Chronic jet lag-like conditions dysregulate molecular profiles of neurological disorders in nucleus accumbens and prefrontal cortex

BackgroundPatients with neurological disorders often display altered circadian rhythms. The disrupted circadian rhythms through chronic jetlag or shiftwork are thought to increase the risk and severity of human disease including, cancer, psychiatric, and related brain diseases.ResultsIn this study, we investigated the impact of shiftwork or chronic jetlag (CJL) like conditions on mice’s brain. Transcriptome profiling based on RNA sequencing revealed that genes associated with serious neurological disorders were differentially expressed in the nucleus accumbens (NAc) and prefrontal cortex (PFC). According to the quantitative PCR (qPCR) analysis, several key regulatory genes associated with neurological disorders were significantly altered in the NAc, PFC, hypothalamus, hippocampus, and striatum. Serotonin levels and the expression levels of serotonin transporters and receptors were significantly altered in mice treated with CJL.ConclusionOverall, these results indicate that CJL may increase the risk of neurological disorders by disrupting the key regulatory genes, biological functions, serotonin, and corticosterone. These molecular linkages can further be studied to investigate the mechanism underlying CJL or shiftwork-mediated neurological disorders in order to develop treatment strategies

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a subtype of stroke with a high mortality rate. Oxidative stress cascades play an important role in brain injury after ICH. Cannabidiol, a major non-psychotropic phytocannabinoids, has drawn increasing interest in recent years as a potential therapeutic intervention for various neuropsychiatric disorders. Here we provide a comprehensive review of the potential therapeutic effects of cannabidiol in countering oxidative stress resulting from ICH. The review elaborates on the various sources of oxidative stress post-ICH, including mitochondrial dysfunction, excitotoxicity, iron toxicity, inflammation, and also highlights cannabidiol’s ability to inhibit ROS/RNS generation from these sources. The article also delves into cannabidiol’s role in promoting ROS/RNS scavenging through the Nrf2/ARE pathway, detailing both extranuclear and intranuclear regulatory mechanisms. Overall, the review underscores cannabidiol’s promising antioxidant effects in the context of ICH and suggests its potential as a therapeutic option

Zika Virus Potentiates the Development of Neurological Defects and Microcephaly: Challenges and Control Strategies

Since the beginning of the Zika Virus (ZIKV) epidemic, thousands of cases presenting ZIKV symptoms were recorded in Brazil, Colombia (South America), French Polynesia and other countries of Central and North America. In Brazil, during ZIKV outbreak thousands of microcephaly cases occurred that caused a state of urgency among scientists and researchers to confirm the suspected association between ZIKV infection and microcephaly. In this review article we comprehensively studied scientific literature to analyze ZIKV relationship with microcephaly, recent experimental studies, challenge and shortcomings in previously published reports to know about the current status of this association. The evidences supporting the association of ZIKV infection with congenital microcephaly and fetal brain tissue damage is rapidly increasing, and supplying recent information about pathology, clinical medicine, epidemiology, mechanism and experimental studies. However, serious attention is required toward ZIKV vaccine development, standardization of anthropometric techniques, centralization of data, and advance research to clearly understand the mechanism of ZIKV infection causing microcephaly

Catechins-Modified Selenium-Doped Hydroxyapatite Nanomaterials for Improved Osteosarcoma Therapy Through Generation of Reactive Oxygen Species

