Effects of Botulinum Toxin-A for Spasticity and Nociceptive Pain in Individuals with Spinal Cord Injury: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to examine the protective effects of botulinum toxin-A (Botox-A) on spasticity and nociceptive pain in individuals with spinal cord injuries (SCIs). PubMed, Embase, and Cochrane Library databases were searched from inception to July 2023. The primary outcome of interest was spasticity and nociceptive pain. We pooled the available data using the generic inverse variance method, and we used a fixed-effect/random-effects model. We then calculated standardized mean difference (SMD) and 95% confidence intervals (95% CIs) to estimate the effect size. A total of fourteen studies meeting the inclusion criteria comprised two randomized controlled trials, five pre-post studies, and seven case reports. Across the various study designs, the majority of trials were assessed to have fair to high quality. The meta-analysis shows that Botox-A significantly decreased spasticity (SMD, -1.73; 95% CI, -2.51 to -0.95; p<0.0001, I2=48%) and nociceptive pain (SMD, -1.79; 95% CI, -2.67 to -0.91; p<0.0001, I2=0%) in SCI patients. Furthermore, Botox-A intervention improved motor function, activities of daily living (ADL), and quality of life. Our study suggests that Botox-A may alleviate spasticity and nociceptive pain in SCI patients. Moreover, the observed improvements in motor function, ADL, and overall quality of life following Botox-A intervention underscore its pivotal role in enhancing patient outcomes.

Understanding COVID-19 Impacts on the Health Workforce: AI-Assisted Open-Source Media Content Analysis.

BACKGROUND: To investigate the impacts of the COVID-19 pandemic on the health workforce, we aimed to develop a framework that synergizes natural language processing (NLP) techniques and human-generated analysis to reduce, organize, classify, and analyze a vast volume of publicly available news articles to complement scientific literature and support strategic policy dialogue, advocacy, and decision-making. OBJECTIVE: This study aimed to explore the possibility of systematically scanning intelligence from media that are usually not captured or best gathered through structured academic channels and inform on the impacts of the COVID-19 pandemic on the health workforce, contributing factors to the pervasiveness of the impacts, and policy responses, as depicted in publicly available news articles. Our focus was to investigate the impacts of the COVID-19 pandemic and, concurrently, assess the feasibility of gathering health workforce insights from open sources rapidly. METHODS: We conducted an NLP-assisted media content analysis of open-source news coverage on the COVID-19 pandemic published between January 2020 and June 2022. A data set of 3,299,158 English news articles on the COVID-19 pandemic was extracted from the World Health Organization Epidemic Intelligence through Open Sources (EIOS) system. The data preparation phase included developing rules-based classification, fine-tuning an NLP summarization model, and further data processing. Following relevancy evaluation, a deductive-inductive approach was used for the analysis of the summarizations. This included data extraction, inductive coding, and theme grouping. RESULTS: After processing and classifying the initial data set comprising 3,299,158 news articles and reports, a data set of 5131 articles with 3,007,693 words was devised. The NLP summarization model allowed for a reduction in the length of each article resulting in 496,209 words that facilitated agile analysis performed by humans. Media content analysis yielded results in 3 sections: areas of COVID-19 impacts and their pervasiveness, contributing factors to COVID-19-related impacts, and responses to the impacts. The results suggest that insufficient remuneration and compensation packages have been key disruptors for the health workforce during the COVID-19 pandemic, leading to industrial actions and mental health burdens. Shortages of personal protective equipment and occupational risks have increased infection and death risks, particularly at the pandemic's onset. Workload and staff shortages became a growing disruption as the pandemic progressed. CONCLUSIONS: This study demonstrates the capacity of artificial intelligence-assisted media content analysis applied to open-source news articles and reports concerning the health workforce. Adequate remuneration packages and personal protective equipment supplies should be prioritized as preventive measures to reduce the initial impact of future pandemics on the health workforce. Interventions aimed at lessening the emotional toll and workload need to be formulated as a part of reactive measures, enhancing the efficiency and maintainability of health delivery during a pandemic.

