Organoids: An Emerging Precision Medicine Model for Prostate Cancer Research.

Prostate cancer (PCa) has been known as the most prevalent cancer disease and the second leading cause of cancer mortality in men almost all over the globe. There is an urgent need for establishment of PCa models that can recapitulate the progress of genomic landscapes and molecular alterations during development and progression of this disease. Notably, several organoid models have been developed for assessing the complex interaction between PCa and its surrounding microenvironment. In recent years, PCa organoids have been emerged as powerful in vitro 3D model systems that recapitulate the molecular features (such as genomic/epigenomic changes and tumor microenvironment) of PCa metastatic tumors. In addition, application of organoid technology in mechanistic studies (i.e., for understanding cellular/subcellular and molecular alterations) and translational medicine has been recognized as a promising approach for facilitating the development of potential biomarkers and novel therapeutic strategies. In this review, we summarize the application of PCa organoids in the high-throughput screening and establishment of relevant xenografts for developing novel therapeutics for metastatic, castration resistant, and neuroendocrine PCa. These organoid-based studies are expected to expand our knowledge from basic research to clinical applications for PCa diseases. Furthermore, we also highlight the optimization of PCa cultures and establishment of promising 3D organoid models for in vitro and in vivo investigations, ultimately facilitating mechanistic studies and development of novel clinical diagnosis/prognosis and therapies for PCa.

Astaxanthin: A Marine Drug That Ameliorates Cerebrovascular-Damage-Associated Alzheimer's Disease in a Zebrafish Model via the Inhibition of Matrix Metalloprotease-13.

Alzheimer's disease (AD) is a major type of dementia disorder. Common cognitive changes occur as a result of cerebrovascular damage (CVD) via the disruption of matrix metalloproteinase-13 (MMP-13). In diabetic cases, the progress of vascular dementia is faster and the AD rate is higher. Patients with type 2 diabetes are known to have a higher risk of the factor for AD progression. Hence, this study is designed to investigate the role of astaxanthin (AST) in CVD-associated AD in zebrafish via the inhibition of MMP-13 activity. CVD was developed through the intraperitoneal and intracerebral injection of streptozotocin (STZ). The AST (10 and 20 mg/L), donepezil (1 mg/L), and MMP-13 inhibitor (i.e., CL-82198; 10 µM) were exposed for 21 consecutive days in CVD animals. The cognitive changes in zebrafish were evaluated through light and dark chamber tests, a color recognition test, and a T-maze test. The biomarkers of AD pathology were assessed via the estimation of the cerebral extravasation of Evans blue, tissue nitrite, amyloid beta-peptide aggregation, MMP-13 activity, and acetylcholinesterase activity. The results revealed that exposure to AST leads to ameliorative behavioral and biochemical changes. Hence, AST can be used for the management of AD due to its multi-targeted actions, including MMP-13 inhibition.

Promising Strategy of mPTP Modulation in Cancer Therapy: An Emerging Progress and Future Insight.

Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspecific channel with a well-defined diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspecific pore is recognized as the mitochondrial permeability transition pore (mPTP). mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment.

Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer.

Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.

Cellular and molecular mechanism in neurodegeneration: Possible role of neuroprotectants.

In recent years, neurodegeneration has been recognized as a clinical condition that is characterized by neuronal death, dementia, and gradual diminish of cognitive function, poor body coordination and motor disorders. Several studies deciphering cellular and molecular mechanisms show a promising insight for several kinds of damages including neurodegeneration in central nervous system. In addition, there has been an inflammatory key mechanism involved in neurodegenerative disorders. There is a paucity of literature in both cellular- and molecular-mediated targets in damaged neurons at both in vitro and in vivo research models. It has been notified that CNS has a very restricted magnitude of regeneration. Numerous key factors have also been studied and considered as possible culprit of neurodegeneration. Autophagy is a well-known degradation process wherein vesicular machinery as autophagosome transports cytoplasmic contents to the lysosomes. In earlier reports, a bridging connection between autophagy and its associated mechanism has been established. Natural compounds as a neuro-therapeutics have been recognized in neurodegeneration. In our review, we discuss the mechanisms for the onset and progression in neurodegeneration, via inflammation and autophagic machine available in cellular compartments in CNS. This review also discusses about the neuroprotective efficacy of natural compounds against neurodegeneration episodes displays in neuronal platform.