Osteosarcoma is the most common bone cancer with limited therapeutic options. It can be treated by selenium-doped hydroxyapatite owing to its known antitumor potential. However, a high concentration of Se is toxic toward normal and stem cells whereas its low concentration cannot effectively remove cancer cells. Therefore, the current study was aimed to improve the anticancer activity of Se-HAp nanoparticles through catechins (CC) modification owing to their high cancer therapeutic value. The sequentially developed catechins modified Se-HAp nanocomposites (CC/Se-HAp) were characterized for various physico-chemical properties and antitumor activity. Structural analysis showed the synthesis of small rod-like single phase HAp nanoparticles (60 +/- 15 nm), which effectively interacted with Se and catechins and formed agglomerated structures. TEM analysis showed the internalization and degradation of CC/Se-HAp nanomaterials within MNNG/HOS cells through a non-specific endocytosis process. Cell toxicity analysis showed that catechins modification improved the antitumor activity of Se-HAp nanocomposites by inducing apoptosis of human osteosarcoma MNNG/HOS cell lines, through generation of reactive oxygen species (ROS) which in turn activated the caspase-3 pathway, without significantly affecting the growth of human normal bone marrow stem cells (hBMSCs). qPCR and western blot analyses revealed that casp3, p53, and bax genes were significantly upregulated while cox-2 and PTK-2 were slightly downregulated as compared to control in CC/Se-HAp-treated MNNG/HOS cell lines. The current study of combining natural biomaterial (i.e., catechins) with Se and HAp, can prove to be an effective therapeutic approach for bone cancer therapy.</p

The Ambiguous Relationship of Oxidative Stress, Tau Hyperphosphorylation, and Autophagy Dysfunction in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid-beta (Aβ)] and neurofibrillary tangles (aggregates of tau). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than Aβ plaques. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagic pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between oxidative stress, tau protein hyperphosphorylation, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on oxidative stress, tau hyperphosphorylation, and autophagy. We also discuss the relationship of these three factors in AD

The 2021 yearbook of neurorestoratology

Breakthroughs with rapid changes are the themes of the development in Neurorestoratology this year. Given the very difficult circumstances of the persistent COVID-19 pandemic, most of the colleagues in Neurorestoratology have conducted meaningful research and obtained encouraging results, as described in the 2020 Yearbook of Neurorestoratology. Neurorestorative progress during 2021 depicts recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. The pathogenesis and risk factors of Alzheimer\u27s disease were parts of the most prominent hot research topics. Yet, it remains controversial whether β-amyloid accumulation and tau protein deposition are the results of, or the reasons for the neurodegenerative processes. Neurogenesis is an important neurorestorative mechanism, however, it is questionable whether neural stem cells are present in the adult humans brain. Thus, neurogenesis may not derive from endogenous neural stem cells in the adult humans. Neurorestorative treatments were important areas of the 2021 research efforts and these therapies are improving the quality of life in patients with neurological diseases. There was major exploration of cell-based therapies for neurological disease and injury. However, unfortunately several multi-center, double-blind or observing-blind, placebo controlled, randomized clinical trials of mesenchymal stromal cells or products of mesenchymal stem cells failed to show positive results in ischemic stroke when employed in the sub-acute or recovery phases as there were no appreciable differences in the quality of life as compared with controls. Excitingly, increased numbers of clinical investigations of brain–computer interface (BCI) were reported that showed benefits for patients with neurological deficits. In pharmaceutical neurorestorative therapies, Aducanumab (Aduhelm) and Sodium Oligomannate are approved respectively by the United States Food and Drug Administration (USFDA) and the China National Medical Products Administration (NMPA) to treat patients with mild-to-moderate Alzheimer\u27s disease. Although, the decisions to approve these drugs are highly contentious in the medical and scientific community because of the contradictory findings or other problems associated with the drug usage. We believe that repeating low-level evidence studies that showed negative results or scanty evidences in randomized control trials is of little significance. However, we strongly recommend conducting multi-center, double-blind, placebo controlled, randomized clinical trials for promising innovative therapeutic methods to facilitate their possible clinical translation

Efficacy of Minocycline in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Rodent and Clinical Studies