Identification of exosomal biomarkers and its optimal isolation and detection method for the diagnosis of Parkinson's disease: A systematic review and meta-analysis.

Recently, there has been growing interest in exosomal biomarkers for their active targeting and specificity for delivering their cargos (proteins, lipids, nucleic acids) from the parent cell to the recipient cell. Currently, the clinical diagnosis of Parkinson's disease (PD) is mainly based on a clinician's neuropsychological examination and motor symptoms (e.g., bradykinesia, rigidity, postural instability, and resting tremor). However, this diagnosis method is not accurate due to overlapping criteria of other neurodegenerative diseases. Exosomes are differentially expressed in PD and a combination of types and contents of exosomes might be used as a biomarker in PD. Here, we systematically reviewed and meta-analyzed exosomal contents, types and sources of exosomes, method of isolation, and protein quantification tools to determine the optimum exosome-related attributes for PD diagnosis. Pubmed, Embase, and ISI Web of Science were searched for relevant studies. 25 studies were included in the meta-analysis. The Ratio of Mean (RoM) with 95% confidence intervals (CI) was calculated to estimate the effect size. Biomarker performances were rated by random-effects meta-analysis with the Restricted Maximum Likelihood (REML) method. The study protocol is available at PROSPERO (CRD42022331885). Exosomal α-synuclein (α-Syn) was significantly altered in PD patients from healthy controls [RoM = 1.67, 95% CI (0.99 to 2.35); p = 0.00] followed by tau [RoM = 1.33, 95% CI (0.79 to 1.87); p = 0.00], PS-129 [RoM = 0.97, 95% CI (0.54 to 1.40); p = 0.00], and DJ-1/PARK7 [RoM = 0.93, 95% CI (0.64 to 1.21); p = 0.00]. Central nervous system derived L1CAM exosome [RoM = 1.24, 95% CI (1.04 to 1.45); p = 0.00] from either plasma [RoM = 1.35, 95% CI (1.09 to 1.61); p = 0.00]; or serum [RoM = 1.47, 95% CI (1.05 to 1.90); p = 0.00] has been found the optimum type of exosome. The exosome isolation by ExoQuick [RoM = 1.16, 95% CI (0.89 to 1.43); p = 0.00] and protein quantification method by ELISA [RoM = 1.28, 95% CI (1.15 to 1.41); p = 0.00] has been found the optimum isolation and quantification method, respectively for PD diagnosis. This meta-analysis suggests that α-Syn in L1CAM exosome derived from blood, isolated by ExoQuick kit, and quantified by ELISA can be used for PD diagnosis.

Changes in Keyboard Typing Accuracy and Spatial Perception after Cardiovascular Fitness Exercise.

Background: This study aimed to identify the association between cardiopulmonary exercise and neurological activation by measuring dictation accuracy and the extent of spatial perception. Methods: First of all, the body composition of subjects was analyzed to verify their physical abnormality. The subjects were given treadmill exercise using modified Bruce protocol. Before and after the treadmill exercise, a spatial perception test and dictation task with auditory and visual stimulation were carried out to identify the changes in neurological activation. Results: The scores of spatial perception after treadmill exercise were higher than those before treadmill exercise (p < 0.05). In addition, the speed of the post-treadmill dictation task with visual stimulation was significantly increased compared to that of the pre-treadmill dictation task (p < 0.05). However, the accuracy of the post-treadmill dictation task with visual stimulation was significantly decreased compared to that of the pre-treadmill dictation task (p < 0.05). Conclusion: In this study, it was shown that spatial perception and speed of visual dictation were increased after treadmill exercise. These results suggest that cardiovascular fitness exercise increases spatial perception and typing speed by facilitating neurological activation.

