Molecular Mechanisms Underlying the Therapeutic Potential of Plant-Based α-Amylase Inhibitors for Hyperglycemic Control in Diabetes.

BACKGROUND: Diabetes mellitus (DM), arising from pancreatic ß-cell dysfunction and disrupted alpha-amylase secretion, manifests as hyperglycemia. Synthetic inhibitors of alphaamylase like acarbose manage glucose but pose adverse effects, prompting interest in plantderived alternatives rich in antioxidants and anti-inflammatory properties. OBJECTIVE: The current review investigates plant-based alpha-amylase inhibitors, exploring their potential therapeutic roles in managing DM. Focusing on their ability to modulate postprandial hyperglycemia by regulating alpha-amylase secretion, it assesses their efficacy, health benefits, and implications for diabetes treatment. METHOD: This review examines plant-derived alpha-amylase inhibitors as prospective diabetic mellitus treatments using PubMed, Google Scholar, and Scopus data. RESULTS: Plant-derived inhibitors, including A. deliciosa, B. egyptiaca, and N. nucifera, exhibit anti-inflammatory and antioxidant properties, effectively reducing alpha-amylase levels in diabetic conditions. Such alpha-amylase inhibitors showed promising alternative treatment in managing diabetes with reduced adverse effects. CONCLUSION: The current literature concludes that plant-derived alpha-amylase inhibitors present viable therapeutic avenues for diabetes management by modulating alpha-amylase secretion by regulating inflammatory, oxidative stress, and apoptotic mechanisms involved in the pathogenesis of diabetes. Further investigation into their formulations and clinical efficacy may reveal their more comprehensive diabetes therapeutic significance, emphasizing their potential impact on glucose regulation and overall health.

Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.

Parkinsons disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and alpha-synuclein aggregation. This comprehensive review examines the intricate role of post-translational modifications (PTMs) in PD pathogenesis, focusing on DNA methylation, histone modifications, phosphorylation, SUMOylation, and ubiquitination. Targeted PTM modulation, particularly in key proteins like Parkin, DJ1, and PINK1, emerges as a promising therapeutic strategy for mitigating dopaminergic degeneration in PD. Dysregulated PTMs significantly contribute to the accumulation of toxic protein aggregates and dopaminergic neuronal dysfunction observed in PD. Targeting PTMs, including epigenetic strategies, addressing aberrant phosphorylation events, and modulating SUMOylation processes, provides potential avenues for intervention. The ubiquitin-proteasome system, governed by enzymes like Parkin and Nedd4, offers potential targets for clearing misfolded proteins and developing disease-modifying interventions. Compounds like ginkgolic acid, SUMO E1 enzyme inhibitors, and natural compounds like Indole-3-carbinol illustrate the feasibility of modulating PTMs for therapeutic purposes in PD. This review underscores the therapeutic potential of PTM-targeted interventions in modulating PD-related pathways, emphasizing the need for further research in this promising area of Parkinsons disease therapeutics.

Imatinib Attenuates Pentylenetetrazole Kindled and Pilocarpine Induced Recurrent Spontaneous Seizures in Mice.

c-Abl is a non-receptor tyrosine kinase that promotes intracellular apoptotic signaling in prolonged epileptic seizures. PTZ and pilocarpine-induced continuous epileptic convulsions cause neuronal death and gliosis. C-Abl is linked to oxidative stress, neuronal hyperexcitability, mitochondrial malfunction, and subsequent seizures. We investigated the involvement of c-Abl in epileptogenesis by employing its selective inhibitor Imatinib (1 & 3 mg/kg; i.p.) together with conventional medication valproate (110 mg/kg; i.p.) tends to be effective in decreasing seizures threshold provoked by PTZ for 15 days and pilocarpine for 37 days. Further, Imatinib was effective in preventing epileptic seizures arbitrated oxidative stress injury. Oxidative stress has been linked to excitotoxicity that is considered to pathogenic factor in epileptic brain damage. As ELIZA and biochemical estimations showed the high level of c-Abl as an indicator of neuronal oxidative and apoptosis under chronic PTZ & pilocarpine epileptic seizures marked by decreased antioxidants and elevated levels of caspase-3 that were successfully prevented with Imatinib treatment same as valproate (standard drug). Further, the aberrant c-Abl activation is also linked with neuroinflammation that is also predisposing factor in the development of seizures. Selective inhibition of c-Abl by Imatinib also showed anti-inflammatory activity marked with suppressed levels of NF-kB and pro-inflammatory mediators (TNF-alpha, IL-1ß, and IL-6) suggesting the neuroprotective effect of Imatinib same as valproate (standard drug) in epilepsy. Therefore, the current study provides preclinical evidence of Imatinib as a potential treatment for seizures, as well as an understanding of potential role of c-Ablin epilepsy.