Objectives: This study aimed to assess the efficacy of minocycline for the treatment of acute ischemic stroke.Background: While there have been meta-analysis that surveyed the efficacy of minocycline in the treatment of acute stroke, they have some methodological limitations. We performed a new systematic review which was distinct from previous one by adding new outcomes and including new studies.Methods: Document retrieval was executed through PubMed, Cochrane Central Register of Controlled Trials, the Stroke Center, NIH's Clinical Trials, Current Controlled Trials, and the WHO International Clinical Trials Registry Platform Search Portal before Jan 2018. The data meeting the inclusion criteria were extracted. Before meta-analysis, publication bias and heterogeneity of included studies were surveyed. Random and fixed-effects models were employed to calculate pooled estimates and 95% confidence intervals (CIs). Additionally, sensitivity and subgroup analyses were implemented.Result: For clinical studies, 4 trials with 201 patients in the minocycline group, and 195 patients in the control group met the inclusion criteria; 3 were randomized trials. At the end of 90-day follow up or discharge day, results showed that the groups receiving minocycline were superior to the control group, with significant differences in the NIHSS scores (mean difference [MD], −2.75; 95% CI, −4.78, 0.27; p = 0.03) and mRS scores (MD, −0.98; 95% CI, −1.27, −0.69; p &lt; 0.01), but not Barthel Index Score (MD, 9.04; 95% CI, −0.78, 18.07; p = 0.07). For rodent experiments, 14 studies were included. Neurological severity scores (NSS) was significantly improved (MD, −1.38; 95% CI, −1.64, −1.31; p &lt; 0.01) and infarct volume was obviously reduced (Std mean difference [SMD], −2.38; 95% CI, −3.40, −1.36; p &lt; 0.01) in the minocycline group. Heterogeneity among the studies was proved to exist for infarct volume (Chi2 = 116.12, p &lt; 0.01; I2 = 0.89) but not for other variables.Conclusions: Based on the results in our study, minocycline appears as an effective therapeutic option for acute ischemic stroke

The potentiality of bacteria to drive SARS-CoV-2 mutation

ABSTRACTA recent study published in mBio by Cao et al. revealed the crucial roles of bacteria in benefitting SARS-CoV-2 mutations (B. Cao, X. Wang, W. Yin, Z. Gao, and B. Xia, mBio e3187-23, 2024, https://doi.org/10.1128/mbio.03187-23). Understanding the underlying mechanisms driving the evolution of SARS-CoV-2 is crucial for predicting the future trajectory of the COVID-19 pandemic and developing preventive and treatment strategies. This study provides important insights into the rapid and complex evolution of viruses facilitated by bacterial-virus interactions

Effects of Threshold Inspiratory Muscle Training Combined with Continuous Positive Airway Pressure on Sleep and Respiratory Function in Stroke Patients with Obstructive Sleep Apnea-hypopnea Syndrome: a Randomized Controlled Trial

Background There is a close association between obstructive sleep apnea-hypopnea syndrome (OSAHS) and stroke. The coexistence of the two diseases not only affects the rehabilitation process of patients, prolongs their hospitalization time, but also may increase the risk of death. At present, there is still a lack of clinical research on continuous positive airway pressure (CPAP) combined with respiratory training for stroke patients with OSAHS. Objective To examine the impact of threshold inspiratory muscle training (TIMT) in conjunction with CPAP on sleep status, pulmonary function, and respiratory muscle strength in stroke patients with OSAHS. Methods Sixty-nine patients with stroke and OSAHS who met the enrollment criteria were selected from the Second Affiliated Hospital of Zhengzhou University from April 2022 to August 2023. The patients were divided into experimental group (n=35) and control group (n=34) by random number table method. The control group received CPAP and conventional treatment, and the experimental group received TIMT on this basis for 6 weeks. The sleep status, lung function and respiratory muscle function of the two groups were compared before and after intervention. Results Six weeks after the intervention, the mean blood oxygen saturation (SpO2), proportion of deep sleep (proportion of N3 sleep in total sleep time), minimum arterial oxygen saturation (LSaO2), forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), one-second rate (FEV1/FVC), maximum expiratory pressure (MEP) and maximum inspiratory pressure (MIP) were all higher than those before intervention in the 2 groups (P&lt;0.05) ; After 6 weeks of intervention, SpO2, proportion of deep sleep (proportion of N3 sleep in total sleep time), LSaO2, FEV1, FVC, FEV1/FVC, MEP and MIP in experimental group were higher than those in control group (P&lt;0.05). Sleep apnea hypopnea index (AHI), oxygen loss index (ODI), arousal index and Epworth lethargy scale (ESS) scores in the 2 groups were lower than those before intervention (P&lt;0.05). After 6 weeks of intervention, the ODI, arousal index and ESS scores of experimental group were lower than those of the control group (P&lt;0.05) . Conclusion TIMT combined with CPAP can significantly improve the sleep disorder of stroke patients with OSAHS, and improve arterial oxygen partial pressure, respiratory muscle strength and pulmonary function