Assessment of functional roles and therapeutic potential of integrin receptors in osteoarthritis: A systematic review and meta-analysis of preclinical studies.

BACKGROUND: Integrins are heterodimeric transmembrane receptors that mediate a variety of biological function and plays a critical role in osteoarthritis (OA) pathogenesis, which may provide new targets for the development of OA therapies. However, the roles of integrins in different stages of OA remain elusive. OBJECTIVES: This study aimed to synthesize all published preclinical evidence on the roles of integrin receptors in different stages of OA to identify the potential target for drug development in alleviating OA pathogenesis. METHODS: Major electronic databases were used to identify related original articles. The methodological quality of all included studies was appraised using the SYRCLE risk of bias tool. We used the generic inverse variance with random effects model to calculate standardized mean differences (SMDs) and 95% confidence interval (CI). RESULTS: Seventeen studies were included in this systematic review. Integrin α5ß1 activation increases the histopathological score both in early [SMD, 6.39; 95%CI (2.90, 9.87); p = 0.0003] and late [SMD, 3.41; 95%CI (2.44, 4.38); p < 0.00001] stage of OA. Integrin α5ß1 also increased the core catabolic factors like MMP-3, IL-1ß, and TNF-α. Interestingly, the inactivation of α5ß1 integrin did not change the histopathological score (p = 0.84). Similarly, ß1 integrin notably increased histopathological score at both stages of OA [early; SMD, 7.13; 95%CI (2.01, 12.24); p = 0.006]; [late; SMD, 10.25; 95%CI (5.11, 15.39); p < 0.0001], and increased the MMP-13 levels. However, integrin ß1 was upregulated at the early stage and downregulated at the late stage of OA. Furthermore, α2ß1 integrin significantly increased histopathological score [SMD, 3.14; 95%CI (2.18, 4.10); p < 0.00001] and MMP-13 [SMD, 2.24; 95%CI (0.07, 4.41); p = 0.04]. Deactivating integrin α1ß1 increased histopathological score in late [SMD, 1.53; 95%CI (0.80, 2.26); p < 0.0001], but not in early [SMD, 0.90; 95%CI (-1.65, 3.45); p = 0.49] stage of OA. CONCLUSION: This study provides evidence that α5ß1, α2ß1, and α1ß1 integrin might be the potential target for future drug development in alleviating OA pathogenesis. Further work is required to establish our findings through activating/deactivating these receptors in different stages of OA.

Microglia in Alzheimer's Disease: A Favorable Cellular Target to Ameliorate Alzheimer's Pathogenesis.

Microglial cells serve as molecular sensors of the brain that play a role in physiological and pathological conditions. Under normal physiology, microglia are primarily responsible for regulating central nervous system homeostasis through the phagocytic clearance of redundant protein aggregates, apoptotic cells, damaged neurons, and synapses. Furthermore, microglial cells can promote and mitigate amyloid ß phagocytosis and tau phosphorylation. Dysregulation of the microglial programming alters cellular morphology, molecular signaling, and secretory inflammatory molecules that contribute to various neurodegenerative disorders especially Alzheimer's disease (AD). Furthermore, microglia are considered primary sources of inflammatory molecules and can induce or regulate a broad spectrum of cellular responses. Interestingly, in AD, microglia play a double-edged role in disease progression; for instance, the detrimental microglial effects increase in AD while microglial beneficiary mechanisms are jeopardized. Depending on the disease stages, microglial cells are expressed differently, which may open new avenues for AD therapy. However, the disease-related role of microglial cells and their receptors in the AD brain remain unclear. Therefore, this review represents the role of microglial cells and their involvement in AD pathogenesis.

Pre- and post-conditioning with poly I:C exerts neuroprotective effect against cerebral ischemia injury in animal models: A systematic review and meta-analysis.

