From lab bench to hope: a review of gene therapies in clinical trials for Parkinson's disease and challenges.

Parkinson's disease (PD) is a chronic neurological disorder that is identified by a characteristic combination of symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It is the second most common neurodegenerative disease after Alzheimer's disease and is characterized by the progressive loss of dopamine-producing neurons in the brain. Currently, available treatments for PD are symptomatic and do not prevent the disease pathology. There is growing interest in developing disease-modifying therapy that can reduce disease progression and improve patients' quality of life. One of the promising therapeutic approaches under evaluation is gene therapy utilizing a viral vector, adeno-associated virus (AAV), to deliver transgene of interest into the central nervous system (CNS). Preclinical studies in small animals and nonhuman primates model of PD have shown promising results utilizing the gene therapy that express glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), aromatic L-amino acid decarboxylase (AADC), and glutamic acid decarboxylase (GAD). This study provides a comprehensive review of the current state of the above-mentioned gene therapies in various phases of clinical trials for PD treatment. We have highlighted the rationale for the gene-therapy approach and the findings from the preclinical and nonhuman primates studies, evaluating the therapeutic effect, dose safety, and tolerability. The challenges associated with gene therapy for heterogeneous neurodegenerative diseases, such as PD, have also been described. In conclusion, the review identifies the ongoing promising gene therapy approaches in clinical trials and provides hope for patients with PD.

Tozinameran (BNT162b2) Vaccine: The Journey from Preclinical Research to Clinical Trials and Authorization.

Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens' expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech's BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.

Protective effects of the resveratrol analog piceid in dopaminergic SH-SY5Y cells.

Age-related motor deficits, such as loss of balance and coordination, are caused, in part, by loss of dopaminergic neurons. Oxidative stress is known to play a role in this neuronal loss. Resveratrol, a natural antioxidant with anticancer and anti-inflammatory potential, has been shown to protect dopaminergic-like cells (SH-SY5Y) against oxidative stress. However, the low bioavailability of resveratrol makes it worthwhile to explore newer compounds with similar properties. Piceid (RV8), an analog of resveratrol, has greater bioavailability than resveratrol, and our studies found that piceid (10, 20, 30 µM) protects SH-SY5Y cells against oxidative stress. Our investigations also found that the neuroprotection afforded by piceid was decreased when the MAP kinases, ERK1/2 and ERK5, were independently inhibited. Since oxidative stress is considered a master operator of apoptosis, our study also scrutinized dopamine-induced apoptosis and whether caspase-3/7 and Bcl-2 are involved, following piceid pretreatment followed by dopamine exposure. Our findings suggested that piceid pretreatment inhibited the dopamine-induced increase in caspase-3/7 activity and dopamine-induced loss of Bcl-2 expression. Overall, these findings suggest that the neuroprotective effects of piceid are mediated via the activation of ERK1/2, ERK5, and inhibition of apoptosis caused by oxidative stress.

Ivermectin: A Multifaceted Drug With a Potential Beyond Anti-parasitic Therapy.

Ivermectin was first discovered in the 1970s by Japanese microbiologist Satoshi Omura and Irish parasitologist William C. Campbell. Ivermectin has become a versatile pharmaceutical over the past 50 years. Ivermectin is a derivative of avermectin originally used to treat parasitic infections. Emerging literature has suggested that its role goes beyond this and may help treat inflammatory conditions, viral infections, and cancers. Ivermectin's anti-parasitic, anti-inflammatory, anti-viral, and anticancer effects were explored. Its traditional mechanism of action in parasitic diseases, such as scabies and malaria, rests on its ability to interfere with the glutamate-gated chloride channels in invertebrates and the lack of P-glycoprotein in many parasites. More recently, it has been discovered that the ability of ivermectin to block the nuclear factor kappa-light-chain enhancer of the activated B (NF-κB) pathway that modulates the expression and production of proinflammatory cytokines is implicated in its role as an anti-inflammatory agent to treat rosacea. Ivermectin has also been evaluated for treating infections caused by viruses, such as SARS-CoV-2 and adenoviruses, through inhibition of viral protein transportation and acting on the importin α/ß1 interface. It has also been suggested that ivermectin can inhibit the proliferation of tumorigenic cells through various pathways that lead to the management of certain cancers. The review aimed to evaluate its multifaceted effects and potential clinical applications beyond its traditional use as an anthelmintic agent.

