kg; po) dosing was started from D-8 and continued up to D-32. SRS exposure caused cognitive inflexibility by producing deficits in intra-dimension (ID) and extra-dimension (ED) set-shifting which was significantly attenuated by donepezil. However, sertraline mitigated only ID shift in SRS-subjected rats. SRS-induced PTSD-like symptoms such as fear response, anxiety-like behaviour and cognitive deficits were attenuated by both donepezil and sertraline. Donepezil did not modulate the SRS-induced hypothalamic–pituitary–adrenal (HPA) axis dysfunction and activation of serotonergic and nor-adrenergic system. Interestingly, exposure of SRS caused a decrease in acetylcholine level and increase in acetylcholine esterase activity in prefrontal cortex (PFC) and hippocampus (HIP) which was only mitigated by donepezil. Donepezil significantly attenuated SRS-induced down-regulation of choline-acetyl transferase and α-7 nicotinic acetylcholine receptor expressions in PFC and HIP. Cognitive inflexibility is developed in the SRS model along with other PTSD-like symptoms which were attenuated by donepezil.

Tissue engineering (TE), a new paradigm in regenerative medicine, repairs and restores the diseased or damaged tissues and eliminates drawbacks associated with autografts and allografts. In this context, many biomaterials have been developed for regenerating tissues and are considered revolutionary in TE due to their flexibility, biocompatibility, and biodegradability. One such well-documented biomaterial is bioactive glasses (BGs), known for their osteoconductive and osteogenic potential and their abundant orthopedic and dental clinical applications. However, in the last few decades, the soft tissue regenerative potential of BGs has demonstrated great promise. Therefore, this review comprehensively covers the biological application of BGs in the repair and regeneration of tissues outside the skeleton system. BGs promote neovascularization, which is crucial to encourage host tissue integration with the implanted construct, making them suitable biomaterial scaffolds for TE. Moreover, they heal acute and chronic wounds and also have been reported to restore the injured superficial intestinal mucosa, aiding in gastroduodenal regeneration. In addition, BGs promote regeneration of the tissues with minimal renewal capacity like the heart and lungs. Besides, the peripheral nerve and musculoskeletal reparative properties of BGs are also reported. These results show promising soft tissue regenerative potential of BGs under preclinical settings without posing significant adverse effects. Albeit, there is limited bench-to-bedside clinical translation of elucidative research on BGs as they require rigorous pharmacological evaluations using standardized animal models for assessing biomolecular downstream pathways.

Chronic D-galactose (D-gal) administration causes cognitive impairment and is used widely in animal models for anti-aging studies. Centella asiatica (CA), a traditional herbal medicine, has been us...

One of the recent challenges in the design/development of prosthetic orthopedic implants is to address the concern of local/systemic toxicity of debris particles, released due to wear or degradation. Such debris particles often lead to inflammation at the implanted site or aseptic loosening of the prosthesis which results in failure of the implant during long run. Several in vitro studies demonstrated the potentiality of piezoelectric sodium potassium niobate [Na

Mitochondria is an essential organelle; it produces 95% of the adenine triphosphate (ATP) of cells, their dysfunction is related to the pathogenesis of multiple diseases, such as diabetes mellitus, cardiovascular and neurological disorders. Various pharmacologic agents are known to target mitochondrial function. Moreover, the toxic side effects of multiple drugs used to treat diseases are related to the impairment of mitochondrial function. Thus, there is a need to develop a method to evaluate the effect of pharmacologic agents for their potential and side effects to identify effective mitochondrial-modulating agents. Therefore, the objective of this study was to develop and validate an ex-vivo method for studying the effect of pharmacologic agents on mitochondrial function and rescue of dysfunction. Dimethyl sulfoxide (DMSO) concentrations that drugs were soluble in and maintained mitochondrial function were determined. Metformin (MET) is a known mitochondrial complex-1 inhibitor tested for its ability to compromise mitochondrion function. Coenzyme Q10 (Q10) and Resveratrol (RSV), which are known to enhance mitochondrial function, were added alone and dose-dependent, tested for the ability to rescue metformin-induced mitochondrial dysfunction. Ex-vivo liver and brain mitochondrial function was assessed using an oxytherm Clark-type oxygen electrode. DMSO was found to be toxic above 10% and drugs insoluble below 5%. The addition of 0.5 mg/ml MET decreased liver and brain mitochondrial respiratory control rate (RCR). At the same time, Q10 improved RCR in normal mitochondria and a concentration-dependent manner in MET-induced dysfunctional mitochondria. RSV was added in the last step of the experiment to confirm that compromised function is due to MET. Hence this method can be used to screen pharmacological agents for their potential therapeutics or toxic effect on mitochondria.