Pharmacological evaluation of Thuja occidentalis for the attenuation of neuropathy via AGEs and TNF-α inhibition in diabetic neuropathic rats.

When diabetes neuropathy occurs, the oxidative stress caused by chronic hyperglycemia may result in chronic neuronal damage. To mitigate the effects of hyperglycemia-induced neuronal damage, it may be beneficial to address oxidative stress and inflammation in the body. The current study evaluated the neuroprotective efficacy of Thuja occidentalis in streptozotocin (STZ)-nicotinamide (NAD)-induced diabetic neuropathy in male Wistar rats. A single dose of STZ (65 mg/kg, i.p.) was used to induce diabetic neuropathy in Wistar rats. Serum insulin, glucose, hyperalgesia, oxidative stress, inflammatory markers, and histopathology of the sciatic nerve were evaluated for neuropathy. Wistar rats were treated with varying doses of hydroalcoholic extracts of Thuja occidentalis (HAETO) and gabapentin for 30 days. Thuja occidentalis considerably corrected the levels of inflammatory markers and oxidative stress caused by hyperglycemia; also, it led to the restoration of neuronal functions, indicating that it is effective in treating diabetic neuropathy. Furthermore, the molecular docking of thujone at the active pockets of various inflammatory mediators (IL-1ß, IL-6, TGF-ß1, and TNF-α) has shown good interactions with critical amino acid residues. These findings indicate that the hydroalcoholic extract of Thuja occidentalis effectively inhibits the development of diabetic neuropathy. The hypoglycemic, antioxidant, anti-hyperalgesia, and anti-inflammatory properties of Thuja occidentalis are thought to be responsible for the neuroprotective benefit.

Covid-19: pharmacotherapeutic insights on various curative approaches in terms of vulnerability, comorbidities, and vaccination.

A novel coronavirus disease (COVID-19), caused by a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was discovered in Wuhan, China, in December 2019, and the world has suffered from a pandemic. As of 22nd March 2020, at least 185 countries worldwide had been affected by COVID-19. SARS-CoV-2, leading to COVID-19 pneumonia, infects cells through ACE-2 receptors. The disease has different clinical signs and symptoms, including chills, high fever, dyspnea, and cough. Other symptoms including haemoptysis, myalgia, diarrhoea, expectoration, and fatigue may also occur. The rapid rise in confirmation cases is severe in preventing and controlling COVID-19. In this review, the article will explore and evaluate the insights into how COVID influences patients with other comorbid conditions such as cardiovascular disease, diabetes, Parkinson's, and how conditions Urolithiasis, anosmia, and anuria may develop after infection. The virus mutates and the variants are now prevalent in the present scenario where the world stands in eradicating the pandemic by looking into the development of vaccines by several countries and how the vaccination can temporarily help prevent COVID spread.

Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis.

Epileptic seizure-induced brain injuries include activation of neuroimmune response with activation of microglia, astrocytes cells releasing neurotoxic inflammatory mediators underlies the pathophysiology of epilepsy. A wide spectrum of neuroinflammatory pathways is involved in neurodegeneration along with elevated levels of inflammatory mediators indicating the neuroinflammation in the epileptic brain. Therefore, the neuroimmune response is commonly observed in the epileptic brain, indicating elevated cytokine levels, providing an understanding of the neuroinflammatory mechanism contributing to seizures recurrence. Clinical and experimental-based evidence suggested the elevated levels of cytokines responsible for neuronal excitation and blood-brain barrier (BBB) dysfunctioning causing the drug resistance in epilepsy. Therefore, the understanding of the pathogenesis of neuroinflammation in epilepsy, including migration of microglial cells releasing the inflammatory cytokines indicating the correlation of elevated levels of inflammatory mediators (interleukin-1beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) triggering the generation or recurrence of seizures. The current review summarized the knowledge regarding elevated inflammatory mediators as immunomodulatory response correlating multiple neuroinflammatory NF-kB, RIPK, MAPK, ERK, JNK, JAK-STAT signaling cascades in epileptogenesis. Further selective targeting of inflammatory mediators provides beneficial therapeutic strategies for epilepsy.

Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice.

Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly (p < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1ß, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1ß, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.

Emerging perspectives on mitochondrial dysfunctioning and inflammation in epileptogenesis.

