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Background and Aims A short branched chain fatty acid, valproic acid (VPA), has been used worldwide for decades in the intervention of seizure disorders, neuropathic pain and migraine. However, several adverse effects of VPA have been reported over the years. The aim of our investigation was to evaluate the adverse effects of VPA on synaptic functions by using synaptosomal preparation of rat brain as an in vitro model and the possible protective role of melatonin against VPA induced neurotoxicity. Melatonin is an antioxidant and scavenger of free radicals secreted by the pineal gland. Methods In the present investigation, synaptosomes prepared from rat brain were co-treated with melatonin (10 μmol) and VPA (5 mmol) for 2 h under in vitro conditions. Results In this study, co-treatment of melatonin with VPA significantly restored the elevated levels of lipid peroxidation (LPO) and protein oxidation. In addition, melatonin prevented VPA induced alterations in non-enzymatic antioxidant defence reduced glutathione (GSH) and activities of synaptosomal integral enzymes such as AChE, Na+, K+ -ATPase and MAO. A significant increase in the generation of reactive oxygen species (ROS) induced by VPA was observed and melatonin ameliorated elevated level of ROS generation. Moreover, the enhanced level of NO and diminished activity of synaptosomal mitochondrial membrane potential was completely prevented by melatonin treatment. Conclusion Our results corroborate the use of melatonin as a nutraceutical and mitigatory agent against VPA induced neurotoxicity in brain synaptosomes. [ABSTRACT FROM AUTHOR]

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) (Phyt) is a saturated branched chain fatty acid which originates after the breakdown of chlorophyll molecule, phytol. It plays an important role in a variety of metabolic disorders with peroxisomal impairments. The aim of our investigation was to evaluate the adverse effects of Phyt on synaptic functions by using synaptosomal preparation of rat brain as an in vitro model and the possible protective role of melatonin against Phyt-induced neurotoxicity. Melatonin is an antioxidant, secreted by the pineal gland. Melatonin and its metabolites have neuroprotective effects on cellular stress, by reducing reactive oxygen species (ROS) and reactive nitrogen species (RNS). In the present investigation, synaptosomes prepared from rat brain were co-treated with melatonin (10 μM) and Phyt (50 μM) for 2 h. Co-treatment of Phyt with melatonin significantly restored the altered levels of protein carbonyl (PC) contents and lipid peroxidation (LPO). It also replenished the Phyt-induced alterations on the levels of non-enzymatic antioxidant defence reduced glutathione (GSH), enzymatic antioxidants such as catalase (CAT) and superoxide dismutase (SOD) and synaptosomal integral enzymes such as AChE, Na + , K + -ATPase and MAO. We observed that Phyt induced oxidative stress in synaptosomes as indicated by an elevation in the generation of ROS and melatonin was able to inhibit the elevated ROS generation. Moreover, the neurotoxic effects elicited by Phyt on NO level and membrane potential were totally prevented by the treatment of melatonin. The results of our investigation emphasize the potential use of melatonin as a nutraceutical and mitigatory agent against Phyt-induced oxidative stress. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multivariate and diversified disease and affects the most sensitive areas of the brain, the cerebral cortex, and the hippocampus. AD is a progressive age-related neurodegenerative disease most often associated with memory deficits and cognition that get more worsen over time. The central theory on the pathophysiological hallmark features of AD is characterized by the accumulation of amyloid β (Aβ) peptides, also associated with tau proteins (τ) dysfunctioning which leads to distorted microtubular structure, affects the cholinergic system, and mitochondrial biogenesis. This review emphasizes how simple it is to find novel treatments for AD and focuses on several recently developed medications through repurposing that can speed up traditional drug development. • Alzheimer's Disease is a multivariate and diversified disease • The cerebral cortex and hippocampus are frequently affected regions in AD. • The pathology of Alzheimer's Disease is characterized by the accumulation of β amyloid peptides and the dysfunctioning of tau proteins. • Recently developed medications through repurposing can speed up traditional drug development. [ABSTRACT FROM AUTHOR]

Background and Aims To explore hepatoprotective action of curcumin (CMN, a bioflavonoid) on oxaliplatin (Oxa)-triggered mitochondrial oxidative stress and respiratory chain complexes in liver of rats. Oxa is a ubiquitously utilized platinum-based chemotherapeutic agent commonly used for the treatment of colorectal cancer. Mitochondria have recently emerged as targets for anticancer drugs in several kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. There is a dearth of evidence involving the role of mitochondria in mediating Oxa-evoked hepatotoxicity and its underlying mechanism is still debatable. Methods The study was performed in mitochondria isolated from liver of Wistar rats. Oxa (200 μg/mL) and CMN (5 μmol) were incubated under in vitro conditions. Results Oxa evoked a significant increase in the membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, decrease in reduced glutathione (GSH) and nonprotein thiol (NP-SH) levels. Oxa also caused a marked decline in the activities of enzymatic antioxidants and respiratory chain enzymes (I, II, III and V) in liver mitochondria. CMN pre-treatment significantly prevented the activities of enzymatic antioxidants and mitochondrial respiratory chain enzymes. CMN also restored the LPO and PC contents, GSH and NP-SH levels in liver mitochondria. Conclusion CMN intake might be effective in regulation of Oxa-evoked mitotoxicity during chemotherapy. Moreover, it is included in the armamentarium for anticancer agent-induced oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: Anticancer agents help to suppress cellular damage but subsequently can lead to side effects and toxic manifestations. Toxicity of anticancer drug cisplatin (CP) is attributed to its interference of biological enzymes in metabolic pathways. Mitochondria have been recognized as targets in various kinds of toxicity including neurotoxicity and hepatotoxicity that can lead to neoplastic disease. Curcumin (CMN) is a known cytoprotectant with comprehensive anti-inflammatory and anti-cancerous properties. The aim of the present study was to evaluate the damage caused by CP and its abrogation by using antioxidant potential of CMN. CP caused a significant enhancement in the mitochondrial lipid peroxidation (LPO) levels and protein carbonyl (PC) content. Pre-treatment of rat with CMN significantly restored the mitochondrial LPO levels and PC content. It also replenished the CP induced modulatory effects on altered enzymatic and non-enzymatic antioxidants in both brain and liver mitochondria. It is suggested that CMN, by attenuating mitochondrial oxidative stress, holds promise that can decline CP induced adverse effects in brain and liver. CMN should be investigated as a potential safe and remarkable approach in attenuating the adverse effects induced by CP-related toxicants. [Copyright &y& Elsevier]

Abstract: Methotrexate (MTX) is a folic acid antagonist widely used as a cytotoxic chemotherapeutic agent for leukemia and other malignancies. The purpose of this study was to investigate the damage caused by MTX on liver mitochondria and its protection by using antioxidant properties of lipoic acid. MTX substantially affects mitochondrial function by reducing glutathione levels leading to disturbances in antioxidant enzyme defense system. Lipoic acid occurs naturally in mitochondria as a coenzyme. In various studies lipoic acid has been convincingly shown to exhibit an antioxidant role when supplemented exogenously. We studied the effect of lipoic acid pre-treatment on the toxicity of MTX in mouse liver mitochondria focusing specifically on the oxidative stress. MTX caused a significant rise in the mitochondrial lipid peroxidation (LPO), protein carbonyl (PC) content and superoxide radical generation. It also affected the mitochondrial thiol profile. Pre-treatment of mice with lipoic acid (35mg/kg) markedly lowered mitochondrial LPO, PC content and superoxide radical generation. It also restored decreased enzymatic and non-enzymatic antioxidants of mitochondria. It is suggested that lipoic acid has a potential role in suppressing MTX-induced mitochondrial toxicity, and it affords protection either by reversing the decline of antioxidants or by the directly scavenging the free radicals. [Copyright &y& Elsevier]