MicroRNA-183-5p: A New Potential Marker for Prostate Cancer.

The microRNA (miR)-183-5p is expressed at high level in the majority of cancer. The purpose of present study was to investigate the role of oncogenic miR-183-5p in prostate cancer (PCa) as biomarker. We carried out our experiment in 50 prostate cancer patients and 40 patients of benign prostatic hyperplasia (BPH) and 40 adjacent controls tissue. The expression of miR-183-5p was evaluated through reverse transcription qualitative polymerase chain reaction. We found that the expression of miR-183-5p in PCa tissue was significantly up regulated as compared to BPH patients and adjacent normal tissues as control. Additionally, miR-183 expression was correlated with higher prostate-specific antigen, higher Gleason Score and metastatic condition. A receiver operating characteristic curve analysis revealed that miR-183-5p distinguished PCa patients from BPH patients and also from control. In conclusion, our data suggest that oncogenic miR-183-5p may be useful as a new tissue specific diagnostic biomarker in prostate cancer.

Ellagic acid mitigates arsenic-trioxide-induced mitochondrial dysfunction and cytotoxicity in SH-SY5Y cells.

In the current study, neuroprotective significance of ellagic acid (EA, a polyohenol) was explored by primarily studying its antioxidant and antiapoptotic potential against arsenic trioxide (As2 O3 )-induced toxicity in SH-SY5Y human neuroblastoma cell lines. The mitigatory effects of EA with particular reference to cell viability and cytotoxicity, the generation of reactive oxygen species, DNA damage, and mitochondrial dynamics were studied. Pretreatment of SH-SY5Y cells with EA (10 and 20 µM) for 60 min followed by exposure to 2 µM As2 O3 protected the SH-SY5Y cells against the harmful effects of the second. Also, EA pre-treated groups expressed improved viability, repaired DNA, reduced free radical generation, and maintained altered mitochondrial membrane potential than those exposed to As2 O3 alone. EA supplementation also inhibited As2 O3 -induced cytochrome c expression that is an important hallmark for determining mitochondrial dynamics. Thus, the current investigations are more convinced for EA as a promising candidate in modulating As2 O3 -induced mitochondria-mediated neuronal toxicity under in vitro system.

Retrospective case-control study of correlation between MTHFR gene and OSCC risk in North India.

BACKGROUND: Oral squamous cell carcinoma (OSCC) occurrence appears to be the number one among all cancers in India. Folate is a methyl donor during DNA methylation, as it provides substrate for methylenetetrahydrofolate reductase (MTHFR) to convert 5,10-MTHF to 5-MTHF and subsequently metabolizes it to methionine. The purpose of this study was to identify MTHFR C677T gene polymorphism in patients with OSCC. MATERIALS AND METHODS: A total of 350 OSCC cases and 350 healthy controls participated in this study. MTHFR C677T single-nucleotide polymorphism was evaluated by PCR-RFLP. RESULTS: In the present study, MTHFR gene 677CC, CT, and TT genotype frequencies of the total OSCC cases were 74.8; 19.4 and 5.71; and 88.5, 9.42, and 2.0 % in controls. The average frequency of the MTHFR 677T allele was 15.4 % in OSCC cases compared to 6.71 % in the controls. The CT genotype occurrence prevailed more in patients than controls in contrast to TT genotype, although both the genotypes were statistically significant for OSCC. Moreover, we found that T allele was significant in cases of smoking and tobacco chewing. CONCLUSIONS: In this study, we found that the homozygous mutant T allele appeared to have significantly higher risk of OSCC especially in late stages and therefore supporting in OSCC susceptibility and its progression.