From Lab Bench to Hope: Emerging Gene Therapies in Clinical Trials for Alzheimer's Disease.

Alzheimer's disease is a progressive neurodegenerative disorder that affects memory and cognitive abilities, affecting millions of people around the world. Current treatments focus on the management of symptoms, as no effective therapy has been approved to modify the underlying disease process. Gene therapy is a promising approach that can offer disease-modifying treatment for AD, targeting various aspects of the pathophysiology of the disease. This review presents a comprehensive overview of the current state of gene therapy research for AD, with a specific focus on clinical trials and preclinical studies that have used nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), apolipoprotein E2 (APOE2), and human telomerase reverse transcriptase (hTERT) as therapeutic gene therapy approaches. These gene targets have shown potential to alleviate the neuropathology of AD in animal studies and have demonstrated feasibility and safety in non-human primates. Despite the failure of the NGF gene therapy approach in clinical trials, we have reviewed and highlighted the reported findings and evaluations from the trials. Furthermore, the review included the conclusions of postmortem brain tissue analysis of AD patients who received NGF gene therapy. The goal is to learn from the failed trials and improve the approach in the future. Although gene therapy shows promise, it faces several challenges and limitations, including optimizing gene delivery methods, enhancing safety and efficacy profiles, and determining long-term results. This review contributes to the growing body of literature on innovative treatments for AD and highlights the need for more research and development to advance gene therapy as a viable treatment option for AD.

Progressive supranuclear palsy: Neuropathology, clinical presentation, diagnostic challenges, management, and emerging therapies.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of 4R-tau protein aggregates in various brain regions. PSP leads to neuronal loss, gliosis, and tau-positive inclusions, such as neurofibrillary tangles, tufted astrocytes, and coiled bodies. These pathological changes mainly affect the brainstem and the basal ganglia, resulting in distinctive MRI features, such as the hummingbird and morning glory signs. PSP shows clinical heterogeneity and presents as different phenotypes, the most classical of which is Richardson's syndrome (PSP-RS). The region of involvement and the mode of atrophy spread can further distinguish subtypes of PSP. PSP patients can experience various signs and symptoms, such as postural instability, supranuclear ophthalmoplegia, low amplitude fast finger tapping, and irregular sleep patterns. The most common symptoms of PSP are postural instability, falls, vertical gaze palsy, bradykinesia, and cognitive impairment. These features often overlap with those of Parkinson's disease (PD) and other Parkinsonian syndromes, making the diagnosis challenging. PSP is an essential clinical topic to research because it is a devastating and incurable disease. However, there are still many gaps in knowledge about its pathophysiology, diagnosis, and treatment. Several clinical trials are underway to test noveltherapies that target tau in various ways, such as modulating its post-translational modifications, stabilizing its interaction with microtubules, or enhancing its clearance by immunotherapy. These approaches may offer new hope for slowing down the progression of PSP. In this review, we aim to provide an overview of the current knowledge on PSP, from its pathogenesis to its management. We also discuss the latest advances and future directions in PSP research.

Advances in Anti-obesity Pharmacotherapy: Current Treatments, Emerging Therapies, and Challenges.

Obesity is a major public health concern linked to health risks such as hypertension, hyperlipidemia, type 2 diabetes mellitus (T2DM), stroke, metabolic syndrome, asthma, and cancer. It is among the leading causes of morbidity and mortality worldwide caused by an unhealthy diet and lack of physical activity, but genetic or hormonal factors may also contribute. Over a third of adults in the United States are obese. Pharmacological agents have been designed to reduce weight gain caused by excessive calorie intake and low physical activity. They work by inhibiting the absorption of dietary fat or stimulating the secretion of satiety hormones. These drugs include lipase inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. However, the current weight-loss strategies do not effectively treat genetic-related diseases, such as generalized lipodystrophy, Bardet-Biedl syndrome, and proopiomelanocortin (POMC) deficiency. Emerging therapies for these gene mutations have been developed targeting leptin and melanocortin-4 receptors (MC4Rs), restoring the normal function of leptin or melanocortin-4 receptors regulating energy balance and appetite. Leptin analogs and MC4R agonists are novel therapies that target genetic or hormonal causes of obesity. This article provides a comprehensive review of anti-obesity medications (AOMs). In this review, we discuss the clinical trials, efficacy, United States FDA-approved indication, contraindications, and serious side effects of different classes of drugs, including lipase inhibitors, GLP-1 agonists, leptin analogs, and MC4R agonists.