The present study investigated the cardioprotection of Indole-3-carbinol on isoproterenol (ISO)-induced myocardial infarction in Wistar rats. I3C treatment significantly reduced the prolongation of the QRS complex, QT interval, and ST-segment elevation. I3C was also able to normalise blood pressure (SBP, DBP, and MAP) and HR. I3C significantly decreased heart weight, cardiac troponin I (cTn I), CK-MB, LDH, AST and ALT. I3C ameliorated acute hyperglycaemia, hyperlipidemia, and myocardial infarction (%) in ISO rats. I3C treatment significantly elevated the antioxidant enzymes like SOD, CAT, and GSH and attenuated the MDA levels. I3C reduced the inflammatory cytokines (TNF-α and IL-6) and increased the anti-inflammatory cytokine 1 L-10. Furthermore, I3C significantly recovered myocardial structure by inhibiting neutrophil infiltration and oedema. Moreover, I3C attenuated apoptotic markers (cytochrome C, caspase 9 and caspase 3). Consequently, I3C restored cardiac function in MI rats by alleviating oxidative stress, inflammation, and apoptosis, and I3C could be used to treat myocardial infarction.

The effects of ELF-PEMF exposure on spontaneous alternation, anxiety, motor coordination, and locomotor activity have been discussed in various pre-clinical and clinical settings. Several epidemiological and experimental studies have demonstrated the potential effects of ELF-PEMF when exposed ∼1 h/day; however, very few studies have focused on understanding the influence of ELF-PEMF exposure of 1-3 mT with an exposure duration of 1 h/day on spontaneous alternation, anxiety, motor coordination, and locomotor activity. Hence, we attempted to study the effects of ELF-PEMF exposure of 1-3 mT, 50 Hz with an exposure duration of 20 min each with a 4 h gap (2 times) on the cellular proliferation and morphologies of C6 (Glial) cells and spontaneous alternation, anxiety, motor coordination and locomotor activity of Wistar rats under in vitro and in vivo conditions, respectively. The results showed that ELF-PEMF exposure did not induce any significant levels of cellular fragmentation and changes in the morphology of glial cells. Also, the outcomes revealed no noticeable effects on spontaneous alternation, anxiety, motor coordination, and locomotor activity in PEMF-exposed groups compared with the control. No undesirable side effects were observed at the highest dose (B=3 mT). We also performed histological analysis of the selected brain sections (hippocampus and cortex) following ELF-PEMF exposure. Incidentally, no significant changes were observed in cortical cell counts, tissue structure, and morphology.

This study aims to synthesize pseudo-wollastonite and wollastonite base glass-ceramic from solid wastes, and a comparative study of their physico-mechanical, bioactivity, and hemolysis properties is conducted. The stoichiometric amount of chicken eggshells derived CaO (~99%), and rice husk ash (RHA) derived nano SiO2 (~99%) is used as ingredients for the formulation of wollastonite. The pseudo-wollastonite (α-W) is synthesized by sintering the ingredients at 1200 °C for 4 h, and wollastonite glass is made through the quenching method after melting of the ingredients at 1400 °C. The wollastonite glass-ceramic (GC) is prepared by control heat-treatment of wollastonite glass at 1200 °C for 1 h. Numerous characterizations like X-ray diffraction (XRD), scanning electron microscopy (SEM), apparent porosity and bending strength of α-W and GC are comparatively investigated. The GC is composed of the collaborative pseudo-wollastonite nucleation (~35%) and amorphous phases. α-W and GC show the apparent porosity about 4.23 % and 2.77 %, bending strength about 108 MPa and 139 MPa, and an average grain size about 2.30 μm and 0.60 μm, respectively. The obtained results exhibit that the waste-derived both α-W and GC have excellent bioactivity and good hemolysis index (

Aim: A breakthrough in modern medicine, in terms of treatment of Alzheimer’s disease, is yet to be seen, as the scene is currently plagued with numerous clinical trial failures. Here, we are exploring multifunctional hybrid sulfonamides for their anti-Alzheimer activity due to the complex nature of the disease. Results & methodology: Compound 41 showed significant inhibition of MMP-2 (IC50: 18.24 ± 1.62 nM), AChE (IC50: 4.28 ± 0.15 μM) and BuChE (IC50: 1.32 ± 0.02 μM). It also exhibited a metal-chelating property, as validated by an in vitro metal-induced Aβ aggregation assay using confocal fluorescence imaging. Whereas, MTT and DPPH assays revealed it to be nontoxic and neuroprotective with substantial antioxidant property. Conclusion: The present study puts forth potent yet nontoxic lead molecules, which foray into the field of multitargeted agents for the treatment of Alzheimer’s disease.