Biochemical, histopathological, and transmission electron microscopic ultrastructural changes in mice after exposure to silver nanoparticles.

Four-week-old mice, weighing about 25-35 g were divided into five groups (8 mice in each group): vehicle control, low- (0.5 g/kg), middle- (1 g/kg), high- (3 g/kg), and exceptionally high-dose (5 g/kg). After first and second weeks of intraperitoneal exposure to AgNPs, biochemical, histopathological, and electron microscopic ultrastructural changes were investigated. No significant changes were observed in SGOT and ALP levels after first week of exposure, while the level of SGPT significantly increased (p < 0.05) in 2nd week treated mice, indicating that inflammatory of liver might be induced by high-dose (3 and 5 g/kg) of AgNPs. No obvious changes were observed for UA and BUN in all groups of treated mice. However, significant (p < 0.05) decrease in CR level was noticed in all groups of treated mice only at high-dose (3 and 5 g/kg). No remarkable changes in lipid profile were observed. Light microscopic histopathological investigation shows that first week treatment had not perceptible effect on the cytoarchitecture on liver, kidney, and spleen; while, second week treatment had only sporadic mild effects on these organs. However, no ultrastructural electron microscopic changes were observed in liver, kidney, and spleen of mice treated with 0.5, 1, and 3 g/kg of AgNPs when sacrificed on first and second week; while, exceptionally high-dose (5 g/kg) of AgNPs resulted in slight nuclear chromatin condensation and irregularities in nuclear membrane. The results suggested that AgNPs could be well tolerated in mice when given intraperitoneally and no death has been found during the experiment in any groups of treated mice. Interestingly, significant (<0.05) decrease in glucose levels in all experiment group is suggestive of curious hypoglycemic role of AgNPs warranting further study to explore its possible therapeutic potential in hyperglycemic conditions as well as its mechanism of action at molecular level. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 945-956, 2016.

A study on oncogenic role of leptin and leptin receptor in oral squamous cell.

Leptin been mainly produced by adipose tissue and cancer cells is the most studied adipokine, amongst the several cytokines. Leptin is an antiapoptotic molecule and inducer of cancer stem cells as well as activates cell proliferation. Its oncogenic, mitogenic, proinflammatory and proangiogenic actions lead to its vital roles in tumourigenesis. Two common functional DNA polymorphisms in the genes of leptin G2548A (LEP) and leptin receptor A668G (LEPR) affect the amount of circulating cytokine-type hormone leptin with risk for development of oral squamous cell carcinoma (OSCC). The present study investigated whether these LEP and LEPR gene polymorphisms are affecting risk for OSCC by comparing the genotypes of patients with controls. A total of 306 OSCC and 228 controls participated in this study. We have determined the frequency of LEP (G2548A) and LEPR (A668G) gene polymorphisms in OSCC cases and controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The incidence of leptin gene G2548A homozygous mutant AA polymorphism was significantly increased in the OSCC patients (p = 0.002, odds ratio (OR) = 2.4, 95 % confidence interval (CI) = 1.37-4.22) when compared with controls, and leptin receptor A668G homozygous mutant GG polymorphism was significantly high in the OSCC patients as compared to controls (p = 0.000, OR = 3.8, 95 % CI = 1.98-7.62). The polymorphism of homozygous mutant allele A of leptin gene and G allele of leptin receptor may be associated with increased risk for OSCC. The observations showed regular increase of supporting role of leptin in OSCC. The present study showed an association of AA genotype and A allele of LEP G2548A as well as GG genotype and G allele of LEPR A668G polymorphisms with increased risk for OSCC in north Indian patients. Moreover, the combination of both the polymorphisms may be involved in susceptibility and progression of OSCC.

Cisplatin hepatotoxicity mediated by mitochondrial stress.