BACKGROUND: Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear. METHODS: We evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion. RESULTS: Poly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre- and post-conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor-κB (NF-κB) [SMD = -1.78; CIs (-2.67, -0.88); p = 0.0)], and tumor necrosis factor alpha (TNF-α) [SMD = -16.83; CIs (-22.63, -11.02); p = 0.00]. CONCLUSION: We showed that poly I:C is neuroprotective and acts via the TLR3/NF-κB/TNF-α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.

Exploring the role of senescence inducers and senotherapeutics as targets for anticancer natural products.

During the last few decades, cancer has remained one of the deadliest diseases that endanger human health, emphasizing urgent drug discovery. Cellular senescence has gained a great deal of attention in recent years because of its link to the development of cancer therapy. Senescent cells are incapable of proliferating due to irreversibly inhibition of the initiation of the cell cycle pathways. However, senescent cells aggregate in tissues and produce a pro-inflammatory secretome called senescence-associated secretory phenotype (SASP) that can cause serious harmful effects if not managed properly. There is mounting evidence that senescent cells lead to various phases of tumorigenesis in various anatomical sites, owing mostly to the paracrine activities of the SASP. Therefore, a new treatment field called senotherapeutics has been established. Senotherapeutics are newly developed anticancer agents that have been demonstrated to inhibit cancer efficiently. In light of recent findings, several promising natural products have been identified as senescence inducers and senotherapeutics, including, miliusanes, epigallocatechin gallate, phloretin, silybin, resveratrol, genistein, sulforaphane, quercetin, allicin, fisetin, piperlongumine, berberine, triptolide, tocotrienols and curcumin analogs. Some of them have already been validated through preclinical trials and exert an enormous potential for clinical trials. This review article focuses on and summarizes the latest advances made on cellular senescence and its potential as a target for cancer treatment and highlights the well-known natural products as senescence inducers and senotherapeutics for cancer treatment.

Neurodegenerative effect of DAPK1 after cerebral hypoxia-ischemia is associated with its post-transcriptional and signal transduction regulations: A systematic review and meta-analysis.

Cerebral hypoxia-ischemia (CHI) causes brain aging, neurological disorders, cognitive decline, motor function impairment, and mortality. Inhibiting death-associated protein kinase 1 (DAPK1) has shown therapeutic potential against CHI, but several reports contradict its protective function, mechanism of activation, and signal transduction. Here, we systematically reviewed the role and the activation mechanism of DAPK1, and quantitatively assess the efficacy of DAPK1 inhibition (DI) methods in neuroprotection, following a CHI in animal models. Embase and PubMed were searched for relevant studies. Overall, 13 studies met the inclusion criteria, and the SYRCLE Risk of bias tool (RoB) tool was used to assess RoB. StataSE 16 was used for meta-analysis and network meta-analysis (NMA). Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated to estimate the effect size. DI was associated with the reduction of brain infarct volume (BIV) [SMD = -1.70, 95% CI (-2.10, -1.30); p = 0.00], neurological score (N.S.), neuronal degeneration, with no change in the level of in cell death [SMD = -0.83, 95% CI (-2.00, 0.35); p = 0.17], indicating the protective role of DI against CHI. No differences were found in DAPK1 mRNA and protein levels [SMD = 0.50, 95% CI (-0.05, 1.04); p = 0.07] {single-study driven; upregulated after exclusion (p = 0.01, I2 = 36.43)}, whereas phospho-DAPK1 [SMD = -2.22, 95% CI (-3.69, -0.75); p = 0.00] was downregulated and phosphorylated myosin light chain [SMD = 3.37, 95% CI (2.51, 4.96); p = 0.00] was upregulated between CHI and sham groups. Furthermore, we performed NMA to understand the molecular level at which DI offers maximum protection against BIV. Post-transcriptional inhibition (PTI; SUCRA, 82.6%) and gene knockout showed best (KO; SUCRA, 81.3%), signal transduction inhibition (STI; SUCRA, 49.5%) offered 3rd best, while catalytic activity inhibition (CAI; SUCRA, 0.3%) exhibited the lowest reduction in BIV against CHI. The results demonstrate that DI has a neuroprotective effect against CHI and DAPK1 might be regulated at the post-transcriptional and post-translational levels after CHI. Inhibiting DAPK1 at the post-transcriptional level and blocking multiple signal transduction pathways of DAPK1 could lead to better functional recovery against CHI. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Melatonin Maintains Anabolic-Catabolic Equilibrium and Regulates Circadian Rhythm During Osteoarthritis Development in Animal Models: A Systematic Review and Meta-analysis.

