Klotho: molecular mechanisms and emerging therapeutics in central nervous system diseases.

Klotho is recognized as an aging-suppressor protein that is implicated in a variety of processes and signaling pathways. The anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-tumor bioactivities of klotho have extended its application in neurosciences and made the protein popular for its lifespan-extending capacity. Furthermore, it has been demonstrated that klotho levels would reduce with aging and numerous pathologies, particularly those related to the central nervous system (CNS). Evidence supports the idea that klotho can be a key therapeutic target in CNS diseases such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and Alzheimer's disease. Reviewing the literature suggests that the upregulation of klotho expression regulates various signaling pathways related to autophagy, oxidative stress, inflammation, cognition, and ferroptosis in neurological disorders. Therefore, it has been of great interest to develop drugs or agents that boost or restore klotho levels. In this regard, the present review was designed and aimed to gather the delegated documents regarding the therapeutic potential of Klotho in CNS diseases focusing on the molecular and cellular mechanisms.

Clinical application of stem cell therapy in neurogenic bladder: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: This review aims to investigate the effect of stem cell (SC) therapy on the management of neurogenic bladder (NGB) in four neurological diseases, including spinal cord injury (SCI), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, in the clinical setting. METHODS: An electronic database search was conducted in the Cochrane Library, EMBASE, Proquest, Clinicaltrial.gov , WHO, Google Scholar, MEDLINE via PubMed, Ovid, Web of Science, Scopus, ongoing trial registers, and conference proceedings in June 2019 and updated by hand searching on 1 February 2021. All randomized controlled trials (RCTs), quasi RCTs, phase I/II clinical trials, case-control, retrospective cohorts, and comprehensive case series that evaluated the regenerative potential of SCs on the management of NGB were included. Cochrane appraisal risk of bias checklist and the standardized critical appraisal instrument from the JBI Meta-Analysis of Statistics, Assessment, and Review Instrument (JBI-MAStARI) were used to appraise the studies. RESULTS: Twenty-six studies among 1282 relevant publications met our inclusion criteria. Only SC therapy was applied for SCI or MS patients. Phase I/II clinical trials (without control arm) were the most conducted studies, and only four were RCTs. Four studies with 153 participants were included in the meta-analysis. The main route of transplantation was via lumbar puncture. There were no serious adverse events. Only nine studies in SCI and one in MS have used urodynamics, and the others have reported improvement based on patient satisfaction. SC therapy did not significantly improve residual urine volume, detrusor pressure, and maximum bladder capacity. Also, the quality of these publications was low or unclear. CONCLUSION: Although most clinical trials provide evidence of the safety and effectiveness of MSCs on the management of NGB, the meta-analysis results did not show a significant improvement; however, the interpretation of study results is difficult because of the lack of placebo controls.

Intranasal administration of mitochondria alleviated cognitive impairments and mitochondrial dysfunction in the photothrombotic model of mPFC stroke in mice.

OBJECTIVES: Dysfunction in mitochondrial activity may have profound role in ischemic stroke-induced neuronal death, hence maintaining the mitochondrial function seems to be valuable for neuronal viability and neurological improvement. METHODS: C57BL/6J mice were allocated into sham and stroke groups. Mice in the stroke groups underwent photothrombosis-induced stroke in the medial prefrontal cortex (mPFC) and were divided into the following subgroups; RB, Mito 85, Mito 170, and Mito 340, and received their respective treatments via intra-nasal route every other day (3 days per week) for one week. A battery of behavioral tests including social interaction, passive avoidance, and the Lashley III maze was used to investigate social, contextual, and spatial memories. Moreover, changes in mitochondrial function, including reactive oxygen species (ROS) and ATP levels, and mitochondrial membrane potential, were assessed in mPFC. The expression of growth-associated protein 43 (GAP-43), post-synaptic density-95 (PSD-95), and synaptophysin (SYP) was detected by western blotting. RESULTS: Behavioral results revealed that mitotherapy alleviated ischemia-induced memory impairment. Also, transplantation of exogenous mitochondria lowered ROS, restored ATP generation, and improved mitochondrial membrane potential. Induction of ischemia decreased the levels of synaptic markers in mPFC while exogenous mitochondria (170 and 340µg) significantly upregulated the expression of GAP-43 and PSD-95 after ischemic stroke. CONCLUSION: Our research highlighted the importance of mitotherapy in regulating synaptic markers expression and mitochondria function, which could represent a potential strategy for improving cognitive and memory deficits following stroke.

