Agmatine alleviates ethanol withdrawal-associated cognitive impairment and neurochemical imbalance in rats.

The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.

Agmatine as a novel intervention for Alzheimer's disease: Pathological insights and cognitive benefits.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and a significant societal burden. Despite extensive research and efforts of the multidisciplinary scientific community, to date, there is no cure for this debilitating disease. Moreover, the existing pharmacotherapy for AD only provides symptomatic support and does not modify the course of the illness or halt the disease progression. This is a significant limitation as the underlying pathology of the disease continues to progress leading to the deterioration of cognitive functions over time. In this milieu, there is a growing need for the development of new and more efficacious treatments for AD. Agmatine, a naturally occurring molecule derived from L-arginine, has emerged as a potential therapeutic agent for AD. Besides this, agmatine has been shown to modulate amyloid beta (Aß) production, aggregation, and clearance, key processes implicated in AD pathogenesis. It also exerts neuroprotective effects, modulates neurotransmitter systems, enhances synaptic plasticity, and stimulates neurogenesis. Furthermore, preclinical and clinical studies have provided evidence supporting the cognition-enhancing effects of agmatine in AD. Therefore, this review article explores the promising role of agmatine in AD pathology and cognitive function. However, several limitations and challenges exist, including the need for large-scale clinical trials, optimal dosing, and treatment duration. Future research should focus on mechanistic investigations, biomarker studies, and personalized medicine approaches to fully understand and optimize the therapeutic potential of agmatine. Augmenting the use of agmatine may offer a novel approach to address the unmet medical need in AD and provide cognitive enhancement and disease modification for individuals affected by this disease.

Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases.

Neurodegenerative disorders are distinguished by the progressive loss of anatomically or physiologically relevant neural systems. Atypical mitochondrial morphology and metabolic malfunction are found in many neurodegenerative disorders. Alteration in mitochondrial function can occur as a result of aberrant mitochondrial DNA, altered nuclear enzymes that interact with mitochondria actively or passively, or due to unexplained reasons. Mitochondria are intimately linked to the Endoplasmic reticulum (ER), and ER-mitochondrial communication governs several of the physiological functions and procedures that are disrupted in neurodegenerative disorders. Numerous researchers have associated these disorders with ER-mitochondrial interaction disturbance. In addition, aberrant mitochondrial DNA mutation and increased ROS production resulting in ionic imbalance and leading to functional and structural alterations in the brain as well as cellular damage may have an essential role in disease progression via mitochondrial malfunction. In this review, we explored the evidence highlighting the role of mitochondrial alterations in neurodegenerative pathways in most serious ailments, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

Recent Perspectives on Cardiovascular Toxicity Associated with Colorectal Cancer Drug Therapy.

Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment. Although 5-fluorouracil is still the backbone of chemotherapy regimen for colorectal, gastric, and breast cancers, cardiotoxicity caused by 5-fluorouracil might affect anywhere from 1.5% to 18% of patients. The precise mechanisms underlying cardiotoxicity associated with CRC treatment are complex and may involve the modulation of various signaling pathways crucial for maintaining cardiac health including TKI ErbB2 or NRG-1, VEGF, PDGF, BRAF/Ras/Raf/MEK/ERK, and the PI3/ERK/AMPK/mTOR pathway, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, ultimately damaging cardiac tissue. Thus, the identification and management of cardiotoxicity associated with CRC drug therapy while minimizing the negative impact have become increasingly important. The purpose of this review is to catalog the potential cardiotoxicities caused by anticancer drugs and targeted therapy used to treat colorectal cancer as well as strategies focused on early diagnosing, prevention, and treatment of cardiotoxicity associated with anticancer drugs used in CRC therapy.

Overview on the Polyphenol Avenanthramide in Oats (Avena sativa Linn.) as Regulators of PI3K Signaling in the Management of Neurodegenerative Diseases.

Avenanthramides (Avns) and their derivatives, a group of polyphenolic compounds found abundantly in oats (Avena sativa Linn.), have emerged as promising candidates for neuroprotection due to their immense antioxidant, anti-inflammatory, and anti-apoptotic properties. Neurodegenerative diseases (NDDs), characterized by the progressive degeneration of neurons, present a significant global health burden with limited therapeutic options. The phosphoinositide 3-kinase (PI3K) signaling pathway plays a crucial role in cell survival, growth, and metabolism, making it an attractive target for therapeutic intervention. The dysregulation of PI3K signaling has been implicated in the pathogenesis of various NDDs including Alzheimer's and Parkinson's disease. Avns have been shown to modulate PI3K/AKT signaling, leading to increased neuronal survival, reduced oxidative stress, and improved cognitive function. This review explores the potential of Avn polyphenols as modulators of the PI3K signaling pathway, focusing on their beneficial effects against NDDs. Further, we outline the need for clinical exploration to elucidate the specific mechanisms of Avn action on the PI3K/AKT pathway and its potential interactions with other signaling cascades involved in neurodegeneration. Based on the available literature, using relevant keywords from Google Scholar, PubMed, Scopus, Science Direct, and Web of Science, our review emphasizes the potential of using Avns as a therapeutic strategy for NDDs and warrants further investigation and clinical exploration.