Mechanism of Artesunate Regulating NLRP3/ASC/Caspase-1 Signaling Pathway to Reduce Inflammation and Protect Neurological Function in Mice with Intracerebral Hemorrhage

Background The inflammatory response is a major factor in the progression of intracerebral hemorrhage (ICH). Artesunate (ART) has antibacterial and anti-inflammatory pharmacological activity with high concentrations in the brain, but its neuroprotective effect on cerebral hemorrhage injury remains unclear. Objective To observe the effect of ART on inflammatory response after intracerebral hemorrhage and explore its mechanism. Methods From March 2022 to February 2023, 108 male C57BL/6 mice aged 8 to 10 weeks were selected and randomly divided into the sham-operated group (Sham group, n=36), ICH control group (ICH+Vehicle group, n=36) and ART treatment group (ICH+ART group, n=36). ICH model was established. The mice in the ICH+ART group were intraperitoneally injected with 150 mg·kg-1·d-1 2 h after modeling, and the mice in the ICH+Vehicle group were intraperitoneally injected with 5% sodium bicarbonate solution for 3 consecutive days. The behavioral indicators of mice were observed. The brain tissue damage of mice in each group was observed by HE staining; the number of positive cells per unit area of interleukin (IL) 6, IL-1&#x03B2; and myeloperoxidase (MPO) were detected by immunohistochemical staining; the activation of microglia/macrophages was observed by IBA1 immunofluorescence staining. TUNEL/NeuN immunofluorescence double staining was performed to observe neuronal death. The levels of MPO, IL-1&#x03B2;, tumor necrosis factor &#x03B1; (TNF-&#x03B1;), Nod-like receptor protein 3 (NLRP3), apoptosis-related granuloid protein (ASC) and cysteine aspartic protease 1 (Caspase-1) were compared by western blotting. Results The modified neurological severity scores and percentages of right turn of mice were higher in the ICH+Vehicle group than the Sham group, and lower in the ICH+ART group than the ICH+Vehicle group (P&lt;0.05). HE staining results showed that there was a small amount of blood around the striatum in the Sham group and negligible edema. In the ICH+Vehicle group, brain tissue was seriously damaged, with increased intercellular space, perivascular hematoma and inflammatory cell infiltration. All of the above symptoms were significantly improved in the ICH+ART group. The numbers of IL-6, IL-1&#x03B2; and MPO positive cells in the ICH+Vehicle group were higher than the Sham group, the numbers of IL-6, IL-1&#x03B2; and MPO positive cells in the ICH+ART group were lower than the ICH+Vehicle group (P&lt;0.05). The number of activated microglia/macrophages in the ICH+Vehicle group was higher than the Sham group, the number of activated microglia/macrophages in the ICH+ART group was lower than the ICH+Vehicle group (P&lt;0.05). The number of neuron death in the ICH+Vehicle group was higher than the Sham group, and lower in the ICH+ART group than the ICH+Vehicle group (P&lt;0.05). The levels of MPO, IL-1&#x03B2;, TNF-&#x03B1;, NLRP3, ASC and Caspase-1 in the ICH+Vehicle group were higher than the Sham group, the levels of MPO, IL-1&#x03B2;, TNF-&#x03B1;, NLRP3, ASC and Caspase-1 in the ICH+ART group were lower than the ICH+Vehicle group (P&lt;0.05) . Conclusion ART therapy after ICH attenuates the inflammatory response of striatum and the activation of microglia in mice through targeted regulation of NLRP3/ASC/Caspase-1 signaling pathway, and ultimately reduces striatal neuronal apoptosis and improves brain edema