Urodynamic Parameters in Spinal Cord Injury-Induced Neurogenic Bladder Rats after Stem Cell Transplantation: A Narrative Review.

Neurogenic bladder (NGB) secondary to spinal cord injury (SCI) is accompanied with several complications such as urinary tract deterioration, urinary incontinence, and consequently lower quality of life (QoL), significant morbidities, and occasionally death. Current therapeutic methods have some side effects and there is no treatment for the upper urinary tract injuries. Stem cell therapy is a promising method for treating this condition. However, the best timing and the best route of its transplantation have not yet been determined. Animal models of SCI, especially in rats, are the most commonly used method for evaluating the efficacy of cell therapy in NGB improvement, and the most common assessment method is the urodynamic studies (UDS). However, there are variations in the range of UDS parameters among the published studies. The current review aimed to discuss the effect of stem cell transplantation on bladder dysfunction recovery based on urodynamic parameters after SCI in rats. For this purpose, the cell source, doses, the route of administration, and the complete UDS equipment and its parameters were summarized in SCI models in rats. In some urodynamic test results, to some extent, an improvement in the lower urinary system function was observed in each treatment group. However, this improvement was far from full functional recovery. The average cell dose was about 1 million cells in every injected site. In most studies, the stem cells (SCs) were transplanted 9 days after the injury using PE-50 and PE-60. Many researchers have recommended further experimental and clinical studies to confirm this treatment modality.

Effect of cerebrolysin on bladder function after spinal cord injury in female Wistar rats.

OBJECTIVES: To study the effect of cerebrolysin on bladder function after spinal cord injury using functional measurements in rats. METHODS: A total of 60 female rats were enrolled in this study. After induction of complete transection at T9-T10 spinal vertebrae, cerebrolysin was injected intraperitoneally, and daily in three dosages until 7 days (1 week) and continued until 28 days (4 weeks) in three groups to show the impact of that on the bladder function. Urodynamic parameters were measured in the different groups. RESULTS: Cerebrolysin injection in a dose of 1 mL/kg for 1 week showed a slight improvement in urodynamic parameters. However, infusion of 2.5 and 5 mL/kg cerebrolysin for 1 week caused an elevation in contractions and a decrease in compliance. In long-term 2.5 mL/kg cerebrolysin injection, an improvement in compliance was observed, despite relative contractions. Furthermore, the bladder pressure pattern in the 2.5 mL/kg infused rats for 4 weeks was similar to the control group, but in the group receiving 5 mL/kg cerebrolysin for 4 weeks, reduced bladder contractions and function were observed. CONCLUSIONS: Our findings suggest that cerebrolysin might be able to inhibit the emergence of neurogenic detrusor overactivity in spinal cord injured female rats.

Aging and age-related diseases with a focus on therapeutic potentials of young blood/plasma.

Aging is accompanied by alterations in the body with time-related to decline of physiological integrity and functionality process, responsible for increasing diseases and vulnerability to death. Several ages associated with biomarkers were observed in red blood cells, and consequently plasma proteins have a critical rejuvenating role in the aging process and age-related disorders. Advanced age is a risk factor for a broad spectrum of diseases and disorders such as cardiovascular diseases, musculoskeletal disorders and liver, chronic kidney disease, neurodegenerative diseases, and cancer because of loss of regenerative capacity, correlated to reduced systemic factors and raise of pro-inflammatory cytokines. Most studies have shown that systemic factors in young blood/plasma can strongly protect against age-related diseases in various tissues by restoring autophagy, increasing neurogenesis, and reducing oxidative stress, inflammation, and apoptosis. Here, we focus on the current advances in using young plasma or blood to combat aging and age-related diseases and summarize the experimental and clinical evidence supporting this approach. Based on reports, young plasma or blood is new a therapeutic approach to aging and age-associated diseases.

Cosmetic Breast Implants and the Risk of Suicide: A Systematic Review and Meta-Analysis.