Abstract: Ropinirole, an agonist of the post-synaptic dopamine D2-receptor, exerts neuroprotective activity. The mechanism is still under discussion. Assuming that this neuroprotection might be associated with inhibition of the apoptotic cascade underlying cell death, we examined a possible effect of ropinirole on the permeability transition pore (mtPTP) in the mitochondrial inner membrane. Using isolated rat liver mitochondria, the effect of ropinirole was studied on Ca2+-triggered large amplitude swelling, membrane depolarization and cytochrome c release. In addition, the effect of ropinirole on oxidation of added, membrane-impermeable NADH was investigated. The results revealed doubtlessly, that ropinirole can inhibit permeability transition. In patch-clamp experiments on mitoplasts, we show directly that ropinirole interacts with the mtPTP. Thus, ropinirole reversibly inhibits the opening of mtPTP with an IC50 of 3.4µM and a Hill coefficient of 1.3. In both systems (i.e. energized mitochondria and mitoplasts) the inhibitory effect on permeability transition was attenuated by increasing concentrations of inorganic phosphate. In addition, we showed with antimycin A-treated mitochondria that ropinirole failed to suppress respiratory chain-linked reactive oxygen species release. In conclusion, our data suggest that the neuroprotective activity of ropinirole is due to the blockade of the Ca2+-triggered permeability transition. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that the progesterone (PROG) metabolite allopregnanolone (AP) is more potent than PROG in the treatment of traumatic brain injury (TBI) and stroke, but the mechanisms for this differential effect are little understood. The mitochondrial permeability transition pore (mtPTP) appears to be a key player in the intrinsic pathway of apoptosis-induced loss of neurons. Its activation is accompanied by the release of cytochrome c (cyt c) from the intermembrane gap and subsequent cell death. We investigated whether mtPTP is implicated in the mechanisms of PROG and AP neuroprotection following traumatic and ischemic brain injury. To assess the neurosteroids'' direct effects on mtPTP activity at the single-channel level, recordings from the inner mitochondrial membrane were obtained by a patch-clamp approach in rat liver mitoplasts. AP but not PROG strongly inhibited mtPTP currents. Interaction of AP with the PTP was further supported by a swelling assay demonstrating that AP inhibited Ca2+-triggered swelling in functionally intact rat liver and brain mitochondria. If AP inhibits the mtPTP, it should prevent the mitochondrial cyt c release seen in stroke and TBI. To test this idea, we subjected one group of rats to cortical contusion injury (CCI) and another to transient middle cerebral artery occlusion (MCAO). AP-treated animals showed substantially decreased cyt c release and AP was more potent than PROG in inhibiting mitochondrial cyt c release at 24 h post-CCI and -MCAO. Our results demonstrate that AP inhibits the mtPTP current. This may help to explain its more potent anti-apoptotic and neuroprotective effects compared to PROG. [Copyright &y& Elsevier]

Abstract: The trace metals are frequently encountered as mixtures of essential and non-essential elements. Therefore, evaluation of their toxic effects individually does not offer a realistic estimate of their impact on biological processes. We studied effects of a mixture of four essential and toxic metals (Cu, Cd, Fe and Ni) on biochemical and morphological characteristics of the gills of a biomarker freshwater fish Channa punctata (Bloch) using environmentally relevant concentrations. Fish were exposed to metal mixture through tank water for 7, 15 and 30 days. Biochemical studies as well as light microscopy (LM) and scanning electron microscopy (SEM) revealed significant metal exposure-induced alterations in gills. Besides ultastructural changes, activities of antioxidant enzymes such catalase (CAT), glutathione S-transferase (GST) and superoxide dismutase (SOD) were significantly altered in the gills of exposed fish. The reduced glutathione (GSH) was significantly (p <0.001) decreased, while lipid peroxidation (LPO) was significantly (p <0.001) increased. The main alterations in general morphology of fish gills included spiking and fusion of secondary lamellae, formation of club-shaped filaments, and vacuolization and necrosis of filament epithelium in the interlamellar regions. SEM studies showed gradual increase of the density and apical surface area of the chloride cells and transformation of the surface structure of the pavement cells. The results of this study indicate adaptive as well a toxic responses in fish gills exposed to mixture of trace metals. Low concentrations of trace metal appear to compromise the antioxidant defense of gills. Lesions in the gill morphology caused by the effect of low concentrations of trace metals could lead to functional alterations and interference with fundamental processes such as maintenance of osmoregulation, gas exchange and xenobiotic metabolism in the exposed fish populations. [Copyright &y& Elsevier]

Abstract: The present investigation was carried out by sampling water, sediment and fish during a fish-kill episode at Panipat (Haryana, India), and again sampling at the same site was conducted after a gap of two months. During the second sampling no fish-kill was observed and the water was relatively less turbid and clear. Antioxidant profile and lipid peroxidation (LPO) in fish tissues were studied. Analysis was also carried out on the physico-chemical characteristics of water samples along with heavy metal and pesticide analysis in water and sediment samples during and after the episode. Dissolved oxygen level was substantially low during the fish-kill episode. Heavy metals (copper and chromium) and pesticides like BHC (Benzene hexachloride), DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) were also detected during the episode in water and sediment samples. Various oxidative stress biomarkers in liver, kidney and gill tissues in the Indian freshwater fish Wallago attu (Bl. and Sch.) collected from the site were investigated. The levels of reduced glutathione and non-protein thiol were significantly (P <0.001) higher in the liver of Wallago attu collected from Panipat after the fish-kill episode. Ascorbic acid levels in all the tissues did not change significantly after the episode. The LPO in liver, kidney and gills was significantly low (P <0.01–0.001) in all tissues of fish collected after the fish-kill episode. The protein carbonyl levels were significantly low (P <0.05–0.01) in all the fish organs sampled after the fish-kill episode. The findings suggest that industrial effluent may result in the massive loss of a commercial commodity. The simultaneous measurement of the physicochemical parameters of the water samples showed a good correlation between the biomarkers responses and the environmental chemical stress conditions. [Copyright &y& Elsevier]

Abstract: Natural antioxidants like catechin are now known to have a modulatory role on physiological functions and biotransformation reactions involved in the detoxification process, thereby affording protection from toxic metabolic actions of xenobiotics. Reactive oxygen intermediates have been demonstrated to play an etiological role in anticancer drug-induced toxicity. This study was performed to explore the modulatory and protective effect of catechin on the toxicity of an anticancer drug, tamoxifen (TAM) with special reference to protection against disruption of glutathione metabolizing and antioxidant enzymes. TAM treatment resulted in a significant increase in the lipid peroxidation (LPO), H2O2 generation and protein carbonyl (PC) contents in the liver and kidney as compared to controls while catechin+TAM-treated group showed significant decrease in LPO levels, H2O2 generation and PC contents in liver and kidney when compared with TAM-treated group. Non-enzymatic antioxidants like reduced glutathione (GSH) and low molecular antioxidants like ascorbic acid (AsA) also showed normalcy due to exogenous catechin administration. Catechin pre-treatment showed restoration in the level of cytochrome P450 (CYP) content and in the activities of glutathione metabolizing enzymes, viz., glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and other antioxidant enzymes such as, glucose-6-phosphate dehydrogenase (G6-PD), catalase (CAT) and superoxide dismutase (SOD) in both liver and kidney when compared to TAM-treated animals. The results of the study show that catechin supplementation might be helpful in abrogation of TAM toxicity during chemotherapy. Additionally, it makes it a prophylactic and preventive agent of anticancer drug-induced oxidative stress. [Copyright &y& Elsevier]

