Involvement of adenylate cyclase/cAMP/CREB and SOX9/MITF in melanogenesis to prevent vitiligo.

Vitiligo is autoimmune, acquired, idiopathic, chronic, and progressive de/hypopigmentary cutaneous condition that targets the cell-producing pigment called melanin. It binds to a thread of great disappointment and emotional stress in societies. Combining multiple stress-related theories like toxic compound accumulation, autoimmunity, mutations, altered cellular environment, infection, impaired migration/proliferation, and immunological mismatch of anti-melanocyte and self-reactive T-cells that cause melanocytes damage is formulated resulting in vitiligo. Vitiligo has an orphan status for drug synthesis. Still, different therapies are available, with topical steroids and narrow-band ultraviolet-B monotherapy being the most common treatments, others including medical, physical, or surgical, but not effective. Each modality has its baggage of disadvantages and side effects. Stimulation of the transcriptional process for melanogenesis is mainly achieved by the cAMP-dependent activation of several melanogenic genes by MITF. In this review, we summarized that cAMP encourages the expression of the enzyme tyrosinase, TYRP1, TYRP2, and most other biological effects of cAMP are mediated through the cAMP-dependent PKA pathway resulting in CREB phosphorylation. It has been shown that TYRP1 and 2 do not have cAMP response elements (CREs) in promoting regions; the regulation of these genes by cAMP occurs through the direct participation of MITF during melanogenesis. The available medicines, therefore, only provide symptomatic relief, but do not stop the disease progression. In addition, the treatment process needs to be changed; existing approaches need to be overlooked for patients who are suffering and therefore analyze its efficacy and safety to achieve a favorable risk-benefit ratio.

Potential role of IGF-1/GLP-1 signaling activation in intracerebral hemorrhage.

IGF-1 and GLP-1 receptors are essential in all tissues, facilitating defense by upregulating anabolic processes. They are abundantly distributed throughout the central nervous system, promoting neuronal proliferation, survival, and differentiation. IGF-1/GLP-1 is a growth factor that stimulates neurons' development, reorganization, myelination, and survival. In primary and secondary brain injury, the IGF-1/GLP-1 receptors are impaired, resulting in further neuro complications such as cerebral tissue degradation, neuroinflammation, oxidative stress, and atrophy. Intracerebral hemorrhage (ICH) is a severe condition caused by a stroke for which there is currently no effective treatment. While some pre-clinical studies and medications are being developed as symptomatic therapies in clinical trials, there are specific pharmacological implications for improving post-operative conditions in patients with intensive treatment. Identifying the underlying molecular process and recognizing the worsening situation can assist researchers in developing effective therapeutic solutions to prevent post-hemorrhagic symptoms and the associated neural dysfunctions. As a result, in the current review, we have addressed the manifestations of the disease that are aggravated by the downregulation of IGF-1 and GLP-1 receptors, which can lead to ICH or other neurodegenerative disorders. Our review summarizes that IGF-1/GLP-1 activators may be useful for treating ICH and its related neurodegeneration.

Targeting Abnormal PI3K/AKT/mTOR Signaling in Intracerebral Hemorrhage: A Systematic Review on Potential Drug Targets and Influences of Signaling Modulators on Other Neurological Disorders.

PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin) signaling pathway is an important signal transduction pathway mediated by enzyme-linked receptors with many biological functions in mammals. This pathway modulates the epigenetic modification of DNA and target gene histones and plays a significant role in regulating biological activity, disease progression, oncogenesis, and cancer progression. PI3K/AKT/mTOR signaling pathway involves and mediates many cellular processes such as nutrient uptake, proliferation, anabolic reactions, and cell survival. Several studies have shown that PI3K/AKT/mTOR has been a promising therapeutic approach to intracerebral hemorrhage (ICH). ICH is characterized by the progressive development of hematoma, which leads to the structural destabilization of the neurons and glial cells, leading to neuronal deformation, further contributing to mitochondrial dysfunction, membrane depolarization, oligaemia, and neurotransmitter imbalance. Partial suppression of cell metabolism and necrosis can occur, depending on the degree of mitochondrial dysfunction. Therefore in the following review, we discuss whether or not the activation of the PI3K/AKT/mTOR signaling pathway could minimize neuronal dysfunction following ICH. We further elaborate the review by discussing the updated pathophysiology of brain hemorrhage and the role of molecular targets in other neurodegenerative diseases. This review provides current approachable disease treatment in various disease states, single and dual PI3K/AKT/mTOR signaling pathway modulators.