Objective: Having cosmetic breast implants increases a woman's chance of suicide, which is now a global challenge. This systematic review evaluated the possible risk of suicide among women who undergo cosmetic breast implants. Method : This meta-analysis was done based on Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). In the current systematic review and meta-analysis, we systematically searched for all articles written in both English or Persian that estimated the prevalence of suicidal ideation in women who had cosmetic breast implants. We systematically searched different databases, including MEDLINE (PubMed), Web of Science, Embase, Cochrane, Library ProQuest, Scopus, and Google Scholar, from inception to March 2021. There was also a search for references. Suicidal ideation, a suicide plan, or suicide attempts were the outcomes. In order to determine the total pooled prevalence of suicidal ideation, we utilized a random-effects model. To examine the risks of bias in each study, we applied the Joanna Briggs Institute Critical Appraisal method. Results: We identified 218 citations in our initial search. After omitting duplicated citations and excluding irrelevant studies according to the title and abstract selection, 42 studies were chosen for the full text analysis. Finally, 11 research, examining a total of 324,332 women were incorporated into the systematic review and critical appraisal assessment. Eight of these studies were found to be eligible for meta-analysis. The frequency of suicide in women with cosmetic breast implant was 0.2% (95% CI: 0.1% to 0.4%; P < 0.001) (Q-value: 168.143, I2:95.83). Most of the included studies had moderate quality. Conclusion: There might be a correlation between cosmetic breast implants and suicide risk, which could be stronger in the presence of a history of mental illnesses. The evidence about the possible effects of breast implants on the risk of suicide is still inconclusive, and there is a need for future well-designed studies on this topic.

Prevalence of proximal contact loss between implant-supported fixed prosthesis and adjacent teeth and associated factors: A systematic review and meta-analysis.

Background. This systematic review and meta-analysis investigated the prevalence of proximal contact loss and its associated factors. Methods. A bibliographic search was conducted in June 2021 with no limitation in the article date or language and updated in January 2022 by hand searching. There was no time limit on the search to retrieve all studies. The search included randomized controlled trials or quasi-experiments, and cross-sectional or cohort studies were included in the absence of these studies. Two authors screened the title and abstract. After evaluating the full texts of selected articles, irrelevant studies and or non-English papers that were impossible to translate were excluded. Disagreements between the re-viewers' selection process were resolved by debate on the eligibility of studies. Standardized critical appraisal instruments from the Joanna Briggs Institute for different types of studies were used to assess the studies' quality. Comprehensive Meta-Analysis (CMA) software (Version 2.2; Biostat, Englewood, NJ) was used for data analysis. Results. The proximal contact loss (PCL) frequency was %29. According to the results, the frequencies of PCL for the distal and mesial aspects were %7 and %21, respectively. The meta-analysis results showed that the contact loss events on the mesial aspect were statistically higher than on the distal aspect (P<0.0001). There were no significant differences between other associated factors such as the mandibular or maxillary arch, retention type, opposing dentition, implant type, molar or non-molar, parafunction behaviors, and vitality of adjacent teeth. There was a significant association between bone loss and PCL, and in individuals with bone loss >%50, the proximal contact loss was higher (OR: %95[ 2.43 CI: 4.03‒1.47], P=0.0006). The PCL in the anterior area was lower than in the posterior area (P=0.004). Although the frequency of contact loss in females was higher than in males, this rate was not statistically significant. Conclusion. The PCL on the mesial aspect and the posterior area was high. In individuals with bone loss >%50, the proximal contact loss was higher than in others.

Clinical Presentation of Iranian Patients Affected with COVID-19: A Thousand Faces Disease.

The coronavirus disease 2019 (COVID-19) pandemic in Iran is part of the worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The present study aimed to demonstrate the clinical characteristics of patients affected by COVID-19, in our tertiary teaching hospital. Medical records and compiled data of 668 patients with suspected COVID-19 were obtained retrospectively between January to April 2020. The present study outcomes included demographic features of infected patients, underlying diseases and conditions, the relationship between the results of reverse transcription-polymerase chain reaction (RT-PCR) or CT-scan with the manifestations of the disease, mortality rate, and age distribution of fatalities among men and women. The median age of hospitalized patients was 63 years old (from 18 to 94). The patients' chief complaints in the admission time were cough, dyspnea, fever, and gastrointestinal problems, respectively. Hospitalized patients' common comorbidities were hypertension (HTN), and cardiovascular disease (CVD) (24%), diabetes mellitus (DM) (21.5%), asthma, or chronic obstructive pulmonary disease (COPD) (6%), or other underlying diseases (15.5%). One-third of patients had no comorbidity according to the data of medical records. In hospitalized patients, 169 (84.5%) had positive RT-PCR, and 156 (78%) had positive chest CT findings. The mortality rate of males was higher than females (66.3% vs. 33.3%) and in patients with positive RT-PCR compared to patients with positive chest CT-scan findings. The majority of deaths had a history of DM or HTN/CVD in their medical records. The chief complaint of patients was cough. DM and HTN or CVD were the common underlying disease related to death in hospitalized cases. Besides, the hospitalization and mortality rate in males was higher than in females. About 87% of dead hospitalized cases had positive RT-PCR results, and this rate was 82% for chest CT results.