Abstract: The assessment of the ecotoxicological risks caused by pesticides to ecosystems are based on data on the toxicity and effects of pesticide preparations to non-target organisms like fish. Deltamethrin is a widely used pesticide based on pyrethroids, which is reported to be extremely toxic to fish species. Modulatory effect of copper pre-exposure (10ppb) on deltamethrin (0.75μgl−1)-induced oxidative stress was investigated in freshwater fish Channa punctata (Bloch). Non-enzymatic antioxidants were studied as biomarkers of exposure to deltamethrin and possible protection afforded by copper pre-exposure. Glutathione levels were reduced significantly (P <0.05) in liver of copper-acclimatized deltamethrin-exposed group when compared with deltamethrin-exposed groups. The total thiol levels of copper-acclimatized deltamethrin-exposed group was significantly lowered (P <0.01) in liver when compared with deltamethrin-exposed group, while non-protein thiol levels recorded a significant (P <0.01) increase in liver of copper-acclimatized deltamethrin-exposed group when compared with deltamethrin-exposed group. The lipid peroxidation levels of copper-acclimatized deltamethrin-exposed groups were significantly lowered (P <0.01) in liver when compared with deltamethrin-exposed group. Deltamethrin is known to induce toxic responses by generating reactive oxygen species and to neutralize its toxic effect various non-enzymatic antioxidants were found to be modulated thus implicating their role as biomarkers in pollution control programmes. [Copyright &y& Elsevier]

Abstract: It has been established in mammalian system including humans that direct damage to proteins or chemical modification of amino acids in proteins during oxidative stress can give rise to protein carbonyls. Protein carbonyl induction, as a biomarker of oxidative stress was used in laboratory studies to assess the toxic effects of pesticides in freshwater fish, Channa punctata (Bloch), exposed to deltamethrin, endosulfan and paraquat. Protein carbonyls were measured in gills, kidney and liver. Significant (P &#60;0.05–0.001) increase in protein carbonyls was observed in response to single 48h exposure to various pesticides in all the tissues. The time kinetics study involving deltamethrin (0.75μg/L) also showed a significant (P &#60;0.05–0.001) induction of protein carbonyls in all the organs. The induction was significant (P &#60;0.05–0.001) in all the durations of exposure (12h, 96h, 7 days, 14 days, 28 days). However, relatively pronounced induction was observed during shorter duration of exposure. The findings of the present investigation showed that deltamethrin had the maximum oxidative stress-inducing potential among the three pesticides used and gills are the most sensitive organs prone to oxidative damage. It is suggested that measurement of carbonyl groups may provide a convenient technique for detecting and quantifying oxidative modification of proteins during oxidative stress. The induction of protein carbonyl in fish was identified as a potentially useful biomarker of oxidative stress that warrants its application in the field investigations. [Copyright &y& Elsevier]

Various oxidative stress biomarkers in gill, kidney and liver tissues in the Indian freshwater fish Wallago attu (Bl. & Schn.) were investigated. Fish were collected from two sites along the river Yamuna, which differ in their extent and type of pollution load. A comparison was made between the biomarker responses and general water chemistry at the two sites. The oxidative stress biomarkers that were analyzed included superoxide dismutase (SOD), catalase (CAT), xanthine oxidase (XOD) and glutathione redox cycle enzymes viz., glutathione peroxidase (GPx), glutathione reductase (GR) and glucose 6-phosphate dehydrogenase (G6PD). Levels of reduced glutathione (GSH) and lipid peroxidation (LPO) were also evaluated. All biomarkers; SOD (P<0.001 in liver, kidney and gill), XOD (P<0.01 in kidney and P<0.001 in liver and gill), GR (P<0.01 in liver, P>0.05 in kidney and P<0.001 in gill), G6PD (P<0.001 in liver, P>0.05 in kidney and P<0.01 in gill), GSH (P<0.001 in liver, kidney and gill) and LPO (P>0.05 in liver, kidney and gill) were found to be substantially higher in the fish collected from Panipat when compared with values in tissues of fish collected from Agra site. GPx and CAT showed a varied response. GPx activity was higher (P<0.001) in gills and kidney of the fish collected at Panipat site. However, liver showed significant low values (P<0.01) when compared with Agra site values. CAT activity was found to be significantly low, in both liver (P<0.01) and kidney (P<0.001) whereas in gills non-significant (P>0.05) low values were observed. Water chemistry data at two sites indicated that Panipat site with higher biochemical oxygen demand, chemical oxygen demand, pH and low dissolved oxygen was comparatively more polluted than Agra site. Industrial activity profile of both the sites also indicates that Panipat has vigorous industrial activity coupled with intensive use of chemicals in agricultural practices in Haryana state. The findings of the present investigation provide a rational use of oxidative stress biomarkers in aquatic ecosystem pollution biomonitoring. This is also the first such attempt reported from India. [Copyright &y& Elsevier]

[Display omitted] Traumatic brain injury (TBI) triggers a bevy of changes including mitochondrial dysfunction, apoptosis, oxidative stress, neurobehavioural impairment, and neuroinflammation, among others. Dantrolene (DNT), a muscle relaxant which inhibits intracellular Ca2+ signaling from the ER, has been repurposed as a potential neuroprotective agent in various neurological diseases. However, there have been limited studies on whether it can mitigate TBI-induced deficits and restore impaired mitochondrial dynamics. This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary Acidic Protein (GFAP) and immunohistochemistry with NF-κβ to investigate neuroinflammation. H&E staining was also performed post-TBI. Our findings revealed DNT administration inhibits mitochondria-mediated apoptotis and reduces heightened oxidative stress. DNT treatment was also found to reverse neurobehavioural impairments and offer neuroprotection by preserving neuronal architechture. We also demonstrated that DNT inhibits neuronal autophagy and alleviates neuroinflammation following TBI by modulating the NF-κβ/Akt signaling pathway. Thus, our results suggest a novel application of DNT in ameliorating the multitude of deficits induced by TBI, thereby conferring neuroprotection. [ABSTRACT FROM AUTHOR]

COVID-19, the greatest public health emergency of the 21st century, has affected 215 countries and territories around the world resulting in 15,151,738 confirmed cases and 621,121 deaths. The outbreak has continued at breakneck pace despite stringent public health measures, ravaging the global economy and causing profound human casualties. Vaccination is currently the best bet for the prevention of COVID-19. Still, in its absence, there has been considerable interest in repurposing existing therapeutic agents to reduce the severity of the illness and ease the burden on the already strained healthcare systems. This review outlines the current evidence regarding proposed treatments- experimental or repurposed, for COVID-19, and gives an insight into the clinical trial landscape for drugs as well as vaccines. [ABSTRACT FROM AUTHOR]

[Display omitted] • Current status of fast, rapid and on spot diagnosis of rape drugs. • Techniques including identification of several majorly known drugs are illuminated. • Biosensing methods with their future development and possibilities are summarised in this review. Drugs are extracted from plants and synthetic chemicals for their medicinal values and healing properties, these various drugs present worldwide can be of uncountable importance with each of it having different medicinal values that may help in the treatment of numerous lethal diseases, but on the other hand Illegitimate drug-associated incidents like sexual assaults and traffic accidents are gaining recurrence proportions worldwide. As for the clinical and forensic use to spot the evidences in case of sexual assaults the detection of drugs in biological fluids can be very important. Furthermore, there is widespread drug usage at some crucial workplaces, which can cause serious safety issues. This article would shed some light on the drugs that are widely involved in sexual assaults, as well as the many conventional techniques for detecting illicit drugs that have been developed. Ultraviolet spectroscopy, mass spectrometry (MS), thin layer chromatography, Microcrystalline test, infrared spectrometry, ion mobility spectrometry (IMS), Raman spectroscopy, Xray diffraction, spot/colour test, and immunoassay are some of the more prevalent procedures. These methods are primarily employed to identify illicit drugs, but they are both costly and time-consuming. For the fast diagnosis of these drugs, various sensors such as colorimetric sensors, fluorescence sensors, and electrochemical sensors were developed for most popular rape medications, including cocaine, cannabis, methamphetamine, fentanyl, morphine, heroin, and benzodiazepine (diazepam, oxazepam, clonazepam etc). [ABSTRACT FROM AUTHOR]