Background: The driving force behind osteoarthritis (OA) pathogenesis is an anabolic-catabolic (a/c) imbalance. Melatonin (MT) is a key player in maintaining a/c stability and mitigates OA pathogenesis, but mechanisms underlying its effects remain poorly understood. Objectives: We performed a systematic review analyzing the experimental data that support the clinical applicability of MT in the treatment of OA pathogenesis, placing particular emphasis on the regulation of circadian rhythms and a/c balance. Methods: Major electronic databases and grey literature were used to identify related original articles. Methodological quality of all selected studies was evaluated using the SYRCLE risk of bias tool. Pooled mean differences (MDs)/standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to estimate the effect size. Results: Eleven trials were included in this systematic review. Compared with the control group, MT significantly decreased the levels of interleukin-1ß (IL-1ß; SMD = -5.45; 95% CI [-6.78, -4.12]; p < 0.00001, and histological grading scale (SMD = -3.46; 95% CI, [-5.24, -1.68]; p < 0.0001). MT significantly increased the transforming growth factor-ß1 (TGF-ß1; SMD = 1.17; 95% CI [0.31, 2.03]; p < 0.0007). Furthermore, core circadian clock genes Per2 and Cry1 mRNA levels were regulated by MT treatment in OA progression. Conclusion: MT may maintain a/c balance and regulate circadian rhythms during OA development. MT could be used in as adjunct with other interventions to manage pain and OA severity.

Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer's disease and insomnia: A systematic review and meta-analysis of randomized controlled trials.

Endogenous melatonin levels are inversely associated with age and cognitive deficits. Although melatonin can improve psychopathological behavior disturbances in clinical trials, whether melatonin may also enhance cognitive function remains elusive. This study examined cognitive outcomes from randomized trials of melatonin treatment for Alzheimer's disease (AD), insomnia, and healthy-subjects. Twenty-two studies met the inclusion criteria (AD = 9, insomnia = 2, healthy-subjects = 11). AD patients receiving >12 weeks of melatonin treatment improved mini-mental state examination (MMSE) score [MD: 1.82 (1.01; 2.63) p < 0.0001]. Importantly, melatonin significantly improved MMSE score in mild stage of AD [MD: 1.89 (0.96; 2.82) p < 0.0001]. In healthy-subjects, although daytime melatonin treatment notably decreased in accuracy by correct responses [SMD: -0.74 (-1.03; -0.45) p < 0.00001], the reaction-time score on different stimuli (p = 0.37) did not increased. Additionally, by pooling of short-term, spatial, and visual memory scores, melatonin did not reduce memory function (p = 0.08). Meta-analysis of MMSE score suggested that melatonin is effective in treatment for mild stage of AD. Additionally, we propose that melatonin may be preferable to traditional hypnotics in management of insomnia.

Deciphering the Interacting Mechanisms of Circadian Disruption and Alzheimer's Disease.

Alzheimer's disease (AD) is one of the crucial causative factors for progressive dementia. Neuropathologically, AD is characterized by the extracellular accumulation of amyloid beta plaques and intracellular neurofibrillary tangles in cortical and limbic regions of the human brain. The circadian system is one of the many affected physiological processes in AD, the dysfunction of which may reflect in the irregularity of the sleep/wake cycle. The interplay of circadian and sleep disturbances inducing AD progression is bidirectional. Sleep-associated pathological alterations are frequently evident in AD. Understanding the interrelation between circadian disruption and AD may allow for earlier identification of AD pathogenesis as well as better suited approaches and potential therapies to combat dementia. In this article, we examine the existing literature related to the molecular mechanisms of the circadian clock and interacting mechanisms of circadian disruption and AD pathogenesis.