INTRODUCTION: Mitochondrial dysfunction is a common denominator of neuroinflammation recognized by neuronal oxidative stress-mediated apoptosis that is well recognized by common intracellular molecular pathway-interlinked neuroinflammation and mitochondrial oxidative stress, a feature of epileptogenesis. In addition, the neuronal damage in the epileptic brain corroborated the concept of brain injury-mediated neuroinflammation, further providing an interlink between inflammation, mitochondrial dysfunction, and oxidative stress in epilepsy. MATERIALS AND METHODS: A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to provide evidence of preclinical and clinically used drugs targeting such nuclear, cytosolic, and mitochondrial proteins suggesting that the correlation of mechanisms linked to neuroinflammation has been elucidated in the current review. Despite that, the evidence of elevated levels of inflammatory mediators and pro-apoptotic protein levels can provide the correlation of inflammatory responses often concerned with hyperexcitability attributing to the fact that mitochondrial redox mechanisms and higher susceptibilities to neuroinflammation result from repetitive recurring epileptic seizures. Therefore, providing an understanding of seizure-induced pathological changes read by activating neuroinflammatory cascades like NF-kB, RIPK, MAPK, ERK, JNK, and JAK-STAT signaling further related to mitochondrial damage promoting hyperexcitability. CONCLUSION: The current review highlights the further opportunity for establishing therapeutic interventions underlying the apparent correlation of neuroinflammation mediated mitochondrial oxidative stress might contribute to common intracellular mechanisms underlying a future prospective of drug treatment targeting mitochondrial dysfunction linked to the neuroinflammation in epilepsy.

Apoptotic Pathways and Alzheimer's Disease: Probing Therapeutic Potential.

Apoptosis is an intrinsic biochemical, cellular process that regulates cell death and is crucial for cell survival, cellular homeostasis, and maintaining the optimum functional status. Apoptosis in a predetermined and programmed manner regulates several molecular events, including cell turnover, embryonic development, and immune system functions but may be the exclusive contributor to several disorders, including neurodegenerative manifestations, when it functions in an aberrant and disorganized manner. Alzheimer's disease (AD) is a fatal, chronic neurodegenerative disorder where apoptosis has a compelling and divergent role. The well-characterized pathological features of AD, including extracellular plaques of amyloid-beta, intracellular hyperphosphorylated tangles of tau protein (NFTs), inflammation, mitochondrial dysfunction, oxidative stress, and excitotoxic cell death, also instigate an abnormal apoptotic cascade in susceptible brain regions (cerebral cortex, hippocampus). The apoptotic players in these regions affect cellular organelles (mitochondria and endoplasmic reticulum), interact with trophic factors, and several pathways, including PI3K/AKT, JNK, MAPK, mTOR signalling. This dysregulated apoptotic cascade end with an abnormal neuronal loss which is a primary event that may precede the other events of AD progression and correlates well with the degree of dementia. The present review provides insight into the diverse and versatile apoptotic mechanisms that are indispensable for neuronal survival and constitute an integral part of the pathological progression of AD. Identification of potential targets (restoring apoptotic and antiapoptotic balance, caspases, TRADD, RIPK1, FADD, TNFα, etc.) may be valuable and advantageous to decide the fate of neurons and to develop potential therapeutics for treatment of AD.

Reviving mitochondrial bioenergetics: A relevant approach in epilepsy.

Epileptogenesis is most commonly associated with neurodegeneration and a bioenergetic defect attributing to the fact that mitochondrial dysfunction plays a key precursor for neuronal death. Mitochondria are the essential organelle of neuronal cells necessary for certain neurophysiological processes like neuronal action potential activity and synaptic transmission. The mitochondrial dysfunction disrupts calcium homeostasis leading to inhibitory interneuron dysfunction and increasing the excitatory postsynaptic potential. In epilepsy, the prolonged repetitive neuronal activity increases the excessive demand for energy and acidosis in the brain further increasing the intracellular calcium causing neuronal death. Similarly, the mitochondrial damage also leads to the decline of energy by dysfunction of the electron transport chain and abnormal production of the ROS triggering the apoptotic neuronal death. Thus, the elevated level of cytosolic calcium causes the mitochondria DNA damage coinciding with mtROS and releasing the cytochrome c binding to Apaf protein further initiating the apoptosis resulting in epileptic encephalopathies. The various genetic and mRNA studies of epilepsy have explored the various pathogenic mutations of genes affecting the mitochondria functioning further initiating the neuronal excitotoxicity. Based on the results of previous studies, the recent therapeutic approaches are targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria and hold great promise to attenuate epileptogenesis. Therefore, the current review emphasizes the emerging insights to uncover the relation between mitochondrial dysfunction and ROS generation contributing to mechanisms underlying epileptic seizures.

An Insight into Molecular Mechanisms and Novel Therapeutic Approaches in Epileptogenesis.