Memories are acquired and stored in two forms, short-term memory (STM) and long-term memory (LTM). For the consolidation of LTM, de novo protein synthesis is required, which are also known as plasticity related proteins. Long-term potentiation is a form of synaptic plasticity and it is considered as a cellular model of learning and memory. One of the Long-term potentiation specific plasticity related proteins, PKM-ζ, is required for the formation of LTM as well as for the maintenance of Long-term potentiation. In our study, we have shown that for the consolidation of LTM, in addition to Long-term potentiation -specific plasticity related proteins, synaptic tags are required to interact with each other. In the present study, we investigated the involvement of Long-term potentiation -specific PKM-ζ and learning tags within a critical time window, which are required for the formation of LTM without affecting STM. Behavioral tagging is an established model for the assessment of some forms of learning and memory. Despite being studied for LTM formation for many years, no studies so far have investigated the role of PKM-ζ in Behavioral tagging model. Hence, by using these two different memories based tasks (i.e., Inhibitory avoidance and Novel object recognition tasks), we observed how PKM-ζ activated by exposing a novel arena after a weak training and led to the consolidation of memory. These findings thus show how the process of behavioral tagging activates Long-term potentiation -specific PKM-ζ for the formation of LTM. • For the establishment of LTM protein synthesis is required. • PRP's are captured in the activated learning tags set during the learning session. • PKM-ζ plays an important role as a LTP-specific PRP in behavior tagging. • Up-regulation of PKM-ζ mRNA leads to the consolidation of long term memory. • Expression of PKM-ζ in contributes to formation of novel object recognition memory. [ABSTRACT FROM AUTHOR]

Spontaneous preterm birth (sPTB) is a global health concern and it is the most prevalent cause of infant mortality and morbidity with occurrence rate of 5 – 18% worldwide. Studies suggest infection and infection-driven activation of inflammatory responses are the potential risk factors for sPTB. MicroRNAs (miRNAs) are thought to control the expression of several immune genes, making them crucial components of the intricate immune regulatory network and the dysregulation of miRNAs in placenta has been associated to several pregnancy-related complications. However, studies on possible role of miRNAs in immunomodulation of cytokine signalling in infection-associated sPTB are scarce. Present study aimed to investigate expression/ correlation of a few circulating miRNAs (miR-223, −150-5p, −185-5p, −191-5p), miRNA target genes and associated cytokines in sPTB women found infected with Chlamydia trachomatis / Mycoplasma hominis / Ureaplasma urealyticum. Non-heparinized blood and placental sample were collected from 140 sPTB and 140 term women visiting Safdarjung hospital, New Delhi (India) for conducting PCR and RT-PCR for pathogen detection and miRNA/ target gene/ cytokine expression, respectively. Common target genes of differentially expressed miRNAs were obtained from databases. The correlation between select target genes/ cytokines and serum miRNAs was determined by Spearman's rank correlation. 43 sPTB were infected with either pathogen and a significant upregulation of serum miRNAs was observed. However, miR-223 and 150–5p showed maximum fold-change (4.78 and 5.58, respectively) in PTB versus control group. IL-6ST, TGF-β R3 and MMP-14 were important target genes among 454 common targets, whereas, IL-6 and TGF-β were associated cytokines. miR-223 and 150–5p showed significant negative correlation with IL-6ST/ IL-6/ MMP-14 and positive correlation with TGF-β R3/ TGF-β. A significant positive correlation was found between IL-6ST and IL-6, TGF-β R3 and TGF-β. However, miR-185–5p and 191–5p were not significantly correlated. Although post-transcriptional validation is required, yet on the basis of mRNA findings, the study concludes that miR-223 and 150–5p are apparently of clinical importance in regulation of inflammatory processes during infection-associated sPTB. • Significant upregulation of miRs with highest fold-change in miR-223 and miR-150–5p. • Significant upregulation of miRs target genes and associated cytokines. • miR-223 and miR-150–5p were negatively correlated with IL-6ST, IL-6 and MMP-14. • miR-223 and miR-150–5p were positively correlated with TGF-βR3 and TGF-β. • miR-223 and miR-150–5p play immunomodulatory function during pre-mature labour. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Role of astaxanthin on hippocampal insulin resistance in rat model of Alzheimer's disease. • Aβ (1–42) peptides enhanced Insulin receptor Substrate-1 S307 phosphorylation. • Astaxanthin reduced Insulin receptor Substrate-1 S307 phosphorylation. • Astaxanthin ameliorated GSK-3β phosphorylation and Aβ (1–42) level. • Astaxanthin showed neuroprotective and anti-amyloidogenic effects in neurohistology. Abstract With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer's disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-β (1–42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Aβ (1–42) peptides infused Wistar rats. ASX also significantly attenuated soluble Aβ (1–42) level, IRS-S307 activity, GSK-3β activity, TNF-α level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer's disease complications, supporting potential role of hippocampal insulin resistance targeting against AD. [ABSTRACT FROM AUTHOR]

Globally, Ischemic stroke (IS) has become the second leading cause of mortality and chronic disability. The process of IS has triggered by the blockages of blood vessels to form clots in the brain which initiates multiple interactions with the key signaling pathways, counting excitotoxicity, acidosis, ionic imbalance, inflammation, oxidative stress, and neuronal dysfunction of cells, and ultimately cells going under apoptosis. Currently, FDA has approved only tissue plasminogen activator therapy, which is effective against IS with few limitations. However, the mechanism of excitotoxicity and acidosis has spurred the investigation of a potential candidate for IS therapy. Acid-sensing ion channels (ASICs) and Voltage-gated Ca2+ channels (VDCCs) get activated and disturb the brain's normal physiology. Animal toxins are novel inhibitors of ASICs and VDCCs channels and have provided neuroprotective insights into the pathophysiology of IS. This review will discuss the potential directions of translational ASICs and VDCCs inhibitors research for clinical therapies. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), an acquired brain injury imparted by a mechanical trauma to the head, has significant ramifications in terms of long-term disability and cost of healthcare. TBI is characterized by an initial phase of cell death owing to direct mechanical injury, followed by a secondary phase in which neuroinflammation plays a pivotal role. Activation of inflammasome complexes triggers a cascade that leads to activation of inflammatory mediators such as caspase-1, Interleukin (IL)-18, and IL-1β, eventually causing pyroptosis. NLRP3 inflammasome, a component of the innate immune response, has been implicated in a number of neurodegenerative diseases, including TBI. Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation and improve cognition and motor function in TBI. The NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. Although several therapeutic agents have shown promising results in pre-clinical studies, none of them have been effective in human trials for TBI, to date. Thus, it is imperative that such promising therapeutic candidates are evaluated in clinical trials to assess their efficacy in alleviating neurological impairments in TBI. This review offers an insight into the pathophysiology of TBI, with an emphasis on neuroinflammation in the aftermath of TBI. We highlight the NLRP3 inflammasome and explore its role in the neuroinflammatory cascade in TBI. We also shed light on its potential as a prospective biomarker and therapeutic target for TBI management. [Display omitted] • Traumatic brain injury (TBI) is an acquired brain injury induced by an external trauma to the head. • Despite causing high mortality rates and significant healthcare costs, there exists no effective therapy for TBI. • NLRP3 inflammasome triggers the activation of several inflammatory mediators like caspase-1, IL-18, and IL-1β. • Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation in the wake of TBI. • NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. [ABSTRACT FROM AUTHOR]