Disease-modifying agents are unmet medical need for Parkinson's disease (PD). Drugs are under clinical trial to halt its progression, such as ambroxol due to its glucocerebrosidase (GCase)-stimulating activity. However, the neurorestorative effect of ambroxol is not yet investigated in any of the well-established PD models in vivo. Ambroxol was administered as 400 mg/kg orally twice a day from D-28 to D-70 after the unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in male rats. Behavioral parameters were observed every week, and at last, tyrosine hydroxylase (TH), dopamine transporter (DAT), glucocerbrosidase (GCase) enzymatic and mitochondrial complex-I activity, α-synuclein levels, and Nissl's staining were performed. Behavioral functions were progressively recovered. Ambroxol restored TH and DAT levels on D-71 as the markers of dopaminergic cell and extracellular DA concentration respectively, indicating the recovery of dopaminergic system. Factors involved in PD pathogenesis such as GCase enzymatic and mitochondrial complex-I activity were restored, and α-synuclein pathology was decreased by ambroxol. GCase deficiency is involved in mitochondrial impairment and formation of oligomeric α-synuclein aggregates which negatively affect mitochondrial function. Nissl bodies were also normalized. Therefore, both the GCase-stimulating and α-synuclein pathology-diminishing effects of ambroxol may be responsible for increment in mitochondrial function and restoration of dopaminergic system. These may act as significant mechanisms for disease-modifying potential of ambroxol. The current study provides the preclinical evidence to support the neurorestorative potential of ambroxol in 6-OHDA-induced hemiparkinson's rat model and indicates its possible use as disease-modifying agent in PD.

Long term exposure of electromagnetic radiations (EMR) from cell phones and Wi-Fi hold greater propensity to cause anxiety disorders. However, the studies investigating the effects of repeated exposure of EMR are limited. Therefore, we investigated the effects of repeated exposure of discrete frequencies of EMR in experimental animals. Male rats were exposed to EMR (900, 1800 and 2450 MHz) for 28 (1 h/day) days. Long term exposure of EMR (2450 MHz) induced anxiety like behavior. It deregulated the hypothalamic pituitary adrenal (HPA) axis in rats as observed by increase in plasma corticosterone levels apart from decreased corticotrophin releasing hormone-2 (CRH-2) and Glucocorticoid receptor (GR) expression in amygdala. Further, it impaired mitochondrial function and integrity. The expression of Bcl2 showed significant decrease while Bax and ratio of Bax: Bcl2 were increased in the mitochondria and vice versa in cytoplasm indicating altered regulation of apoptosis. EMR exposure caused release of cytochrome-c and expression of caspase-9 ensuing activation of apoptotic cell death. Additional set of experiments performed to estimate the pattern of cell death showed necrotic and apoptotic amygdalar cell death after EMR exposure. Histopathological studies also revealed a significant decrease in neuronal cells in amygdala. The above findings indicate that long-term exposure of EMR radiation (2450 MHz) acts as a stressor and induces anxiety-like behaviors with concomitant pathophysiological changes in EMR subjected rats.