CONTEXT: Chemotherapy has long been the keystone of cancer regimen, and comprehensive research has been done on the development of more potent and less toxic anti-cancer agents. Cisplatin (CP) is a potent and extensively used chemotherapeutic agent. There is paucity of literature involving role of mitochondria in mediating CP-induced hepatic toxicity, and its underlying mechanism remains unclear. Oxidative stress is a well-established biomarker of the mitochondrial toxicity. OBJECTIVE: This study evaluates the dose-dependent effects of CP-induced mitotoxicity under in vitro conditions, using mitochondria from rat liver. MATERIALS AND METHODS: The aim of our study was to determine the effect of CP with different concentrations in isolated liver mitochondria as an in vitro model. RESULTS: CP exposure showed significantly compromised level of non enzymatic and enzymatic antioxidants with higher extent of lipid and protein oxidation. CP also caused significant alterations in the activity of respiratory chain enzymes (complex I-III and V) in liver mitochondria. DISCUSSION AND CONCLUSION: It is suggested that mitochondria can be employed as a model for future investigations of anticancer drug-induced hepatotoxicity under in vitro conditions. Studies with selected pharmaceuticals and nutraceuticals might certainly play a definite role in deciphering cellular and molecular mechanisms of CP-induced hepatotoxicity and its amelioration.

Combination of miR-99b-5p and Enzalutamide or Abiraterone Synergizes the Suppression of EMT-Mediated Metastasis in Prostate Cancer.

Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Androgen deprivation therapy (ADT) has been systemically applied as a first-line therapy for PCa patients. Despite the initial responses, the majority of patients under ADT eventually experienced tumor progression to castration-resistant prostate cancer (CRPC), further leading to tumor metastasis to distant organs. Therefore, identifying the key molecular mechanisms underlying PCa progression remains crucial for the development of novel therapies for metastatic PCa. Previously, we identified that tumor-suppressive miR-99b-5p is frequently downregulated in aggressive African American (AA) PCa and European American (EA) CRPC, leading to upregulation of mTOR, androgen receptor (AR), and HIF-1α signaling. Given the fact that mTOR and HIF-1α signaling are critical upstream pathways that trigger the activation of epithelial-mesenchymal transition (EMT), we hypothesized that miR-99b-5p may play a critical functional role in regulating EMT-mediated PCa metastasis. To test this hypothesis, a series of cell biology, biochemical, and in vitro functional assays (wound healing, transwell migration, cell/ECM adhesion, and capillary-like tube formation assays) were performed to examine the effects of miR-99b-5p mimic on regulating EMT-mediated PCa metastasis processes. Our results have demonstrated that miR-99b-5p simultaneously targets MTOR and AR signaling, leading to upregulation of E-cadherin, downregulation of Snail/N-cadherin/Vimentin, and suppression of EMT-mediated PCa metastasis. MiR-99b-5p alone and in combination with enzalutamide or abiraterone significantly inhibits the EMT-mediated metastasis of AA PCa and EA CRPC.

Mitochondria-mediated mitigatory role of curcumin in cisplatin-induced nephrotoxicity.

Cisplatin (CP) is one of the most potent chemotherapeutic anti-tumour drugs, and it has been implicated in renal toxicity. Oxidative stress has been proven to be involved in CP-induced toxicity including nephrotoxicity. However, there is paucity of literature involving role of mitochondria in mediating CP-induced renal toxicity, and its underlying mechanism remains unclear. Therefore, the present study was undertaken to examine the antioxidant potential of curcumin (CMN; a natural polyphenolic compound) against the mitochondrial toxicity of CP in kidneys of male rats. Acute toxicity was induced by a single intra-peritoneal injection of CP (6 mg kg(-1) ). We studied the ameliorative effect of CMN pre-treatment (200 mg kg(-1) ) on the toxicity of CP in rat kidney mitochondria. CP caused a significant elevation in the mitochondrial lipid peroxidation (LPO) levels and protein carbonyl (PC) content. Pre-treatment of rat with CMN significantly replenished the mitochondrial LPO levels and PC content. It also restored the CP-induced modulatory effects on altered enzymatic and non-enzymatic antioxidants in kidney mitochondria. We hypothesize that the reno-protective effects of CMN may be related to its predisposition to scavenge free radicals, and upregulate antioxidant machinery in kidney mitochondria.