As the primary bioactive compound of glycyrrhiza rhizome, the triterpene glycoside conjugate Glycyrrhizic acid (GA) has demonstrated neuroprotective effects in vivo. This study evaluates the effectiveness of GA as an inhibitor of GuHCl-induced amyloid aggregation of hen egg white lysozyme (HEWL). Fibril formation as measured by Thioflavin-T fluorescence, 900 light scattering, and 8-Anilinonaphthalene-1-sulfonic acid (ANS) fluorescence illustrated ∼90 % prevention of fibrils at [GA]/[HEWL] ≥2:1. Images of Transmission electron microscopy evidence for the absence of any fibril or amorphous aggregation products. The spectral characteristics of soluble HEWL were in close resemblance to unfolded monomer. Computational and fluorescence investigations performed to analyse GA-HEWL interactions demonstrated slightly higher affinity of GA to unfolded HEWL and aggregation-prone regions. The likely mechanism of monomer level aggregation prevention by GA as dermined by computational, stability, and ANS experiments illustrated that GA modulated the compactness, solvent-accessible surface, and solvent-exposed hydrophobic surfaces of aggregation-prone state of HEWL. Our findings corroborate GA as an effective inhibitor of HEWL amyloid formation. To our knowledge, GA interaction-induced inhibition of aggregation-prone states has not been previously discussed. GA's modulation of aggregation-prone states of disease-related proteins will successfully develop GA as an amyloid inhibitor for clinical trials of amyloidosis and neurodegenerative illnesses. • Glycyrrhizic acid (GA) is a molecule found inmglycyrrhiza rhizome (Mulethi) and shows neuroprotective activity. • GA binds to the monomeric aggregation precursor state of lysozyme and completely prevents its fibrillation. • GA prevents aggregation by masking the aggregation-prone surfaces. • GA may be developed into a new drug for treatment of lysozyme amyloidosis. [ABSTRACT FROM AUTHOR]

Agents capable of providing protection, mitigation or therapy against radiation injuries have long been of interest of radiation biologists owing to the ever expanding application of radiation in our day to day life despite the well reported ill effects of exposure. The current study investigates radiomitigating potential of EGCG (epigallocatechin gallate), a tea polyphenol with known DNMT inhibitory property, in C57 Bl/6 mice model. Treatment with 0.1833 mg/kg body weight EGCG, 1.5 h post-irradiation to lethally whole body irradiated mice rendered 45% survival for 30 days and also helped restoring the body weight of the animals. An early recovery of various hematological parameters was observed in EGCG treated animals compared to radiation alone group. Significant recovery in the number of bone marrow colony forming cells was observed in EGCG treated irradiated animals. EGCG reduced cytogenetic damage to bone marrow cells in radiation exposed mice significantly as studied by micronucleus assay without any significant affect on cell cycle distribution of the bone marrow cells. ELISA assay with bone marrow cell lysates showed EGCG as an inhibitor of HDAC activity and DNase accessibility assay showed EGCG treatment increased the accessibility of chromatin to the enzyme. The results suggest EGCG provides mitigation against radiation injury to the hemopoietic system of mice and also inhibits HDAC enzyme activity. However, further studies are required to understand its mechanism of action. [ABSTRACT FROM AUTHOR]

Nonylphenol (NP), an environmental endocrine disruptor mimics estrogen and is a potential toxicant both under in vitro and in vivo conditions. In this study, the effect of melatonin on NP- induced neurotoxicity and cognitive alteration was investigated in adult male Wistar rats. Melatonin supplementation has been known to protect cells from neurotoxic injury. The animals were divided into three groups namely, control (vehicle) which received olive oil orally and treated rats received NP (25 mg/kg, per os ) thrice a week for 45 days while the third group i.e., NP + melatonin, animals were co-administered melatonin (10 mg/kg, i.p. ) along with NP. On the 46th day, rats were assessed for anxiety, motor co-ordination, grip strength and cognitive performance using Morris water maze test and then sacrificed for biochemical and histopathological assays in brain tissues. Melatonin improved the behavioral performance in NP exposed group. The results showed that NP significantly decreased the activity of acetylcholine esterase (AchE), monoamine oxidase (MAO) and Na + /K + -ATPase, in rat brain tissue along with other enzymes of antioxidant milieu. The outcome of the study shows that NP, like other persistent endocrine disrupting pollutants, creates a potential risk of cognitive, neurochemical and histopathological perturbations as a result of environmental exposure. Taken together, our study demonstrates that melatonin is protective against NP-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

There is increasing recognition of the magnitude of mitochondria in neurodegenerative disorders. Mitochondria play a key role in apoptotic and necrotic cell death. Melatonin (Mel), an indoleamine produced in several organs including the pineal gland has been known for its neuroprotective actions. In our study, we have investigated whether the mitochondrial ATP sensitive potassium (mtK ATP ) channel blocker 5-hydroxydecanoate (5-HD) and calcium (Ca 2 + ) affects permeability transition pore (PTP) alterations in isolated brain mitochondria treated with melatonin (Mel) and cyclosporin A (CsA). Mitochondrial swelling, mitochondrial membrane potential (Δψ m ), ROS measurement and mitochondrial respiration were evaluated in isolated brain mitochondria. In our results, mitochondrial swelling stimulated by exposing Ca 2 + ions and 5-HD associated by mPTP opening as depicted by modulation of CsA and Mel. In addition, Ca 2 + and 5-HD decreased Δψ m , depleted intracellular ROS, and inhibition of mitochondrial respiration (state 3 and state 4) in isolated brain mitochondria. Addition of Mel and CsA has shown significant restoration in mitochondrial swelling, Δψ m , intracellular ROS measurement and mitochondrial respiration in isolated brain mitochondria. Therefore, we speculate the modulatory effect of Mel and CsA in mitochondria treated with 5-HD and Ca 2 + hinders the mPTP-mediated mitochondrial dysfunction and cellular oxidative stress. We conclude that inhibition of mPT is one likely mechanism of CsA's and its neuroprotective actions. Development of neuroprotective agents including Mel targeting the mPTP therefore bears hope for future treatment of severe neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Neurotoxicity is a burdensome consequence of platinum-based chemotherapy that neutralizes the administration of effective dosage and often prompts treatment withdrawal. Oxaliplatin (Oxa), a third-era platinum analogue that is active against both early-organize and progressed colorectal growth, produces critical neurotoxicity. It has been reported that the Melatonin (Mel) is a pineal hormone its metabolites display important antioxidant properties in nervous system. There is dearth of literature involving the role of mitochondria and cytosolic compartments mediated Oxa-induced neurotoxicity and its underlying mechanisms are still debatable. Rats were pre-treated with Mel (10 mg/kg b.wt., i.p. ) and treated with Oxa (4 mg/kg b.wt. i.p. ) for 5 consecutive days. For neurobehavioral performances, decreased locomotor activity and muscular strength were observed in rats. Treatment with Mel in Oxa treated rats could protect the Oxa induced alterations in motor activity and muscular strength. For painful neuropathy, thermal hyperalgesia/nociceptive tests were evaluated. In addition, pre-treatment of Mel could block or alter the inactivation of Bcl-2, caspase 3 apoptotic protein and alterations Cytochrome c (Cyt c) release in an Oxa rich environment. Pre-treatment of Mel have shown an alteration in hyperalgesia behaviour in Oxa treated rats. Oxidative stress biomarkers, levels of non-enzymatic antioxidants and mitochondrial complexes were evaluated against neurotoxicity induced by Oxa. Mel pre-treatment replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. Mel also modulated altered non-enzymatic, enzymatic antioxidants and complex enzymes of mitochondria. Futures studies are also required to identify other molecular markers involved in neurotoxicity induced by Oxa and possible action of Mel in its modulation. [ABSTRACT FROM AUTHOR]