Neurological-Type Wilson Disease: Epidemiology, Clinical Manifestations, Diagnosis, and Management.

Wilson disease (WD) is a complex metabolic disorder caused by disruptions to copper regulation within the body, leading to an unregulated accumulation of copper within various tissues. A less understood organ affected by the collection of copper is the brain, which further leads to the generation of oxygen-free radicals and resultant demyelination. Healthcare providers must keep the neurological form of WD in their list of differentials when patients present with diverse neurological manifestations. The initial step to diagnosis will be to distinguish the characteristic disease presentation with a thorough history and physical and neurological examination. A high clinical disease suspicion of WD should warrant further investigation by laboratory workup and imaging modalities to support the clinical findings and confirm the diagnosis of WD. Once a WD diagnosis is established, the healthcare provider should treat the underlying biological process of WD symptomatically. This review article discusses the epidemiology and pathogenesis of the neurological form of WD, its clinical and behavioral implications, diagnostic features, and treatment modalities (current and emerging therapies), further aiding healthcare professionals in early diagnosis and management strategies.

Duchenne muscular dystrophy: Current treatment and emerging exon skipping and gene therapy approach.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder that causes debilitating muscle weakness and atrophy due to a loss of the dystrophin protein. Patients with DMD are commonly diagnosed at about 3-5 years of age and progressively decline until complications of the disease often result in death at about 20 years of age. While there is no current cure for DMD, several treatment options focus on improving the quality of life and slowing progression of symptoms associated with the disease. The current treatment for DMD is glucocorticoids and physical therapy. Respiratory therapy, cardiac management, bone health maintenance, orthopedic interventions, and dietary considerations are also utilized in managing DMD patients. Emerging therapeutic approaches include gene transfer therapy using adeno-associated virus (AAV) vectors, and exon skipping agents. Both approaches have been shown to be relatively safe, with few significant side effects. Even though exon skipping agents produce a smaller dystrophin protein, they effectively preserve a significant portion of its function. Exon skipping agents have clinical advantages over traditional therapies, such as corticosteroids, because they slow the progression of DMD in addition to relieving symptoms. This review discusses the pathogenesis of DMD and explores the current treatment options as well as new and emerging therapies.

Body Mass Index (BMI): A Screening Tool Analysis.

Body mass index (BMI), a measurement based on a person's height and weight, allows the classification of individuals into categories such as obese or overweight. With these classifications, we can assess risk for hypertension, diabetes, cancer, hypercholesterolemia, and other chronic diseases. Furthermore, childhood BMI serves as a prediction method for health and disease later in life. Along with BMI, researchers also study waist circumference and waist-to-hip ratio in correlation with the above-mentioned chronic illnesses. This brief review explores the associations between body mass index, waist circumference, and the waist-hip ratio as measurements and their capability as predictors for persistent conditions like diabetes and hypertension.

Poststroke Seizure and Epilepsy: A Review of Incidence, Risk Factors, Diagnosis, Pathophysiology, and Pharmacological Therapies.

Stroke is the most common cause of epilepsy and ultimately leads to a decrease in the quality of life of those affected. Ischemic and hemorrhagic strokes can both lead to poststroke epilepsy (PSE). Significant risk factors for PSE include age < 65age less than 65 years, stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS), cortical involvement, and genetic factors such as TRPM6 polymorphism. The diagnosis of PSE is made by using imaging modalities, blood biomarkers, and prognostic criteria. Electroencephalography (EEG) is currently the gold standard to diagnose PSE, while new combinations of modalities are being tested to increase diagnostic specificity. This literature review uncovers a newly found mechanism for the pathology of poststroke epilepsy. The pathogenesis of early-onset and late-onset is characterized by sequelae of neuronal cellular hypoxia and disruption of the blood-brain barrier, respectively. Interleukin-6 is responsible for increasing the activity of glial cells, causing gliosis and hyperexcitability of neurons. Epinephrine, high-mobility group protein B1, downregulation of CD32, and upregulation of HLA-DR impact the pathology of poststroke epilepsy by inhibiting the normal neuronal immune response. Decreased levels of neuropeptide Y, a neurotransmitter, act through multiple unique mechanisms, such as inhibiting intracellular Ca2+ accumulation and acting as an anti-inflammatory, also implemented in the worsening progression of poststroke epilepsy. Additionally, CA1 hippocampal resonant neurons that increase theta oscillation are associated with poststroke epilepsy. Hypertensive small vessel disease may also have an implication in the temporal lobe epilepsy by causing occult microinfarctions. Furthermore, this review highlights the potential use of statins as primary prophylaxis against PSE, with multiple studies demonstrating a reduction in incidence using statins alone, statins in combination with antiepileptic drugs (AEDs), and statins with aspirin. The evidence strongly suggests that the second generation AEDs are a superior treatment method for PSE. Data from numerous studies demonstrate their relative lack of significant drug interactions, increased tolerability, and potential superiority in maintaining seizure-free status.