Identification of potential phytochemicals and their inhibitory effect on the PERK receptor mediated UPR pathway for neuronal disease regulation: an in silico insight.

The endoplasmic reticulum (ER) has been considered as the key site of protein biosynthesis and maturation in the eukaryotic cell. In recent years, the sequence at the N-terminal region of translated protein has shown a particular emphasis as a signal responsible for site-specific translocation mediated by post-translational modification. Once the native conformation is not achieved, the degradation pathway is activated, and therefore the restoration of the homeostasis of ER function in UPR pathway is initiated. One of the transmembrane proteins, PKR-like ER kinase (PERK) plays a key role in the activation of UPR through the inhibition of the translation process, thus preventing the cells from apoptosis due to chronic ER stress. Dysregulation of the neuronal proteostasis often results in neuronal dysfunction and its crucially associated neurodegenerative diseases or its manifestation of neuropathic pain. The correlation between ER stress and its associated signaling cascade, namely UPR, is well established in context of neuropathological modifications. This furthermore suggests that the proteins of the signaling cascade such as PERK can serve as a potential target during the onset of neuronal damage. The aim of this study was to identify the potential phytocompounds by evaluating the physicochemical properties, Lipinski screening, ADMET and toxicity properties of the selected phytocompounds by using SwissADME, MolInspiration and pKCSM webservers, which could establish a comparatively better affinity and binding energy than the control drug as GSK2606414 in set up the treatment of the neuronal diseases through molecular docking via PyRx and validating their structural stability through simulation using the Sybyl software for over100ns.Communicated by Ramaswamy H. Sarma.

Tumor suppressive miR-99b-5p as an epigenomic regulator mediating mTOR/AR/SMARCD1 signaling axis in aggressive prostate cancer.

Introduction: African American (AA) men exhibited 2.3-fold higher PCa incidence and 1.7-fold higher PCa mortality rates when compared to the European American (EA) men. Besides the socioeconomic factors, emerging evidence has highlighted that biological risk factors may play critical roles in the AA PCa disparities. Previously, we have shown that downregulated miR-99b-5p and upregulated mTOR cooperatively promotes the AA PCa aggressiveness and drug resistance. Methods: In this study, we aimed to explore the miR-99b-5p/mTOR/AR/SMARCD1 signaling axis in AA PCa aggressiveness. The analyses used in the study included immunofluorescence, western blot, in-vitro functional assays (TUNEL, colony forming, and MTT), and chromatin immunoprecipitation (ChIP)-qPCR assays in 2D and/or 3D culture model of EA PCa and AA PCa cell lines. Results: Specifically, the immunofluorescence staining, and western blot analysis has revealed that nuclear mTOR, AR, and SMARCD1 were highly expressed in AA PCa (MDA PCa 2b) compared to EA PCa (LNCaP) cell line. Western blot analysis further revealed that miR-99b-5p inhibited protein levels of mTOR, AR/AR-V7 and SMARCD1 in cytoplasm and nuclei of EA and AA PCa. The in-vitro functional (MTT, TUNEL, and clonogenic) assays have demonstrated that miR-99b-5p effectively inhibited cell proliferation/survival and induced cell apoptosis in EA and AA PCa cells. Moreover, combination of miR-99b-5p and enzalutamide (Enz) synergistically enhances the cytotoxicity against aggressive AA PCa and castration-resistant prostate cancer (CRPC). mTOR ChIP-qPCR assays further demonstrated that miR-99b-5p or miR-99b-5p/Enz significantly reduces the recruitment of mTOR to the genes involved in the metabolic reprogramming in CRPC. Discussion: Taken together, miR-99b-5p may function as an epigenomic driver to modulate the mTOR/AR/SMARCD1 signaling axis in AA PCa and resistant CRPC.