Molecular understanding of ER-MT communication dysfunction during neurodegeneration.

Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca2+ homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.

Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.

Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.

Mitophagy regulation in aging and neurodegenerative disease.

Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.

Involvement of molecular chaperone in protein-misfolding brain diseases.

Protein misfolding causes aggregation and build-up in a variety of brain diseases. There are numeral molecules that are linked with the protein homeostasis mechanism. Molecular chaperones are one of such molecules that are responsible for protection against protein misfolded and aggregation-induced neurotoxicity. Many studies have explored the participation of molecular chaperones in Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, and Huntington's diseases. In this review, we highlighted the constructive role of molecular chaperones in neurological diseases characterized by protein misfolding and aggregation and their capability to control aberrant protein interactions at an early stage thus successfully suppressing pathogenic cascades. A comprehensive understanding of the protein misfolding associated with brain diseases and the molecular basis of involvement of chaperone against aggregation-induced cellular stress might lead to the progress of new therapeutic intrusion-related to protein misfolding and aggregation.

Exercise and Nutraceuticals: Eminent Approach for Diabetic Neuropathy.

Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal- based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health. It has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including Herbal and nutraceuticals therapy. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.

Alzheimer's disease and sleep disorders: Insights into the possible disease connections and the potential therapeutic targets.

One of the comorbid conditions in an individual with Alzheimer's disease is a sleep disorder. Clinical features of sleep disorders involve various sleep disturbances such as Obstructive Sleep Apnea (OSAS), Excessive Daytime Sleepiness (EDS), Rapid Eye Movement (REM), Breathing Disorders, Periodic limb movements in sleep (PLMS), etc. The primary tools used for the identification of such disturbances are Polysomnography (PSG) and Wrist actigraphy. This review will highlight and explains the different approaches used in the treatment of sleep disorders. Non-pharmacological treatments include Peter Hauri rules, sleep education program, and light therapy which play a key role in the regulation of sleep-wake cycles. Pharmacological therapy described in this article may be useful in treating sleep destruction in patients with Alzheimer's disease. Along with the Non-pharmacological and pharmacological treatment, here we discuss five commonly recognized plant-based nutraceuticals with hypothesized impact on sleep disorders: caffeine, chamomile, cherries, L-tryptophan, and valerian by the proper emphasis on the known mechanism of their action.

Interweaving epilepsy and neurodegeneration: Vitamin E as a treatment approach.

Epilepsy is the most common neurological disorder, affecting nearly 50 million people worldwide. The condition can be manifested either due to genetic predisposition or acquired from acute insult which leads to alteration of cellular and molecular mechanisms. Evaluating the latest and the current knowledge in regard to the mechanisms underlying molecular and cellular alteration, hyperexcitability is a consequence of an imbalanced state wherein enhance excitatory glutamatergic and reduced inhibitory GABAergic signaling is considered to be accountable for seizures associated damage. However, neurodegeneration contributing to epileptogenesis has become increasingly appreciated. The components at the helm of neurodegenerative alterations during epileptogenesis include GABAergic neuronal and receptor changes, neuroinflammation, alteration in axonal transport, oxidative stress, excitotoxicity, and other cellular as well as functional changes. Targeting neurodegeneration with vitamin E as an antioxidant, anti-inflammatory and neuroprotective may prove to be one of the therapeutic approaches useful in managing epilepsy. In this review, we discuss and converse about the seizure-induced episodes as a link for the development of neurodegenerative and pathological consequences of epilepsy. We also put forth a summary of the potential intervention with vitamin E therapy in the management of epilepsy.

Agmatine improves the behavioral and cognitive impairments associated with chronic gestational ethanol exposure in rats.

Chronic maternal ethanol exposure leads to poor intelligence, impaired cognition and array of neurological symptoms in offsprings and commonly referred as fetal alcohol spectrum disorder (FASD). Despite high prevalence and severity, the neurochemical basis of FASD remains largely unexplored. The present study evaluated the pharmacological effects of agmatine in cognitive deficits associated with FAS in rat's offsprings prenatally exposed to alcohol. Pregnant rats received ethanol in liquid modified diet during the entire gestational period of 21 days. Offsprings were treated with agmatine (20-80 mg/Kg, i.p.) during early postnatal days (PND: 21-35) and subsequently evaluated for anxiety in elevated plus maze (EPM), depression in forced swim test (FST) and learning and memory in Morris's water maze (MWM) during post adolescent phase. Hippocampal agmatine, BDNF, TNF-α and IL-6 levels were also analyzed in prenatally ethanol exposed pups. Offsprings prenatally exposed to ethanol demonstrated delayed righting reflex, reduced exploratory behavior along with anxiety, depression-like behavior and impaired memory. These behavioral abnormalities were correlated with a significant reduction in hippocampal agmatine and BDNF levels and elevation in TNF-α and IL-6 immunocontent. Chronic agmatine (40 and 80 mg/Kg, i.p.) administration for 15 days (PND: 21-35), improved entries and time spent in open arm of EPM, decreased immobility time in FST. It also reduced latency to reach the platform location; increased the number of entries, time spent in platform quadrant and also number of crossing over platform quadrant when subjected to MWM test in prenatally ethanol exposed offsprings. This study provides functional evidences for the therapeutic potential of agmatine in cognitive impairment and other neurological complications associated with FASD.