New information acquired by our brain is stored in the form of two types of memories: short term memory (STM) and long term memory (LTM). Initially, Synaptic and Capture hypothesis has been proposed to describe the synaptic changes that occur during memory formation. However, recently Behavioral Tagging hypothesis was proposed that relies on the setting of a learning tag and the synthesis of plasticity related proteins (PRPs). Behavioral Tagging has its roots in Synaptic and Capture hypothesis. It seeks to explain that how a learning tag produced as a result of weak training can be paired up with PRPs (formed as a result of novelty) and can lead to long lasting memories. We have focused on describing behavioral paradigms that have been used for establishing the model of “Behavioral Tagging” and the molecules which qualify for potential PRP candidature. [ABSTRACT FROM AUTHOR]

Background and Aims Oxaliplatin is a widely employed platinum-derived chemotherapeutic agent commonly used for the treatment of colorectal cancer. Unfortunately, the benefit of this important drug is compromised by severe side effects such as neuropathy, ototoxicity, gastrointestinal toxicity, and hematological toxicity. Recently, few studies have also suggested the occurrence of hepatotoxicity in oxaliplatin-treated patients. Mitochondria have emerged as targets for anticancer drugs in various kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. Oxidative stress is a well-established biomarker of mitochondrial toxicity. The purpose of this study was to investigate the dose-dependent damage caused by oxaliplatin on isolated liver mitochondria under in vitro conditions. Methods The study was conducted in mitochondria isolated from liver of Wistar rats. Oxaliplatin was incubated with mitochondria in a dose-dependent manner under in vitro conditions. Oxidative stress indexes, non-enzymatic and enzymatic antioxidants were evaluated, looking at the overall armamentarium against the toxicity induced by oxaliplatin. Results Oxaliplatin caused a significant rise in the mitochondrial oxidative stress indexes lipid peroxidation and protein carbonyl. Alterations in the levels of non-enzymatic antioxidants and activities of enzymatic antioxidants were also observed. Conclusion Oxidative stress plays an important role in the mitochondrial toxicity of oxaliplatin. The integrity of the hepatic tissue is compromised by the reactive oxygen species-mediated lipid peroxidation and protein carbonyl formation. [ABSTRACT FROM AUTHOR]

Ropinirole (ROP) is a dopamine agonist that can cross the blood-brain barrier (BBB), which is crucial for drugs targeting neurological conditions like Alzheimer's disease (AD). The rationale for the current research is to investigate the potential of ROP as an inhibitor of Microtubule affinity regulating kinase 4 (MARK4)-NFκβ in neurodegenerative diseases, specifically AD. The interaction between ROP and MARK4-NFκβ holds significant promise in the realm of drug discovery and therapeutic interventions for diseases like AD. Molecular docking and biophysical characterization demonstrate how ROP effectively hinders MARK4 activity, offering detailed insights into their molecular interactions. The present research also investigates the biological aspect of MARK4 shows promise in treating AD, with neuroinflammation playing a crucial role in the disease's progression. Aβ 42 and ROP were co-administered directly into the cells for the establishment of the AD model. We confirmed that ROP can inhibit the path of MARK4 activity, as evidenced by biophysical characterization, and can enhance the cell viability, lowers the expression of MARK4, decrease the rate of oxidative stress, and attenuate the expression of NFκβ, leading to reduced neuronal apoptosis in an in vitro -induced Aβ model. Overall, this research provides valuable mechanistic insights into the neuroprotective potential of ROP and its ability to target the MARK4-NFκβ pathway. The amyloid hypothesis (AH) suggests that Alzheimer's disease (AD) begins with the breakdown of amyloid precursor protein (APP) by β-secretase (BACE1), forming APP carboxyl-terminal fragments (CTFs). Subsequent processing by γ-secretase produces Aβ, leading to the formation of senile plaques in the extracellular space involving proteoglycans and apolipoproteins. Extracellular Aβ oligomers can trigger caspases via cell surface receptors, while intracellularly, Aβ may activate caspases through endoplasmic reticulum or mitochondrial stress. Immune response dysregulation can harm cells at a molecular level, releasing inflammatory markers and reactive oxygen species, culminating in cell death and plaque development in AD. The NFκβ and MARK4 pathway is highlighted as a key contributor to AD pathogenesis. [Display omitted] • Biophysical/kinetic confirming that ROP has inhibitory potential in the path of MARK4 activity. • The neuroprotective efficacy of ROP against the Aβ 42 model by enhancing cell viability • Lowering the expression of MARK4 can reduce oxidative stress and neuronal apoptosis by attenuating the NF-κB pathway. • The findings suggest that MARK4 inhibition can be a potential therapeutic approach for managing MARK4-associated diseases [ABSTRACT FROM AUTHOR]

A schematic representation of chrysin (CHR) binding induced conformational dynamics and stability moderation in human serum albumin (HSA). [Display omitted] • The ligand binding-induced conformational alterations of protein are primary in drug discovery methods. • This study aims to elucidate chrysin binding-induced conformational dynamics and stability of human serum albumin. • We report noteworthy changes in conformational dynamics of the protein on chrysin binding. • The chrysin binding increase the thermal stability of HSA and modulate the unfolding pathway. Studies on the interactions between ligands and proteins provide insights into how a possible medication alters the structures and activities of the target or carrier proteins. The natural flavonoid aglycone Chrysin (CHR) has demonstrated anti-inflammatory, antioxidant, antiapoptotic, neuroprotective, and antineoplastic effects, both in vitro and in vivo. In this work, we investigated the impact of CHR binding on the as-yet-unexplored conformation, dynamics, and unfolding mechanism of human serum albumin (HSA). We determined CHR binding to HSA domain-II with the association constant (K a) of 2.70 ± 0.21 × 105 M−1. The urea-induced sequential unfolding mechanism of HSA was used to elucidate the debatable binding location of CHR. CHR binding induced both secondary and tertiary structural alterations in the protein as studied by far-UV circular dichroism and intrinsic fluorescence spectroscopy. Red edge excitation shift (REES) indicated a decrease in conformational dynamics of the protein on the complex formation. This suggested an ordered compact and spatial arrangement of the CHR-bound molecule. The binding of CHR was found to significantly modulate the urea-induced unfolding pathway of HSA. Urea-induced unfolding pathway of HSA became a two-state process (N-U) from a three-state process (N-I-U). The interaction of CHR is found to increase the thermal stability of the protein by ∼4 °C. This study focuses on the fundamental sciences and demonstrates how prospective medication compounds can alter the dynamics and stability of protein structure. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a neurodegenerative illness linked to ageing, marked by the gradual decline of dopaminergic neurons in the midbrain. The exact aetiology of Parkinson's disease (PD) remains uncertain, with genetic predisposition and environmental variables playing significant roles in the disease's frequency. Epidemiological data indicates a possible connection between pesticide exposure and brain degeneration. Specific pesticides have been associated with important characteristics of Parkinson's disease, such as mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation, which are crucial for the advancement of the disease. Recently, many animal models have been developed for Parkinson's disease study. Although these models do not perfectly replicate the disease's pathology, they provide valuable insights that improve our understanding of the condition and the limitations of current treatment methods. Drosophila, in particular, has been useful in studying Parkinson's disease induced by toxins or genetic factors. The review thoroughly analyses many animal models utilised in Parkinson's research, with an emphasis on issues including pesticides, genetic and epigenetic changes, proteasome failure, oxidative damage, α-synuclein inoculation, and mitochondrial dysfunction. The text highlights the important impact of pesticides on the onset of Parkinson's disease (PD) and stresses the need for more research on genetic and mechanistic alterations linked to the condition. • Pesticide exposure is a common risk factor for Parkinson's disease. • Several epidemiological investigations highlight a notable correlation between PD and pesticide exposure. • Existing animal models for PD, although valuable, do not fully replicate disease symptoms, posing challenges for research. • Drosophila's genetic composition and evolutionary robustness render it essential for investigating PD. • Discovering biomarkers for assessing past environmental exposure is crucial for managing neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Highlights: [•] BLM and CP induce toxicity in lungs by compromising antioxidant defense. [•] ROS generation causes redox imbalance and inflammation in lungs. [•] EA administration reduces lung injury markers in BALF. [•] EA abrogates drug-induced oxidative stress and inflammatory response in lungs. [•] EA abrogates drug-induced histological alterations. [ABSTRACT FROM AUTHOR]