Effects of COVID-19 on Pregnant Women and Newborns: A Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus originated in Wuhan, China, and spread all over the world, causing the worst pandemic of the century. The disease has a broad continuum of clinical presentations, from mild to life-threatening. The virus is highly contagious and transmittable to humans. Emerging evidence of its effects on pregnant women and newborns is inconsistent and ever-evolving. Therefore, the objective of this review is to compile the scientific literature on the effects of SARS-CoV-2 coronavirus on pregnancy, pregnant women, and newborns. Data were obtained by several authors using PubMed, MEDLINE, Google Scholar, and Web of Science. "COVID-19", "pregnancy", "vertical transmission", and "newborn" were the search words used to find relevant articles. Most studies suggested pregnant women and newborns are not at additional risk for unfavorable outcomes. Besides, very few studies found newborns who tested positive for SARS-CoV-2 upon delivery from a COVID-positive mother. However, several studies showed no evidence of intrauterine or transplacental transmission of COVID-19 infection. Studies had mixed findings with a few showing the presence of the virus in breastmilk. In conclusion, there is no concrete evidence of additional adverse effects of SARS-CoV-2 on pregnant women and newborns.

A Case of Transverse Myelitis Secondary to COVID-19 Infection.

Infection with COVID-19 (SARS-CoV-2) is associated with a variety of generalized and specific symptoms, including neurological complications of both the peripheral and central nervous systems. In this case report, we present the case of a previously healthy 55-year-old woman who was diagnosed with transverse myelitis following a previous infection with COVID-19. MRI showed progressive demyelination of the cervical and thoracic spinal cord, and cerebrospinal fluid (CSF) showed increased levels of protein and red blood cells and no markers of infection, including negative polymerase chain reaction (PCR) for COVID-19 antibodies. The patient was treated with a course of methylprednisolone, multiple treatments of plasmapheresis, and ongoing treatment with rituximab, all of which were well-tolerated. She was instructed to follow up as an outpatient with the neurologist and primary care physician five to seven days after hospital discharge.

A Review of COVID-19 in Relation to Metabolic Syndrome: Obesity, Hypertension, Diabetes, and Dyslipidemia.

Although severe cases and mortality of coronavirus disease 2019 (COVID-19) are proportionally infrequent, these cases are strongly linked to patients with conditions of metabolic syndrome (obesity, hypertension, diabetes, and dyslipidemia). However, the pathophysiology of COVID-19 in relation to metabolic syndrome is not well understood. Thus, the goal of this secondary literature review was to examine the relationship between severe acute respiratory syndrome (SARS-CoV-2) infection and the individual conditions of metabolic syndrome. The objective of this secondary literature review was achieved by examining primary studies, case studies, and other secondary studies, to obtain a comprehensive perspective of theories and observations of COVID-19 etiology with metabolic syndrome. The most extensive research was available on the topics of diabetes, hypertension, and obesity, which yielded multiple (and sometimes conflicting) hypothetical pathophysiology. The sources on dyslipidemia and COVID-19 were scarcer and failed to provide an equally comprehensive image, highlighting the need for further research. It was concluded that hypertension had the strongest correlation with COVID-19 incidence (followed by obesity), yet the causative pathophysiology was ambiguous; most likely related to cardiovascular, angiotensin-converting enzyme 2 (ACE-2)-related complications from renin-angiotensin-aldosterone system (RAAS) imbalance. Obesity was also positively correlated to the severity of COVID-19 cases and was believed to contribute to mechanical difficulties with respiration, in addition to hypothetical connections with the expression of ACE-2 on abundant adipose tissue. Diabetes was believed to contribute to COVID-19 severity by producing a chronic inflammatory state and interfering with neutrophil and T-cell function. Furthermore, there were indications that COVID-19 may induce acute-onset diabetes and diabetic ketoacidosis. Lastly, dyslipidemia was concluded to potentially facilitate SARS-CoV-2 infection by enhancing lipid rafts and immunosuppressive functions. There were also indications that cholesterol levels may have prognostic indications and that statins may have therapeutic benefits.

