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Lysyl Oxidase-like 2 Dysregulation Increases the Risk of Post-Operative Fibrotic Scars Formation in the Female Reproductive Tract: A Novel Therapeutic Target to Reduce Fibrogenesis
No full textThe formation of fibrotic bands in the female reproductive system, including the uterus, after abdominal and pelvic surgeries, is an important medical challenge associated with many complications, including infertility and pain. Investigating the role of different molecules involved in fibrosis and adhesion formation may help in the development of new drugs to prevent this disorder. Lysyl oxidase-like 2 (LoxL2) is a copper-dependent enzyme that catalyzes the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM) to stabilize ECM. Dysregulation of LoxL2 activity resulting from tissue hypoxia and inflammation after gynecological surgeries in the female reproductive tract increases collagen fibers cross-linking and promotes fibrosis. It has been shown that targeting LoxL2 by Lox inhibitors may reduce fibrosis. Considering the expression of LoxL2 in female reproductive organs and its dysregulation in hypoxia and inflammation, LoxL2 may have theraputic potential as a drug target in the prevention of adhesions. In this review, we discuss the role of LoxL2 in the promotion of fibrotic processes, focusing on its link with inflammatory and hypoxic conditions. We also justify the use of anti-LoxL2 agents as a potential therapeutic strategy for the prevention of post-surgical scar formation
Effect of probiotics on urinary tract infections in children: A systematic review and meta-analysis
No full textBackground: Urinary tract infections (UTIs) are the most prevalent bacterial infections that occur in children worldwide.
Objective: This meta-analysis aims to investigate the utility of probiotics as preventive therapy in children with a UTI.
Methods: The Web of Science, PubMed, and Scopus were searched for articles that investigated the relationship between probiotic consumption and the risk of UTIs. The quality of the articles was evaluated using the Jadad scale. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model. Subgroup analyses and sensitivity analyses were also conducted. The Cochran Q test and the statistic I2 were used to evaluate heterogeneity. To determine any potential publication bias, the Egger's and Begg's tests were used.
Results: In total, eleven studies were selected for systematic review and meta-analysis. Compared to children who did not receive probiotics, the OR of developing or having a recurring urinary tract infection in those who received probiotics was 0.94 (95% CI; 0.88-0.999; p-value=0.046). The Begg's and Egger's tests showed no evidence of publication bias between probiotics and the risk of developing new or recurring urinary tract infections.
Conclusion: Based on this systematic review and meta-analysis, probiotics could be an alternative therapy for children who are at risk of developing a UTI. They are non-pharmaceutical options and could be used as natural prophylaxis for UTIs. However, the currently published evidence does not irrefutably confirm that probiotics provide a protective effect against urinary bacterial infections. Therefore, there need to be large-scale randomized clinical trials undertaken to investigate the possible prophylaxis of probiotics.
Keywords: Child; Lactobacillus; Meta-analysis; Probiotics; Systematic review; Urinary tract infections
Maternal separation stress through triggering of the neuro‐immune response in the hippocampus induces autistic‐like behaviors in male mice
No full textAutism spectrum disorder (ASD) is the fastest-growing neurodevelopmental disease throughout the world. Neuro-immune responses from prenatal to adulthood stages of life induce developmental defects in synaptic signaling, neurotransmitter imbalance, and even structural changes in the brain. In this study, we aimed to focus on the possible role of neuroinflammatory response in the hippocampus in development of the autistic-like behaviors following maternal separation (MS) stress in mice. To do this, mice neonates daily separated from their mothers from postnatal day (PND) 2 to PND 14 for 3 h. During PND45–60, behavioral tests related to autistic-like behaviors including three-chamber sociability, Morris water maze (MWM), shuttle box, resident-intruder, and marble burying tests were performed. Then, hippocampi were dissected out, and the gene expression of inflammatory mediators including TNF-α, IL-1β, TLR4, HMGB1, and NLRP3 was assessed in the hippocampus using RT-PCR. Results showed that MS mice exerted impaired sociability preference, repetitive behaviors, impaired passive avoidance, and spatial memories. The gene expression of inflammatory mediators significantly increased in the hippocampi of MS mice. We concluded that MS stress probably via activating of the HMGB1/TLR4 signaling cascade in the hippocampus induced autistic-like behaviors in mice
Single-cell transcriptional signature-based drug repurposing and in vitro evaluation in colorectal cancer