According to the facts and figures 2023stated that 6.7 million Americans over the age of 65 have Alzheimer's disease (AD). The scenario of AD has reached up to the maximum, of 4.1 million individuals, 2/3rd are female patients, and approximately 1 in 9 adults over the age of 65 have dementia with AD dementia. The fact that there are now no viable treatments for AD indicates that the underlying disease mechanisms are not fully understood. The progressive neurodegenerative disease, AD is characterized by amyloid plaques and neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau protein and senile plaques (SPs), which are brought on by the buildup of amyloid beta (Aβ). Numerous attempts have been made to produce compounds that interfere with these characteristics because of significant research efforts into the primary pathogenic hallmark of this disorder. Here, we summarize several research that highlights interesting therapy strategies and the neuroprotective effects of GLP-1, Sigma, and, AGE-RAGE receptors in pre-clinical and clinical AD models. • Protein aggregates ,abnormal cellular activities, and disturbed inflammatory mechanisms are the major causes of AD progression. • Receptors are the potential pathogenic targets that are primarily focused by research groups nowadays to treat AD. • Inflammatory stimulus increases the secretion of GLP-1 and modulates the phenomenon of various sites of inflammation. • Neuroprotection and anti-inflammation, have been put out to account for the anti-AD actions of sigma-2 ligands. • Advanced glycation end products (AGEs) and related receptor RAGE expression is markedly high in AD patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Aβ) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Aβ (1−42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Aβ (1−42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Aβ (1−42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD. • DPP-4 inhibitors increases GLP-1 level, ameliorates T2DM. • GLP-1 crosses BBB, decreases APP, Aβ peptides and increases insulin secretion. • BIR or T3DM due to serine phosphorylation of IRS-1 at 307 through over activation of JNK. • Microglial activation due to Aβ plaques releases pro-inflammatory cytokines results in BIR. [ABSTRACT FROM AUTHOR]

Immunomodulatory activity of aqueous extract of Trigonella foenum graecum L., a widely used medicinal and dietary herb, was evaluated in male Swiss albino mice. Mice were treated with three doses of extract (50, 100 and 250 mg/kg body weight per os) for 10 days. Body weight, relative organ weight, cellularity of lymphoid organs, delayed type of hypersensitivity (DTH) response, plaque-forming cell (PFC) assay, haemagglutination titre (HT), quantitative haemolysis of SRBC (QHS) assay, phagocytosis, and lymphoproliferation were studied in various groups of animals. At doses of 50 and 100 mg/kg, a significant increase (p<0.05) in relative organ weight of thymus was observed but there was no effect on kidney and spleen weights. Liver weight also increased significantly at doses of 100 and 250 mg/kg. However, no elevation in the levels of liver function test (LFT) enzymes was observed. As regards lymphoid organ cellularity, spleen recorded no significant increase at any dose, whereas cellularities of thymus and bone marrow were significantly increased. T. foenum graecum extract elicited a significant (p<0.001) increase in the DTH response at doses of 50 and 100 mg/kg, but the change at higher dose of 250 mg/kg was not statistically significant. Humoral immunity as measured by PFC showed an elevated response at a dose of 100 mg/kg, but at 50 and 250 mg/kg, no significant effect was observed. In the HT test, plant extract also showed modulatory effect at all the doses. Plant extract elicited a significant increase in phagocytic index and phagocytic capacity of macrophages. Stimulatory response of plant extract was also observed in lymphoproliferation assay but the response was weak. Overall, T. foenum graecum showed a stimulatory effect on immune functions in mice. As it is used for a variety of medicinal purposes, its immunostimulatory effect, as reported in this study, strengthens the rationale of its use in several Ayurvedic and Unani drugs. [Copyright &y& Elsevier]

[Display omitted] • DHPS and DHFR are validated drug targets for sulfadoxine (sdx) and pyrimethamine (pyr) in plasmodial species. • Sdx-Pyr (SP) combination medicine is a widely used antimalarial therapy. • The spread of SP resistance is attributed to increasing numbers of mutations in DHPS and DHFR enzymes. • Surveillance of sdx and pyr resistance mutations in P. falciparum and P. vivax is critical. The global spread of sulfadoxine (Sdx, S) and pyrimethamine (Pyr, P) resistance is attributed to increasing number of mutations in DHPS and DHFR enzymes encoded by malaria parasites. The association between drug resistance mutations and SP efficacy is complex. Here we provide an overview of the geographical spread of SP resistance mutations in Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) encoded dhps and dhfr genes. In addition, we have collated the mutation data and mapped it on to the three-dimensional structures of DHPS and DHFR which have become available. Data from genomic databases and 286 studies were collated to provide a comprehensive landscape of mutational data from 2005 to 2019. Our analyses show that the Pyr-resistant double mutations are widespread in Pf/Pv DHFR (P. falciparum ∼61% in Asia and the Middle East, and in the Indian sub-continent; in P. vivax ∼33% globally) with triple mutations prevailing in Africa (∼66%) and South America (∼33%). For Pf DHPS, triple mutations dominate South America (∼44%), Asia and the Middle East (∼34%) and the Indian sub-continent (∼27%), while single mutations are widespread in Africa (∼45%). Contrary to the status for P. falciparum , Sdx-resistant single point mutations in Pv DHPS dominate globally. Alarmingly, highly resistant quintuple and sextuple mutations are rising in Africa (Pf DHFR-DHPS) and Asia (Pf/Pv DHFR-DHPS). Structural analyses of DHFR and DHPS proteins in complexes with substrates/drugs have revealed that resistance mutations map proximal to Sdx and Pyr binding sites. Thus new studies can focus on discovery of novel inhibitors that target the non-substrate binding grooves in these two validated malaria parasite drug targets. [ABSTRACT FROM AUTHOR]

The research presented aims at developing Ropinirole hydrochloride (RHCl) nanoemulsion (NE) with nigella oil for Parkinson's disease (PD). In silico study was done to explore interactions of ropinirole and thymoquinone at receptor site (TNF-α and NFK-β). Ropinirole and Thymoquinone forms a hydrogen bond with residue Arginine 201 and residue Arginine 253 with a bond length of 1.89 Å and 2.30 Å at the NF-κβ receptor. NE was optimized using Central Composite Rotatable Design (CCRD). The globule size of chitosan coated NE, Polydispersity index (PDI) and zeta potential were 183.7 ± 5.2 nm, 0.263 ± 0.005, and 24.9 mV respectively. NE exhibited 85.28% transmittance showing the formulation was clear and transparent. TEM showed that NE had spherical globules with no aggregation. The formulation had a stable pH value of 5.8 ± 0.18. In vitro release and permeation studies exhibited 2 folds and 3.4 folds enhancement when compared with the drug suspension. Neurobehavioral activity and biochemical parameters corroborated well with the pharmacokinetic results. Histopathological study and immunohistochemical analysis were performed to get better picture of 6-OHDA induced toxicity and reversal of PD symptoms. Thus, the NE tailored is a promising synergistic approach yielding enticing outcomes for better management of PD related symptoms. [ABSTRACT FROM AUTHOR]