The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease.

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between DM and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles. In DM, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3ß (GSK-3ß) activity showing to enhance tau phosphorylation. In DM and AD, GSK-3ß signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why DM patients have an increased risk of developing AD with disease progression and aging. Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in DM have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between DM and AD as it relates to tau pathology. More understanding of the link between DM and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.

Current pharmacological approaches and potential future therapies for Celiac disease.

Celiac Disease (CeD) is estimated to currently affect 2 million Americans in the United States. This autoimmune disorder occurs when the consumption of gluten-based products leads to an inflammatory response in the small intestine. Over time, this inflammatory response permanently damages the villi in the small intestine. Celiac disease patients generally present with fatigue, diarrhea, and weight loss due to the disease. The current gold standard for diagnosing CeD is the endoscopy with duodenal biopsy indicating villous atrophy and crypt hyperplasia. No FDA-approved medication exists for the treatment of CeD and the only recommended course to alleviate CeD induced symptoms is to abstain from consuming any gluten-based products. There are several clinical trials actively developing and testing pharmacological approaches to treat CeD. Two of the further advanced clinical trials include AT-1001 (Larazotide acetate) and IMGX-003 (Latiglutenase; formerly known as ALV003) therapies. These drugs aim to alleviate celiac disease-induced symptoms using two different approaches. AT-1001 aims to close the villi's tight junctions, while IMGX-003 acts as a gluten endopeptidase that degrades gluten before being absorbed in the small intestine. This review article summarizes the various preclinical research and clinical trials being conducted and specifies the mechanism by which these drugs function.

COVID-19 and Pregnancy: Risk, Symptoms, Diagnosis, and Treatment.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel virus responsible for causing an infection known as COVID-19. Several pulmonary and systemic manifestations of the illness have been described since the discovery of this virus. However, there have been higher-risk populations in which this infection has not been well studied nor documented. One of these populations includes the pregnant cohort. The purpose of this article is to describe the clinical manifestations of COVID-19 infection in the pregnant population and review the implications and sequelae of the infection throughout pregnancy and outcomes of live births. Also, we summarize the understanding and safety of current treatments and vaccination in pregnancy. This comprehensive review article comprises several case reports, case series, cohort studies, retrospective studies, and randomized clinical trials. Findings regarding maternal morbidity included an increased risk of acquiring severe COVID-19 infection requiring a higher level of inpatient hospital care along with an increased risk of preterm labor and cesarean delivery. Neonatal COVID-19 vertical transmission was shown to have conflicting data as there was a presence of transmission in certain retrospective studies and absence in others. There was also no evidence of teratogenicity from maternal COVID-19 infection. In conclusion, in part due to the unique physiologic state of pregnancy and part due to unknown factors, pregnant patients are at increased risk for negative outcomes of COVID-19 infection and must be classified as a high-risk population.

The Neurological Complexities and Prognosis of COVID-19.

Several neurological manifestations and complications linked to SARS-CoV-2 have been reported along with well-known respiratory pathology. The global active transmission of SARS-CoV-2 and its unexplained characteristics has led to a pandemic. Since its rapid emergence from Wuhan, China, in December 2019, several studies have reported the impacts of COVID-19 on the CNS and PNS and its implications. This comprehensive review article comprises case reports, case series, metaanalysis, cohort studies, retrospective studies, and narrative reviews focusing on COVID-19-associated CNS and PNS complexities. The authors searched for over 200 articles and used 52 publications related to the neurological complexities of COVID-19 affecting the CNS and PNS as part of the literature review process. The predominant CNS symptoms noted in COVID-19 patients were headaches and dizziness, and the most common PNS symptoms were alterations in smell and taste. Case reports on headache/dizziness, intracerebral hemorrhage, acute hemorrhagic necrotizing encephalopathy, meningitis/encephalitis, encephalopathy, cerebrovascular events, chemosensory dysfunction, Guillain-Barre syndrome, and acute transverse myelitis/acute necrotizing myelitis in PCR-confirmed SARS-CoV-2 subjects are also reported. New-onset neurological symptoms were also observed in children with PCR-confirmed SARS-CoV-2 that developed pediatric multisystem inflammatory syndrome (PIMS). This comprehensive review article will assist the clinicians and researchers to gain information about the neurological manifestations and complications associated with COVID-19 and develop planning to treat these symptoms in concerned patients of all ages. However, it is unclear whether SARS-CoV2-associated neurological effects are due to primary infections or secondary response to the possible mechanisms discussed in this review.