A Recent Update on Pathophysiology and Therapeutic Interventions of Alzheimer's Disease.

AIM: Alzheimer's disease (AD) has been identified as a progressive brain disorder associated with memory dysfunction and the accumulation of ß-amyloid plaques and neurofibrillary tangles of τ protein. Mitochondria is crucial in maintaining cell survival, cell death, calcium regulation, and ATP synthesis. Mitochondrial dysfunction and linked calcium overload have been involved in the pathogenesis of AD. CRM2 (Collapsin response mediator protein-2) is involved in endosomal lysosomal trafficking as well as autophagy, and their reduced level is also a primary culprit in the progression of AD. In addition, Cholinergic neurotransmission and neuroinflammation are two other mechanisms implicated in AD onset and might be protective targets to attenuate disease progression. The microbiota-gut-brain axis (MGBA) is another crucial target for AD treatment. Crosstalk between gut microbiota and brain mutually benefitted each other, dysbiosis in gut microbiota affects the brain functions and leads to AD progression with increased AD-causing biomarkers. Despite the complexity of AD, treatment is only limited to symptomatic management. Therefore, there is an urgent demand for novel therapeutics that target associated pathways responsible for AD pathology. This review explores the role of different mechanisms involved in AD and possible therapeutic targets to protect against disease progression. BACKGROUND: Amidst various age-related diseases, AD is the most deleterious neurodegenerative disorder that affects more than 24 million people globally. Every year, approximately 7.7 million new cases of dementia have been reported. However, to date, no novel disease-modifying therapies are available to treat AD. OBJECTIVE: The aim of writing this review is to highlight the role of key biomarker proteins and possible therapeutic interventions that could play a crucial role in mitigating the ongoing prognosis of Alzheimer's disease. MATERIALS AND METHODS: The available information about the disease was collected through multiple search engines, including PubMed, Science Direct, Clinical Trials, and Google Scholar. RESULTS: Accumulated pieces of evidence reveal that extracellular aggregation of ß-amyloid plaques and intracellular tangles of τ protein are peculiar features of perpetuated Alzheimer's disease (AD). Further, the significant role of mitochondria, calcium, and cholinergic pathways in the pathogenesis of AD makes the respiratory cell organelle a crucial therapeutic target in this neurodegenerative disease. All currently available drugs either delay the clinical damage to cells or temporarily attenuate some symptoms of Alzheimer's disease. CONCLUSION: The pathological features of AD are extracellular deposition of ß-amyloid, acetylcholinesterase deregulation, and intracellular tangles of τ protein. The multifactorial heterogeneity of disease demands more research work in this field to find new therapeutic biological targets.

PM2.5-Induced Cardiac Structural Modifications and Declined Pro-Survival Signalling Pathways Are Responsible for the Inefficiency of GSK-3ß Inhibitor in Attenuating Myocardial Ischemia-Reperfusion Injury in Rats.

Circulatory GSK3ß is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3ß inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3ß signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3ß may not be a reliable therapeutic target for IR in the presence of chronic PM2.5 exposure.

Role of melatonin and quercetin as countermeasures to the mitochondrial dysfunction induced by titanium dioxide nanoparticles.