Learning and memory storage are the fundamental activities of the brain. Aberrant expression of synaptic molecular markers has been linked to memory impairment in AD. Aging is one of the risk factors linked to gradual memory loss. It is estimated that approximately 13 million people worldwide will have AD by 2050. A massive amount of oxidative stress is kept under control by a complex network of antioxidants, which occasionally fails and results in neuronal oxidative stress. Increasing evidence suggests that ROS may affect many pathological aspects of AD, including Aβ accumulation, tau hyperphosphorylation, synaptic plasticity, and mitochondrial dysfunction, which may collectively result in neurodegeneration in the brain. Further investigation into the relationship between oxidative stress and AD may provide an avenue for effective preservation and pharmacological treatment of this neurodegenerative disease. In this review, we briefly summarize the cellular mechanism underlying Aβ induced synaptic dysfunction. Since oxidative stress is common in the elderly and may contribute to the pathogenesis of AD, we also shed light on the role of antioxidant and inflammatory pathways in oxidative stress adaptation, which has a potential therapeutic target in neurodegenerative diseases. • 4-HNE-derived pathological implications may lead to memory dysfunction. • FAB is employed as a pro-oxidant to induce oxidative stress to recreate AD. • ROS-upregulated BACE1 gene expression and Aβ production are highly correlated with AD incidence. • MFRTA suggested that aging is significantly influenced by ROS production and leads to mitophagy. • Dysfunctional UPS components affect synaptic plasticity and lead to the late phase of AD [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis elegans has beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases. • The interruption of cellular proteostasic machinery characterizes neurodegenerative diseases. • The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. • C. elegans has developed as a powerful tool for studying neurodegenerative disease mechanisms. • C. elegans provides a whole-animal system amendable to several molecular and biochemical techniques. [ABSTRACT FROM AUTHOR]

• Aβ (1-42) significantly increases AChE activity, induces of ER stress and apoptosis. • Aβ (1-42) treatment causes increase in oxidative stress and neuronal degeneration. • Aβ (1-42) treatment also results in activation of microglial cells. • Salubrinal attenuates Aβ (1-42) -induced ER and oxidative stress and apoptosis. • Salubrinal attenuates Aβ (1-42) -induced neurodegeneration and microglial activation. Amyloid-β (Aβ) accumulation in the brain is a pathological hallmark of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been implicated in aetiology of neurodegenerative disorders. We studied the involvement of ER stress in Aβ-induced neuronal degeneration in rat brain to correlate it with cellular and molecular modifications in Aβ-induced Alzheimer's like neuropathological process. Aβ (1-42) (5 μg) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats. Acetylcholinesterase (AChE) activity and histological alterations were observed in different brain regions. ER stress-associated proteins- glucose regulated protein-78 (GRP78), eukaryotic translation initiation factor-2α (eIF2α) and growth arrest and DNA damage-inducible protein-153 (GADD153), neuronal marker- microtubule associated protein-2 (MAP-2) and microglial protein- ionized calcium binding adaptor molecule-1 (Iba-1) were measured by western blot. Reduced glutathione (GSH), nitrite level and levels of caspase-12 and caspase-3 were also measured. ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneally, ip) was used to assess the specific role of ER stress. Aβ (1-42) -induced increase in AChE activity, GRP78 and GADD protein levels, dephosphorylation of eIF2-α and caspase-12 and caspase-3 levels and decrease in GSH and MAP-2 levels were attenuated by salubrinal. Increase in Iba-1 protein and nitrite levels after Aβ (1-42) administration were partially attenuated by salubrinal. Aβ (1-42) -induced histological alterations were correlated with findings of ER stress. Results of present study implicate ER stress as a potential molecular mechanism in Aβ-induced Alzheimer's like neuropathology which could serve as surrogate biomarker for study of AD progression and efficacy of therapeutic interventions for AD management. [ABSTRACT FROM AUTHOR]

• Mitochondrial dysfunction has been recognized as a hallmark in ischemia/reperfusion neural damage. • Ropinirole is considered as a promising neurological and functional recovery agent. • Ropinirole restores neurological function and histopathological changes after ischemic injury. • Ropinirole treatment is beneficial in preserving the mitochondrial functions. Stroke is characterized by an initial ischemia followed by a reperfusion that promotes cascade of damage referred to as primary injury. The loss of mitochondrial function after ischemia, which is characterized by oxidative stress and activation of apoptotic factors is considered to play a crucial role in the proliferation of secondary injury and subsequent brain neuronal cell death. Dopamine D2 receptor agonist, Ropinirole, has been found to promote neuroprotection in Parkinson´s disease and restless leg syndrome. The current study was designed to test its efficacy in preclinical model of stroke. Previously it has been demonstrated that Ropinirole mediates its neuroprotection via mitochondrial pathways. Assuming this, we investigated the effect of Ropinirole on mitochondrial dysfunction, we have shown the positive effect of Ropinirole administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats underwent transient middle cerebral artery occlusion and then received the Ropinirole (10 mg and 20 mg/kg b.w.) at 6 h, 12 and 18 h post occlusion. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Our findings revealed a significant improvement with Ropinirole treatment in tMCAO animals. Staining of isolated brain slices from Ropinirole-treated rats with 2, 3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. Ropinirole treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that Ropinirole has a positive effect on mitochondrial bioenergetics. Ropinirole inhibited the translocation of cytochrome c from mitochondria to cytosol reduces the downstream apoptotic processes. In conclusion, these results demonstrate that Ropinirole treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone that is linked to the pathogenesis of schizophrenia. The aim of this study was to assess the potential of melatonin in attenuating MK-801 induced schizophrenia-like behavioral and brain neurotoxicity markers. Swiss albino mice were assigned into three groups (n = 6). Animals were administered MK-801 (1 mg/kg/mL, i. p.). MK-801 treated animals were supplemented with melatonin (10 mg/kg/1 mL i. p.) 10 min prior to MK-801 injection. The relative degrees of modulation of induced behaviors by melatonin were assessed in the open field, elevated plus maze, grip strength and rota rod. The changes in neurotoxicity enzymes and neuronal activity (c-fos) were demonstrated in this study. MK-801 injection effected normal open-field behaviors, c-fos expression, motor coordination and muscular strength. Melatonin was able to reduce the histological changes in the prefrontal cortex of mice brain. Our data demonstrated that the treatment with melatonin attenuates the schizophrenic like symptoms in the mice having a protective effect on prefrontal cortex region of brain by mitigating the alteration of neurotoxicity markers. The protective effect of the treatment was shown to reduced elevation of AChE, c -fos expression and histopathological alterations. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by an adverse cellular environment and pathological alterations in distinct brain regions. The development is triggered or facilitated by a condition such as hypoxia or ischemia, or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Increasing evidence suggests that hypoxia may affect many pathological aspects of AD, including oxidative stress, mitochondrial dysfunction, ER stress, amyloidogenic processing of APP, and Aβ accumulation, which may collectively result in neurodegeneration. Further investigation into the relationship between hypoxia and AD may provide an avenue for the effective preservation and pharmacological treatment of this neurodegenerative disease. This review summarizes the effects of normoxia and hypoxia on AD pathogenesis and discusses the underlying mechanisms. Regulation of HIF-1α and the role of its key players, including P53, VEGF, and GLUT1, are also discussed. • Hypoxia is one detrimental aspect of ischemia and stroke and also leads to AD development. • Hypoxia leads to Mitophagy and ER stress, which ultimately increase the chances of AD. • HIF-1 is known to maintained oxygen homeostasis, cellular energy metabolism, and tumor expression. • HIF-1α has been elucidated the representative transcription factor of hypoxic condition. • Signalling pathways plays a vital role in the induction of endogenous anti-oxidant enzymes against oxidative stress. [ABSTRACT FROM AUTHOR]