Curcumin, Hesperidin, and Rutin Selectively Interfere with Apoptosis Signaling and Attenuate Streptozotocin-Induced Oxidative Stress-Mediated Hyperglycemia.

Type I Diabetes is characterized by the presence of hyperglycemia due to insulin deficiency and consequent impaired hepatic glucose metabolism. During diabetes, the liver becomes the most important tissue for the regulation of serum glucose. However, elevated glucose causes continuous oxidative damage to the liver, reducing its capacity to ameliorate hyperglycemia, which contributes to macrovascular complications [1]. Numerous epidemiological studies have demonstrated that excess human consumption of diets rich in specific bioflavonoid phytochemicals attenuates the effects of diabetes. Thus, this study was designed to investigate whether a bioflavonoid mixture could : i) attenuate streptozotocin (STZ)-induced hyperglycemia, ii) potentiate antioxidant signaling in the liver, and iii) ameliorate the apoptotic signaling cascade in the liver of STZ-induced hyperglycemic mice. In order to examine our hypothesis, three well-investigated antioxidant phytochemicals, curcumin, hesperidin and rutin, were combined into a mixture (CHR) for this study. Diabetes was induced in 6-month-old female ICR mice by STZ (100 mg/kg, i.p.) administration, and CHR or vehicle control was orally administered (200 mg/kg per body weight of each ingredient) to the hyperglycemic mice (blood glucose levels > 250 mg/dl) for a period of 14 days. Administration of CHR to the hyperglycemic mice significantly reduced blood glucose levels, attenuated STZ-induced lipid peroxidation and total nitrate/nitrite levels, and significantly augmented the expression of superoxide dismutase and glutathione in the liver. STZ-induced hyperglycemia resulted in downregulation of antiapoptotic proteins Bcl-2 by 66% and Bcl-XL by 51%, and upregulation of the pro-apoptotic Bad (69%) with an increase in the ratio of cytosolic/mitochondrial cytochrome c by 81% in hepatic tissue. Administration of CHR significantly ameliorated apoptotic signaling in STZ-induced diabetic mice, significantly increasing Bad/Bcl-2 and Bad/Bcl-XL ratios to 410% and 244% respectively in the hyperglycemic group. This study demonstrated that a bioflavonoid mixture of curcumin, hesperidin and rutin (CHR) ameliorates hepatic oxidative stress caused by STZ-induced hyperglycemia, resulting in improved hepatic function and glucose regulation.

ERK1, 2, and 5 expression and activation in dopaminergic brain regions during postnatal development.

Degeneration and dysfunctioning of dopaminergic neurons in the midbrain have been associated with serious neurodegenerative and neuropsychiatric disorders. Elucidating the underlying neurobiology of these neurons during early postnatal development may provide important information regarding the etiology of these disorders. Cellular signaling pathways have been shown to regulate postnatal neuronal development. Among several signaling pathways, extracellular-regulated mitogen kinases (ERK) 1, 2, and 5 have been shown to be crucial for the survival and function of dopaminergic neurons. In this study, the basal expression and activation of ERK1, 2, and 5 were studied during postnatal development in regions rich in DA cells and terminals. In the striatum (STR) and ventral mesencephalon regions of the substantia nigra (SN) and ventral tegmental area (VTA), ERK5 expression and activation were high during early postnatal days and declined with aging. Interestingly, sharp increases in phosphorylated or activated ERK1 and ERK2 were observed at postnatal day (PND) 7 in the SN and VTA. In contrast, in the STR, the levels of phosphorylated ERK1 and 2 were significantly higher at PND0 than at any other PND examined. Overall, the understanding of alterations in ERK signaling in regions rich in DA cells and DA terminals during postnatal neuronal development may provide information about their role in regulation of dopamine neuronal development which may ultimately provide insight into the underlying mechanisms of dopamine neurodegeneration.