Agmatine modulates anxiety and depression-like behaviour in diabetic insulin-resistant rats.

Epidemiological studies indicated that mood disorders like depression and anxiety are highly prevalent in type-II diabetes mellitus (T2DM). However, the neurobiological mechanisms underlying the relationship between T2DM and depression have yet to be identified. Thus, understanding the neural mechanisms that mediate the co-morbidity of depression and type-II diabetes mellitus may unlock new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in T2DM induced depression using forced swim test (FST) and anxiety in the elevated plus-maze (EPM)in rats. T2DM was induced by the combination of high-fat diet (HFD) and streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 12 weeks, HFD fed and STZ injected rats exhibited depression-like behaviors and anxiety. It was associated with increased expression of pro-inflammatory cytokines like IL-6 and TNF-α, and reduced BDNF immunocontent in the hippocampal tissues. The T2DM-induced depression, anxiety, and neuroinflammatory markers were significantly inhibited by agmatine (10-20 mg/kg, i.p.), by once-daily administration during 9th to 12th week of the protocol. Agmatine levels were significantly reduced in the hippocampus of T2DM rats as compared to the normal fed (NF) control animals. In conclusion, the present study suggests the importance of endogenous agmatine in T2DM induced anxiety and depressive-like behavior in rats. The data projects agmatine as a potential therapeutic target for T2DM-associated depression, anxiety, and comorbidities.

Acute orexigenic effect of agmatine involves interaction between central α2-adrenergic and GABAergic receptors.

Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABAA receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABAA positive modulator, allopregnanolone or negative modulator of GABAA receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α2-adrenoceptors and the close association between α2-adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80µg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a α2-adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5µg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5µg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced α2-adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in satiated rats.

Analysis of submerged membrane for a sludge-bed anaerobic membrane bioreactor treating prehydrolysis liquor.

An analysis of foulants and the performance of membranes in innovative sludge-bed anaerobic membrane bioreactors (SB-AnMBRs) were evaluated at mesophilic (35°C for approx. 400 days) followed by thermophilic (55°C for approx. 400 days) temperatures while treating the prehydrolysis liquor (PHL) waste stream from a dissolving pulp production plant. The membrane fouling of SB-AnMBR was analyzed for 0.1, 0.15 and 0.2 m(3)/m(2)/d flux conditions. Physico-chemical analyses of the membrane showed that the combination of 5% citric acid, 0.5% NaOCl and 2% NaOH solutions was effective in achieving more than 80% recovery of membrane flux. Chemical characterization of foulants showed that proteins were more predominant in membrane fouling than carbohydrates. Sugars and lignin contribution were negligible as compared to proteins in the total organic carbon content of the foulant. Membrane fouling occurred through a biofilm-dominated process and organic fouling. Combination of cleaning chemicals which included 0.5% NaClO and 2% NaOH solutions was most effective in the removal of the organic foulants. SEM analysis showed the pictorial evolution of the impact of fouling on the pore openings and the effect of cleaning on the membrane surface.

Performance of novel sludge-bed anaerobic membrane bioreactor (SB-AnMBR) treating prehydrolysis liquor.

The feasibility of a novel sludge-bed anaerobic membrane bioreactor (SB-AnMBR) configuration for treating a waste stream from a dissolving pulp production industry was evaluated. The waste stream, called prehydrolysis liquor (PHL), is generated after the wood chips are subjected to high temperature steam to remove unwanted hemicelluloses. The PHL with total chemical oxygen demand (COD) of approximately 100 g/L contained mainly sugars, furfural, lignin, and acetic acid. The SB-AnMBR was fed with the PHL at organic loading rates in a range of 0.8 to10 kg-COD/(m(3)·d). The COD removal efficiency of more than 85% and an average rate of methane production of 0.35 m(3)/(kg-COD·d) were observed at each loading rate. No detectable sugars or furfural were present in the treated effluent from SB-AnMBR. Lignin removal varied from 60 to 90%. Flat-sheet membranes performed well with one fouling event during first 400 days of operation.