Effect of Melatonin on Endoplasmic Reticulum-Mitochondrial Crosstalk in Stroke.

Ischemic stroke has remained a principal cause of mortality and neurological disabilities worldwide. Blood flow resumption, reperfusion, in the cerebral ischemia prompts a cascade in the brain characterized by various cellular mechanisms like mitochondrial dysfunction, oxidative stresses, endoplasmic reticulum (ER) stress, and excitotoxicity, finally resulting in programmed cell death. Any changes in the ER-mitochondria axis are probably responsible for both the onset and progression of central nervous system diseases. Melatonin, a neurohormone secreted by the pineal gland, has antioxidative, anti-inflammatory, and anti-apoptotic properties. Most studies have shown that it exerts neuroprotective effects against ischemic stroke. It was observed that melatonin therapy after the stroke not only leads to reduce mitochondrial dysfunction but also cause to alleviate ER stress and inflammation. This review discusses the impact of melatonin on mitochondrial, ER function, and on the crosstalk between two organelles as a therapeutic target for stroke. Given that the influences of melatonin on each organelle separately, its effects on mechanisms of crosstalk between ER and mitochondria are discussed.

Determining the risk factors and characteristics of de novo stress urinary incontinence in women undergoing pelvic organ prolapse surgery: A systematic review.

OBJECTIVE: Stress urinary incontinence (SUI) is a common problem in women that affects their quality of life. According to the current evidence, 15%-50% of severe pelvic organ prolapse (POP) surgeries lead to de novo urinary incontinence (UI). This study aimed at determining the risk factors and characteristics of de novo SUI after POP surgeries in a systematic review. MATERIAL AND METHODS: We conducted a systematic search of articles in English related to the risk of UI after POP surgery published until December 2019 in the selected bibliographic databases, including PubMed, EMBASE, Scopus, Cochrane Library, and ProQuest. RESULTS: The initial search resulted in 2,363 studies, and after reviewing the titles and abstracts, 146 studies were identified. Moreover, 2 independent reviewers, using the Joanna Briggs Institute checklists, evaluated the risk of biases in the selected studies. Finally, 40 studies met the inclusion criteria. The most important predictors of UI after POP surgery were positive pessary testing, age >50 years, and maximum urethral closure pressure (MUCP) <60 cmH2O. CONCLUSION: Positive pessary testing, older age, and low MUCP were the most important risk factors for de novo incontinence after POP surgeries.

Intra-bladder wall transplantation of bone marrow mesenchymal stem cells improved urinary bladder dysfunction following spinal cord injury.

BACKGROUND: In the most of previous experiments, intrathecal administration of stem cells (SCs) was seen in the management of neurogenic bladder (NGB) following contusion or complete transaction in the rodent model of spinal cord injury (SCI). Here, we aimed to investigate whether intra bladder wall autologous bone marrow mesenchymal SC (BM-MSCs) transplantation, as a minimally invasive method, could improve bladder dysfunctions after a chronic phase of hemi- and complete-transection SCI in a female rat model. MATERIAL AND METHODS: A total of forty-two female Wistar rats were randomly divided into 6 groups (each in 7) and subjected to complete and incomplete spinal cord transection by a laminectomy at the T9 vertebral level. Four weeks after SCI operation, BM-MSCs (1 × 106/120 µl) were transplanted in six areas of the bladder muscle in rats with complete SCI (cSCI) and hemi SCI (hSCI) groups. In the rats from sham, cSCI and hSCI negative control groups, normal saline was injected instead of BM-MSCs. Four weeks post-cell transplantation, rats were subjected to conscious urodynamic for voiding function assessment. RESULTS: All bladders in cSCI and hSCI groups were the hyperreflexic type. The amplitude of uninhibited contraction in cSCI + BM-MSC group was decreased (p = 0.046). we noted that compliance was recovered in the hSCI + BM-MSCs group (p = 0.041). Residual volume was increased significantly after SCI while cell transplantation decreased this index in both hSCI and cSCI +BM-MSCs groups. The statistically significant result was only seen in the hSCI group (p = 0.046). Data showed that collagen deposition was markedly increased in the SCI group compared to the control or sham groups. These changes were decreased post-treatment in the hSCI group (p = 0.042). CONCLUSION: Our study added a notion that urinary dysfunction associated with SCI, was improved following direct injection of autologous BM-MSC transplantation to bladder wall in the chronic phase of SCI injury.