AIM: Due to the growing commercialization of titanium dioxide nanoparticles (TNPs), it is necessary to use these particles in a manner that is safe, healthy and environmental friendly. Through reactive oxygen species (ROS) generation, it has been discovered that TNPs have a harmful effect on the brain. The aim of this study is to provide valuable insights into the possible mechanisms of TNPs induced mitochondrial dysfunction in brain and its amelioration by nutraceuticals, quercetin (QR) and melatonin (Mel) in in vitro and in vivo conditions. MATERIALS AND METHODS: Whole brain mitochondrial sample was used for in-vitro evaluation. Pre-treatment of QR (30 µM) and Mel (100 µM) at 25 °C for 1 h was given prior to TNPs (50 µg/ml) exposure. For in-vivo study, male Wistar rats were divided into four groups. Group I was control and group II was exposed to TNPs (5 mg/kg b.wt., i.v.). QR (5 mg/kg b.wt.) and Mel (5 mg/kg b.wt.) were given orally as pre-treatment in groups III and IV, respectively. Biochemical parameters, neurobehavioural paradigms, mitochondrial respiration, neuronal architecture assessment were assessed. KEY FINDINGS: QR and Mel restored the mitochondrial oxidative stress biomarkers in both the studies. Additionally, these nutraceuticals resuscitated the neurobehavioural alterations and restored the neuronal architecture alterations in TNPs exposed rats. The mitochondrial dysfunction induced by TNPs was also ameliorated by QR and Mel by protecting the mitochondrial complex activity and mitochondrial respiration rate. SIGNIFICANCE: Results of the study demonstrated that QR and Mel ameliorated mitochondrial mediated neurotoxic effects induced by TNPs exposure.

An In Silico Investigation of Pharmacological Modulators and Inflammasomes in Glioblastoma Multiforme.

For the past decades, inflammatory signals have been considered a possible key for pharmacological interventions. There are several compounds and/or molecules that have been known as most promising medication against inflammation and its mediated chronic disorders. Inflammasomes could be recognized as a trigger by detrimental stimuli as pathogenic attack and endogenous signals mediated injury inside the cells. In addition, there has been an inflammatory key mechanism involved in cancers including glioblastoma multiforme (GBM). GBM has been considered the foremost aggressive primary brain tumors in adult stage. There is a scattered beam of light on both cellular and molecular links in inflammation and GBM. However, the immune response of GBM has been characterized extensively by macrophages and lymphocytes related to tumors, and some recent investigations have pinpointed the focus of inflammasomes on the progression of GBM. Nevertheless, risk factors linked with GBM are still debatable. In our study, the most considerable compounds and their bonded and/or targeted proteins have depicted the most promising highlights under in silico condition. Our in silico investigations have revealed a powerful pharmacological agents/compound against inflammasome-mediated GBM.

The multifactorial role of vanillin in amelioration of aluminium chloride and D-galactose induced Alzheimer's disease in mice.

The onset and progression of Alzheimer's disease (AD) are influenced by a variety of factors. These include oxidative stress, overexpression of acetylcholinesterase (AChE), depletion of acetylcholine levels, increased beta-secretase mediated conversion of Amyloid Precursor Protein (APP) to Amyloid Beta (Abeta), accumulation of Abeta oligomers, decrease in Brain Derived Neurotrophic factor (BDNF) and accelerated neuronal apoptosis due to elevated levels of caspase-3. The currently available therapeutic approaches are inadequate in affecting these pathological processes except maybe the overexpression of AChE (AChE inhibitors like donepezil, rivastigmine). There is an urgent need to develop disease modifying pharmacotherapeutic interventions which have appreciable safety and cost effectiveness. From previously reported in vitro studies and a preliminary assessment of neuroprotective effect in scopolamine induced dementia-like cognitive impairment in mice, vanillin has been used as the compound of interest in the present study. Vanillin, a phytoconstituent, has been used in humans, safely, in the form of a flavouring agent for various foods, beverages, and cosmetics. Owing to its chemical nature i.e. being a phenolic aldehyde, it has an additional antioxidant property that is congruent to the desirable characteristics that are sought in a suitable novel anti-AD agent. In our study, vanillin proved to have a nootropic effect in healthy Swiss albino mice as well as an ameliorative effect in aluminium chloride and D-galactose induced AD model in mice. Apart from tackling oxidative stress, vanillin was found to reduce the levels of AChE, beta secretase, caspase-3, enhance degradation of Abeta plaques and elevate the levels of BDNF, in cortical and hippocampal regions. Vanillin is a promising candidate for being incorporated into the search for safe and effective anti-AD molecules. However, further research might be needed to warrant its application clinically.