The ischemic cascade is initiated in the hypoperfused region of the brain that leads to neuronal cell death. Identification of multi-target inhibitor against prominent molecular mediators of ischemic cascade might be a suitable strategy to combat cerebral ischemic stroke. The present study is designed to evaluate the neuroprotective efficacy of chlorogenic acid (CGA) in the global cerebral ischemic rat model. The effective dose of CGA was evaluated on the basis of reduction in cerebral infarction area percentage, Evans blue extravasation, and restoration of brain water content. The expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and caspase-3 was evaluated by immunohistochemistry and morphological and cellular alterations in the cortex were observed by brain histology. The level of glutamate, calcium, and nitrate in different regions of the brain, as well as cerebrospinal fluid (CSF), was evaluated. The level of calcium and nitrate was compared with ifenprodil-an antagonist of N-methyl-D-aspartate receptor (NMDAR) and 7-nitroindazole-an inhibitor of neuronal nitric oxide synthase (nNOS) respectively. Further, molecular docking was performed to compare the inhibition potential of CGA against NMDAR and nNOS with their inhibitors. Dose optimization results revealed that intranasal administration of CGA (10 mg/kg b.w.) significantly reduced the cerebral infarction area, Evans blue extravasation and restored the brain water content compared with ischemia group. It also significantly reduced the calcium, nitrate, and glutamate levels compared with ischemia group in the cortex, hippocampus cerebellum, and CSF. Immunohistochemical analysis revealed that CGA significantly reduced the expression of TNF-α, iNOS, and caspase-3 as compared with the ischemia group. In molecular docking study, CGA displayed similar binding interaction as that of Ifenprodil and 7-nitroindazole with NMDAR and nNOS respectively. The current findings suggest that the treatment with CGA confers neuroprotection in global ischemic insult by inhibiting and downregulating the different molecular markers of cerebral ischemia.

Disease-modifying treatment strategy for Parkinson's disease (PD) by stabilization of Glucocerebrosidase (GCase) enzyme by chaperones is of particular interest. Wild-type rat is a widely used animal model for PD; however, the in-silico model to elucidate the nature of rat GCase (rGCase)-chaperone interactions, mechanisms, and structural stability is still unavailable. Hence, we have developed pH-dependent rGCase homology models, in-silico (docking and molecular dynamics), and in-vitro techniques (enzyme kinetics and thermal stability) to address this gap. The homology modeling results revealed ≥ 90% rGCase residues were in the favored regions, representing adequate models quality. In-silico studies showed an interaction between chaperone (Ambroxol, AMB) and the active site residues TYR 331, TYR 263, GLN 266, and GLU 358 with the higher affinity at neutral pH than acidic pH. In-vitro studies showed higher inhibitory activity (IC

Bioactive glasses (BAGs) were invented five decades ago and have been widely used clinically in orthopedic and stomatology. However, in the past two decades, BAGs have been explored immensely by several researchers worldwide as a multifunctional delivery system for a multitude of therapeutics ranging from metal ions to small molecules (e.g., drugs) and macromolecules (e.g., DNA). The impetus for devising a BAG-based delivery system in the 21st century is based upon the facilitative properties it offers for entrapment of a wide range of therapeutic molecules and the tailorable controlled release kinetics to the target tissue site along with the biological activity of the ionic dissolution products in several pathological conditions such as osteoporosis, cancer, infection, and inflammation. This review comprises two parts: the first part discusses the need for a new delivery system and how the journey from melt quench progressed towards template-based sol-gel mesoporous. In the second part, we have comprehended the scientific advancements made so far, emphasizing BAGs as a delivery system ranging from therapeutic ions to phytopharmaceuticals. We have also highlighted a few loopholes that have prevented bench-to-bedside clinical translation of a plethora of elucidative researches done so far.

Post-traumatic stress disorder (PTSD) is a psychological disorder affecting many around the world. Growing evidence suggests that orexin-A is involved in the pathophysiology of depression and panic anxiety disorder. However, the role of orexin-A in PTSD remains unclear. Therefore, pharmacological manipulation of orexin-A can be a potential approach for the treatment of PTSD. Male Wistar rats were subjected to stress re-stress (SRS) by restraining them for 2 h followed by foot shock (FS) and halothane exposure on day-2 (D-2). Then the rats were weekly exposed to FS as re-stress cue . Suvorexant, an orexin antagonist (10, 20 and 30 mg/kg p.o.) and paroxetine (10 mg/kg p.o.) were administered from D-8 to D-32. Plasma and cerebrospinal fluid (CSF) were collected for corticosterone and orexin-A measurement. The analysis of serotonin and corticotropin-releasing factor receptor-1 (CRF-R1) were performed in the amygdalar tissue. SRS-induced PTSD-like symptoms like fear response, anxiety-like behaviour and hypocorticosteronism were attenuated by suvorexant and paroxetine. Interestingly, SRS exposed rats showed activation of orexin-A and serotonergic systems, which were also attenuated by suvorexant. Additionally, suvorexant ameliorated the extrahypothalamic induced upregulation of CRH-R1 in SRS-exposed rats. Therefore, orexin-A may be considered as a neurochemical-marker for PTSD and suvorexant alleviated PTSD-like symptoms through modulating orexinergic, serotonergic and neuroendocrine systems.