Neuroprotective Effect of Chrysophanol as a PI3K/AKT/mTOR Signaling Inhibitor in an Experimental Model of Autologous Blood-induced Intracerebral Hemorrhage.

OBJECTIVE: Intracerebral hemorrhage (ICH) refers to predominant, sporadic, and non-traumatic bleeding in the brain parenchyma. The PI3K/AKT/mTOR signaling pathway is an important signal transduction pathway regulated by enzyme-linked receptors and has many biological functions in mammals. It plays a key role in neuronal metabolism, gene expression regulation, and tissue homeostasis in the healthy and diseased brain. METHODS: In the present study, the role of the PI3K/AKT/mTOR pathway inhibitor chrysophanol (CPH) (10 mg/kg and 20 mg/kg, orally) in the improvement of ICH-associated neurological defects in rats was investigated. Autologous blood (20 µL/5 min/unilateral/intracerebroventricular) mimics ICH-like defects involving cellular and molecular dysfunction and neurotransmitter imbalance. The current study also included various behavioral assessments to examine cognition, memory, and motor and neuromuscular coordination. The protein expression levels of PI3K, AKT, and mTOR as well as myelin basic protein and apoptotic markers, such as Bax, Bcl-2, and caspase-3, were examined using ELISA kits. Furthermore, the levels of various neuroinflammatory cytokines and oxidative stress markers were assessed. Additionally, the neurological severity score, brain water content, gross brain pathology, and hematoma size were used to indicate neurological function and brain edema. RESULTS: CPH was found to be neuroprotective by restoring neurobehavioral alterations and significantly reducing the elevated PI3K, AKT, and mTOR protein levels, and modulating the apoptotic markers such as Bax, Bcl-2, and caspase-3 in rat brain homogenate. CPH substantially reduced the inflammatory cytokines like interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. CPH administration restored the neurotransmitters GABA, glutamate, acetylcholine, dopamine, and various oxidative stress markers. CONCLUSION: Our results show that CPH may be a promising therapeutic approach for overcoming neuronal damage caused by the overexpression of the PI3K/AKT/mTOR signaling pathway in ICH-induced neurological dysfunctions in rats.

Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration.

Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-ß deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-ß and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.

Neuroprotective Effect of Chrysophanol as a PI3K/AKT/mTOR Signaling Inhibitor in an Experimental Model of Autologous Blood-induced Intracerebral Hemorrhage.

OBJECTIVE: Intracerebral hemorrhage (ICH) refers to predominant, sporadic, and non-traumatic bleeding in the brain parenchyma. The PI3K/AKT/mTOR signaling pathway is an important signal transduction pathway regulated by enzyme-linked receptors and has many biological functions in mammals. It plays a key role in neuronal metabolism, gene expression regulation, and tissue homeostasis in the healthy and diseased brain. METHODS: In the present study, the role of the PI3K/AKT/mTOR pathway inhibitor chrysophanol (CPH) (10 mg/kg and 20 mg/kg, orally) in the improvement of ICH-associated neurological defects in rats was investigated. Autologous blood (20 µL/5 min/unilateral/intracerebroventricular) mimics ICH-like defects involving cellular and molecular dysfunction and neurotransmitter imbalance. The current study also included various behavioral assessments to examine cognition, memory, and motor and neuromuscular coordination. The protein expression levels of PI3K, AKT, and mTOR as well as myelin basic protein and apoptotic markers, such as Bax, Bcl-2, and caspase-3, were examined using ELISA kits. Furthermore, the levels of various neuroinflammatory cytokines and oxidative stress markers were assessed. Additionally, the neurological severity score, brain water content, gross brain pathology, and hematoma size were used to indicate neurological function and brain edema. RESULTS: CPH was found to be neuroprotective by restoring neurobehavioral alterations and significantly reducing the elevated PI3K, AKT, and mTOR protein levels, and modulating the apoptotic markers such as Bax, Bcl-2, and caspase-3 in rat brain homogenate. CPH substantially reduced the inflammatory cytokines like interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. CPH administration restored the neurotransmitters GABA, glutamate, acetylcholine, dopamine, and various oxidative stress markers. CONCLUSION: Our results show that CPH may be a promising therapeutic approach for overcoming neuronal damage caused by the overexpression of the PI3K/AKT/mTOR signaling pathway in ICH-induced neurological dysfunctions in rats.