Differential role of melatonin in healthy brain aging: a systematic review and meta-analysis of the SAMP8 model.

The relationship between oxidative stress (OS) and cellular senescence (CS) is an important research topic because of the rapidly aging global population. Melatonin (MT) is associated with aging and plays a pivotal role in redox homeostasis, but its role in maintaining physiological stability in the brain (especially in OS-induced senescence) remains elusive. Here, we systematically reviewed the differential role of MT on OS-induced senescence in the SAMP8 mouse model. Major electronic databases were searched for relevant studies. Pooled mean differences (MDs)/standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to estimate the effect size. Overall, 10 studies met the inclusion criteria. MT treatment was associated with the reduction of lipid peroxidation (SMD = -2.00, 95% CI [-2.91, -1.10]; p < 0.0001) and carbonylated protein (MD = -5.74, 95% CI [-11.03, -0.44]; p = 0.03), and with enhancement of the reduced-glutathione/oxidized-glutathione ratio (MD = 1.12, 95% CI [0.77, 1.47]; p < 0.00001). No differences were found in catalase and superoxide dismutase activities between MT-treated and vehicle-treated groups. Furthermore, nuclear-factor-κB, cyclin-dependent kinase-5, and p53 were regulated by MT administration. MT may improve physiological stability during aging by regulating interactions in brain senescence, but acts differentially on the antioxidant system.

Protective Effects of Melatonin against Severe Burn-Induced Distant Organ Injury: A Systematic Review and Meta-Analysis of Experimental Studies.

Extensive burns result in a local wound response and distant-organ injury (DOI) caused by oxidative-stress and inflammation. Melatonin (MT) shows promise in alleviating oxidative-stress and inflammation, but its role in thermal injury is largely unexplored. The present systematic review and meta-analysis were designed to assess the effects of MT on oxidative-stress and inflammatory markers against severe burn-induced DOI. Mean difference (MD)/standard mean difference (SMD) with 95% confidence interval (CI) were estimated using fixed-effect/random-effects models. Eighteen experimental studies met the inclusion criteria. Compared with the control group, MT significantly decreased the levels of malondialdehyde (SMD, -1.03; 95% CI, -1.30, -0.76, p < 0.00001) and 4-hydroxynonenal (MD, -1.06; 95% CI, -1.57, -0.56, p < 0.0001). Additionally, MT increased the levels of glutathione (SMD, 1.94; 95% CI, 1.27, 2.61, p < 0.00001) and superoxide-dismutase (SMD, 0.76; 95% CI, 0.08, 1.45, p = 0.03). Finally, MT significantly decreased the levels of tumor necrosis factor-α (SMD, -1.34; 95% CI, -1.92 to -0.77; p < 0.00001) and C-reactive protein (MD, -12.67; 95% CI, -16.72 to -8.62; p < 0.00001). Meta-analysis indicates that severe burn followed by immediate MT (10 mg/kg) intervention shows significant beneficial effects after 24-h against DOI by regulating oxidative-stress and the inflammatory response.

Emerging Promise of Cannabinoids for the Management of Pain and Associated Neuropathological Alterations in Alzheimer's Disease.