No full textBackground: The need for intelligent and effective treatment of diseases and the increase in drug design costs have raised drug repurposing as one of the effective strategies in biomedicine. There are various computational methods for drug repurposing, one of which is using transcription signatures, especially single-cell RNA sequencing (scRNA-seq) data, which show us a clear and comprehensive view of the inside of the cell to compare the state of disease and health. Methods: In this study, we used 91,103 scRNA-seq samples from 29 patients with colorectal cancer (GSE144735 and GSE132465). First, differential gene expression (DGE) analysis was done using the ASAP website. Then we reached a list of drugs that can reverse the gene signature pattern from cancer to normal using the iLINCS website. Further, by searching various databases and articles, we found 12 drugs that have FDA approval, and so far, no one has reported them as a drug in the treatment of any cancer. Then, to evaluate the cytotoxicity and performance of these drugs, the MTT assay and real-time PCR were performed on two colorectal cancer cell lines (HT29 and HCT116). Results: According to our approach, 12 drugs were suggested for the treatment of colorectal cancer. Four drugs were selected for biological evaluation. The results of the cytotoxicity analysis of these drugs are as follows: tezacaftor (IC10 = 19 µM for HCT-116 and IC10 = 2 µM for HT-29), fenticonazole (IC10 = 17 µM for HCT-116 and IC10 = 7 µM for HT-29), bempedoic acid (IC10 = 78 µM for HCT-116 and IC10 = 65 µM for HT-29), and famciclovir (IC10 = 422 µM for HCT-116 and IC10 = 959 µM for HT-29). Conclusions: Cost, time, and effectiveness are the main challenges in finding new drugs for diseases. Computational approaches such as transcriptional signature-based drug repurposing methods open new horizons to solve these challenges. In this study, tezacaftor, fenticonazole, and bempedoic acid can be introduced as promising drug candidates for the treatment of colorectal cancer. These drugs were evaluated in silico and in vitro, but it is necessary to evaluate them in vivo
Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer immunotherapy
No full textAdvances in cancer immunotherapy over the last decade have led to the development of several agents that affect immune checkpoints. Inhibitory receptors expressed on T cells that negatively regulate the immune response include cytotoxic T‑lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), which have been studied more than similar receptors. Inhibition of these proteins and other immune checkpoints can stimulate the immune system to attack cancer cells, and prevent the tumor from escaping the immune response. However, the administration of anti-PD1 and anti-CTLA4 antibodies has been associated with adverse inflammatory responses similar to autoimmune diseases. The current review discussed the role of the NF-κB pathway as a tumor promoter, and how it can govern inflammatory responses and affect various immune checkpoints. More precise knowledge about the communication between immune checkpoints and NF-κB pathways could increase the effectiveness of immunotherapy and reduce the adverse effects of checkpoint inhibitor therapy
Global incidence and mortality of childhood leukemia and its relationship with the Human Development Index
No full textBackground Childhood leukemia (CL) is a major global concern, accounting for 33% of all new cancer cases and 31% of all cancer deaths in children aged 0–14 years. Our study aimed to analyze the global incidence and mortality rates of CL in 2020 and its relationship with the Human Development Index (HDI). Material and methods In this ecologic study, we analyzed the 2020 cancer incidence and mortality data for children aged 0–14 years from the GLOBOCAN Project. We calculated the Age-Standardized Incidence Rate (ASIR) and Age-Standardized Mortality Rate (ASMR) of CL per 100,000 individuals. Pearson’s correlation coefficient was used to examine the association between childhood leukemia ASIR, ASMR, and the HDI, with a statistical significance threshold of P<0.05. Results In 2020, there were a total of 67,008 new cases of CL worldwide, with males accounting for 57.85%. The global ASIR for CL was 3.4 per 100,000 (3.9 in males, 3 in females). Additionally, there were 25,080 CL-related deaths, with males comprising 58.86%. The overall ASMR for CL was 1.3 (1.4 in males, 1.1 in females). We found a significant positive correlation (r = 0.405, P≤0.001) between the global ASIR and ASMR for CL. There was a strong positive correlation (r = 0.770, P = 0.001) between the HDI and childhood leukemia ASIR, but no significant association (r = 0.077, P = 0.337) was observed with ASMR. Conclusion Our study reveals that CL remains a significant health burden worldwide. We identified a positive correlation between the ASIR of CL and the HDI, indicating a potential role of socioeconomic factors in CL incidence
Clinical and Molecular Spectrum of Autosomal Recessive CA8‐Related Cerebellar Ataxia
No full textBackground: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). Objectives: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. Methods: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. Results: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. Conclusion: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator
Ferulic acid via attenuation of oxidative stress and neuro-immune response utilizes antinociceptive effect in mouse model of formalin test
No full textIntroduction: Plenty evidences suggests that neuroinflammation and oxidative stress augmented the neural sensitivity specifying that neuro-immune response is involved in the pathophysiology of pain. Ferulic acid (FA), a natural antioxidant found in various fruits, has various pharmacological properties. The purpose of the current study was to assess the antinociceptive effect of FA in a mouse model of formalin test with focus on its anti-neuroinflammatory and antioxidative stress effects. Methods: The injection of FA (40 mg/kg), piroxicam (2 mg/kg), and saline (0.9% NaCl) (1 ml/kg) was done intraperitoneally and after one hour, formalin injected into the plantar surface of the hind paw of mice. Then pain behavior was documented during 60 min. Then mice were euthanized and prefrontal cortex (PFC) samples were taken. Malondialdehyde (MDA) level, antioxidant capacity and expression of inflammatory genes, counting tumor necrosis factor (TNF-) and interleukine 1 (IL-1) evaluated in the PFC. Results: exhibited that FA declined the pain behavior following injection of formalin. Besides, FA significantly diminished the MDA level and increased the antioxidant capacity in the PFC. We revealed that FA diminished the expression of TNF-α and IL-1β genes in the PFC. Conclusion: We conclude that FA exerted antinociceptive effects in the formalin test in mice, at least partially, by reducing oxidative stress and neuroimmune response in the PF
Anethole via increase in the gene expression of PI3K/AKT/mTOR mitigates the autistic-like behaviors induced by maternal separation stress in mice
No full textAutism spectrum disorder (ASD) is a neurodegenerative disease with increasing incidence in the world. The maternal separation (MS) stress at early life with its own neuroendocrine and neurostructural changes can provide the basis for development of ASD. Previously it has been reported neuroprotective characteristics for anethole. The PI3K/AKT/mTOR signaling pathway has pivotal role in the function of central nervous system (CNS). This study aimed to evaluate the possible effects of anethole on the autistic-like behaviors in the maternally separated (MS) mice focusing on the potential role of the PI3K/AKT/mTOR pathway. Forty male Naval Medical Research Institute (NMRI) mice were assigned to five groups (n = 8) comprising a control group (treated with normal saline) and four groups subjected to MS and treated with normal saline and or anethole at doses of 31.25, 62.5 and 125 mg/kg, respectively. All gents were administrated via intraperitoneal (i.p.) route for 14 constant days. Behavioral tests were conducted, including the three-chamber test, shuttle box and resident-intruder test. The gene expression of the PI3K, AKT and mTOR assessed in the hippocampus by qRT-PCR. Findings indicated that MS is associated with autistic-like behaviors. Anethole increased the sociability and social preference indexes in the three-chamber test, increased duration of secondary latency in the shuttle box test and decreased aggressive behaviors in the resident-intruder test. Also, anethole increased the gene expression of PI3K, AKT and mTOR in the hippocampus of MS mice. We concluded that anethole through increase in the gene expression of PI3K/ AKT/mTOR mitigated autistic-like behaviors induced by MS in mice
Onabotulinum toxin A improves neurogenic detrusor overactivity following spinal cord injury: a systematic review and meta-analysis
No full textStudy design: Systematic review and meta-analysis. Objectives: The current study aimed to assess the efficacy and safety of Onabotulinum toxin A (OBTX-A) treatment for neurogenic detrusor overactivity (NDO) in spinal cord injury (SCI) patients. Setting: Iran. Methods: All relevant articles of clinical trials and cohort studies indexed in PubMed/MEDLINE, Embase, Scopus, and Web of Science databases up to September 6, 2022, that addressed OBTX-A treatment for NDO following SCI were included. The quality of eligible studies was evaluated using Cochrane criteria. Also, the weighted mean difference (WMD) was measured with a random-effect model. Results: Regarding the overall efficacy after OBTX-A treatment in the short term, volume per void (VV) (WMD = 118.8, 95% CI: 90.9–146.7, p < 0.01), incontinence-quality of life (IQoL) (WMD = 24.3, 95% CI: 15.8–32.8, p < 0.01), and maximum cystometric capacity (MCC) (WMD = 144.5, 95% CI: 132.3 to 156.7, p < 0.01) significantly increased, while maximum detrusor pressure during storage (MDP) (WMD = –30.5, 95% CI: –35.9 to –25.1, p < 0.01) showed a significant decrease. Furthermore, compared to the placebo group at the 200-unit dose, there was a significant increase in MCC (WMD = 113.5, 95% CI: 84.7 to 142.3, p < 0.01) and a significant decrease in MDP (WMD = −27.2, 95% CI: −39.2 to −15.1, p < 0.01). Urinary tract infection (UTI), hematuria, and autonomic dysreflexia were the most common side effects, occurring at rates of 29.6%, 14.8%, and 13.4%, respectively. Conclusion: Our findings highlighted the effectiveness and safety of OBTX-A as a promising treatment of NDO following SCI