Mechanisms of Mitochondrial Malfunction in Alzheimer's Disease: New Therapeutic Hope.

Mitochondria play a critical role in neuron viability or death as it regulates energy metabolism and cell death pathways. They are essential for cellular energy metabolism, reactive oxygen species production, apoptosis, Ca++ homeostasis, aging, and regeneration. Mitophagy and mitochondrial dynamics are thus essential processes in the quality control of mitochondria. Improvements in several fundamental features of mitochondrial biology in susceptible neurons of AD brains and the putative underlying mechanisms of such changes have made significant progress. AD's etiology has been reported by mitochondrial malfunction and oxidative damage. According to several recent articles, a continual fusion and fission balance of mitochondria is vital in their normal function maintenance. As a result, the shape and function of mitochondria are inextricably linked. This study examines evidence suggesting that mitochondrial dysfunction plays a significant early impact on AD pathology. Furthermore, the dynamics and roles of mitochondria are discussed with the link between mitochondrial malfunction and autophagy in AD has also been explored. In addition, recent research on mitochondrial dynamics and mitophagy in AD is also discussed in this review. It also goes into how these flaws affect mitochondrial quality control. Furthermore, advanced therapy techniques and lifestyle adjustments that lead to improved management of the dynamics have been demonstrated, hence improving the conditions that contribute to mitochondrial dysfunction in AD.

Understanding Acquired Brain Injury: A Review.

Any type of brain injury that transpires post-birth is referred to as Acquired Brain Injury (ABI). In general, ABI does not result from congenital disorders, degenerative diseases, or by brain trauma at birth. Although the human brain is protected from the external world by layers of tissues and bone, floating in nutrient-rich cerebrospinal fluid (CSF); it remains susceptible to harm and impairment. Brain damage resulting from ABI leads to changes in the normal neuronal tissue activity and/or structure in one or multiple areas of the brain, which can often affect normal brain functions. Impairment sustained from an ABI can last anywhere from days to a lifetime depending on the severity of the injury; however, many patients face trouble integrating themselves back into the community due to possible psychological and physiological outcomes. In this review, we discuss ABI pathologies, their types, and cellular mechanisms and summarize the therapeutic approaches for a better understanding of the subject and to create awareness among the public.

Neuroprotective potential of solanesol in a combined model of intracerebral and intraventricular hemorrhage in rats.

Intracerebral hemorrhage (ICH) may be caused by trauma, aneurysm and arteriovenous malformation, as can any bleeding within the intracranial vault, including brain parenchyma and adjacent meningeal spaces (aneurism and atreovenous malformation). ICH is the cerebral stroke with the least treatable form. Over time, intraventricular hemorrhage (IVH) is associated with ICH, which contributes to hydrocephalus, and the major cause of most hemorrhagic death (Due to the cerebral hemorrhage and post hemorrhagic surgeries). Most patients suffer from memory impairment, grip strength, posture, and cognitive dysfunctions attributable to cerebral hemorrhage or post-brain hemorrhagic surgery. Nevertheless, a combined model of ICH based IVH is not present pre-clinically. Autologous blood (ALB) injection (20 µl/5 min) in the rat brain triggers hemorrhage, such as factors that further interfere with the normal functioning of neuroinflammatory cytokines, oxidative stress, and neurotransmitter dysfunction, such as CoQ10 insufficiency and dysregulation of mitochondrial ETC-complexes. For the prevention of post-brain hemorrhagic behavioral and neurochemical dysfunctions, there is no specific drug treatment available, only available therapy used to provide symptomatic relief. The current study reveals that long-term administration of Solanesol (SNL) 40 and 60 mg/kg alone and in combination with available drug therapy Donepezil (DNP) 3 mg/kg, Memantine (MEM) 20 mg/kg, Celecoxib (CLB) 20 mg/kg, Pregabalin (PGB) 30 mg/kg, may provide the neuroprotective effect by improving behavioral and neurochemical deficits, and gross pathological changes in ALB induced combined experimental model of ICH-IVH in post brain hemorrhagic conditions in rats. Thus, SNL can be a potential therapeutic approach to improve neuronal mitochondrial dysfunction associated with post brain hemorrhagic behavioral and neurochemical alterations.