Alzheimer's disease (AD) is an irreversible chronic neurodegenerative disorder that occurs when neurons in the brain degenerate and die. Pain frequently arises in older patients with neurodegenerative diseases including AD. However, the presence of pain in older people is usually overlooked with cognitive dysfunctions. Most of the times dementia patients experience moderate to severe pain but the development of severe cognitive dysfunctions tremendously affects their capability to express the presence of pain. Currently, there are no effective treatments against AD that emphasize the necessity for increasing research to develop novel drugs for treating or preventing the disease process. Furthermore, the prospective therapeutic use of cannabinoids in AD has been studied for the past few years. In this regard, targeting the endocannabinoid system has considered as a probable therapeutic strategy to control several associated pathological pathways, such as mitochondrial dysfunction, excitotoxicity, oxidative stress, and neuroinflammation for the management of AD. In this review, we focus on recent studies about the role of cannabinoids for the treatment of pain and related neuropathological changes in AD.

Pathophysiological role of endogenous irisin against tumorigenesis and metastasis: Is it a potential biomarker and therapeutic?

In the last few decades, there has been notable progress in understanding the molecular and cellular basis of the complex process involved in cancer. In this context, tumor-promoting inflammation, dysregulation of apoptotic signaling, tissue invasion and metastasis, and cancer microenvironment have recently attracted interest from researchers. Irisin is a hormone released by muscles during exercise and it directly acts on key functional cells involving energy metabolism and homeostasis. Recently, many studies have reported the anticancer effect of irisin against different types of cancer. Translation of these findings to clinical practice for the diagnosis and treatment of several types of cancer is urgently required. In this review, we summarized preclinical and clinical studies on the anticancer effects of irisin in various types of cancer, and also discussed the mechanisms activated by irisin to suppress cancer pathogenesis. We further discussed the serum level of irisin related to different types of cancer to understand more clearly the association between irisin concentration and tumor burden. This review may serve as a solid foundation for researchers and physicians to support basic and clinical studies on irisin as a promising strategy for early diagnosis and treatment of a various types of cancers.

Melatonin in Alzheimer's Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer's Neuropathology.

Melatonin, a pineal gland synthesized neurohormone is known as a multifunctioning pleiotropic agent which has a wide range of neuroprotective role in manifold age-related neurodegenerative disorders especially Alzheimer's diseases (AD). AD is a devastating neurodegenerative disorder and common form of dementia which is defined by abnormal and excessive accumulation of several toxic peptides including amyloid ß (Aß) plaques and neurofibrillary tangles (NFTs). The Alzheimer's dementia relates to atrophic changes in the brain resulting in loss of memory, cognitive dysfunction, and impairments of the synapses. Aging, circadian disruption, Aß accumulation, and tau hyperphosphorylation are the utmost risk factor regarding AD pathology. To date, there is no exact treatment against AD progression. In this regard, melatonin plays a crucial role for the inhibition of circadian disruption by controlling clock genes and also attenuates Aß accumulation and tau hyperphosphorylation by regulating glycogen synthase kinase-3 (GSK3) and cyclin-dependent kinase-5 (CDK5) signaling pathway. In this review, we highlight the possible mechanism of AD etiology and how melatonin influences neurogenesis by attenuating circadian disruption, Aß formation, as well as tau hyperphosphorylation. Furthermore, we also find out and summarize the neuroprotective roles of melatonin by the blockage of Aß production, Aß oligomerization and fibrillation, tau hyperphosphorylation, synaptic dysfunction, oxidative stress, and neuronal death during AD progression.

Molecular and Functional Interaction of the Myokine Irisin with Physical Exercise and Alzheimer's Disease.

Irisin, a skeletal muscle-secreted myokine, produced in response to physical exercise, has protective functions in both the central and the peripheral nervous systems, including the regulation of brain-derived neurotrophic factors. In particular, irisin is capable of protecting hippocampus. Since this area is the region of the brain that is most susceptible to Alzheimer's disease (AD), such beneficial effect may inhibit or delay the emergence of neurodegenerative diseases, including AD. Also, the factors engaged in irisin formation appear to suppress Aß aggregation, which is the pathological hallmark of AD. This review is based on the hypothesis that irisin produced by physical exercise helps to control AD progression. Herein, we describe the physiology of irisin and its potential role in delaying or preventing AD progression in human.