Epilepsy is the second most common neurological disease with abnormal neural activity involving the activation of various intracellular signalling transduction mechanisms. The molecular and system biology mechanisms responsible for epileptogenesis are not well defined or understood. Neuroinflammation, neurodegeneration and Epigenetic modification elicit epileptogenesis. The excessive neuronal activities in the brain are associated with neurochemical changes underlying the deleterious consequences of excitotoxicity. The prolonged repetitive excessive neuronal activities extended to brain tissue injury by the activation of microglia regulating abnormal neuroglia remodelling and monocyte infiltration in response to brain lesions inducing axonal sprouting contributing to neurodegeneration. The alteration of various downstream transduction pathways resulted in intracellular stress responses associating endoplasmic reticulum, mitochondrial and lysosomal dysfunction, activation of nucleases, proteases mediated neuronal death. The recently novel pharmacological agents modulate various receptors like mTOR, COX-2, TRK, JAK-STAT, epigenetic modulators and neurosteroids are used for attenuation of epileptogenesis. Whereas the various molecular changes like the mutation of the cell surface, nuclear receptor and ion channels focusing on repetitive episodic seizures have been explored by preclinical and clinical studies. Despite effective pharmacotherapy for epilepsy, the inadequate understanding of precise mechanisms, drug resistance and therapeutic failure are the current fundamental problems in epilepsy. Therefore, the novel pharmacological approaches evaluated for efficacy on experimental models of epilepsy need to be identified and validated. In addition, we need to understand the downstream signalling pathways of new targets for the treatment of epilepsy. This review emphasizes on the current state of novel molecular targets as therapeutic approaches and future directions for the management of epileptogenesis. Novel pharmacological approaches and clinical exploration are essential to make new frontiers in curing epilepsy.

Medicinal plants used against various inflammatory biomarkers for the management of rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis is a chronic autoimmune disease manifested clinically by polyarthralgia associated with joint dysfunction triggering the antibodies targeting against the self-neoepitopes determined by autoimmune responses associated with chronic arthritic attacks. The activation of macrophages and other defence cells in response to self-epitopes as biomarkers in RA provides a better understanding of pathogenesis of disease and has led to the development of novel therapeutic approaches acting as potent inhibitors of these cells. KEY FINDINGS: The current review retrieved the various medicinal plants possessing an active phytoconstituents with anti-inflammatory and antioxidant properties, which tends to be effective alternative approach over the synthetic drugs concerned with high toxic effects. The current available literature provided an evident data concluding that the active constituents like fatty acids, flavonoids, terpenes and sesquiterpene lactones attenuate the RA symptoms by targeting the inflammatory biomarkers involved in the pathogenesis of RA. SUMMARY: Despite the various synthetic treatment approaches targeting immune cells, cytokines improved the quality of life but still the drug management is challenging due to toxic and chronic teratogenic effects with anti-arthritic drugs. The current review has elaborated the selected traditionally used herbal medicinal plants with phytoconstituents possessing anti-inflammatory activity by suppressing the inflammatory biomarkers with lesser side effects and providing the future exploration of natural drug therapy for rheumatoid arthritis.

Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer's Disease.

Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer's disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

Role of Nuclear Factor Kappa B (NF-κB) Signalling in Neurodegenerative Diseases: An Mechanistic Approach.

A transcriptional regulatory nuclear factor kappa B (NF-κB) protein is a modulator of cellular biological activity via binding to a promoter region in the nucleus and transcribing various protein genes. The recent research implicated the intensive role of nuclear factor kappa B (NF-κB) in diseases like autoimmune disorder, inflammatory, cardiovascular and neurodegenerative diseases. Therefore, targeting the nuclear factor kappa B (NF-κB) protein offers a new opportunity as a therapeutic approach. Activation of IκB kinase/NF-κB signaling pathway leads to the development of various pathological conditions in human beings, such as neurodegenerative, inflammatory disorders, autoimmune diseases, and cancer. Therefore, the transcriptional activity of IκB kinase/NF- κB is strongly regulated at various cascade pathways. The nuclear factor NF-kB pathway plays a major role in the expression of pro-inflammatory genes, including cytokines, chemokines, and adhesion molecules. In response to the diverse stimuli, the cytosolic sequestered NF-κB in an inactivated form by binding with an inhibitor molecule protein (IkB) gets phosphorylated and translocated into the nucleus further transcribing various genes necessary for modifying various cellular functions. The various researches confirmed the role of different family member proteins of NF-κB implicated in expressing various genes products and mediating various cellular cascades. MicroRNAs, as regulators of NF- κB microRNAs play important roles in the regulation of the inflammatory process. Therefore, the inhibitor of NF-κB and its family members plays a novel therapeutic target in preventing various diseases. Regulation of NF- κB signaling pathway may be a safe and effective treatment strategy for various disorders.