A New Strategy for the Regulation of Neuroinflammation: Exosomes Derived from Mesenchymal Stem Cells.

Neuroinflammation is an important pathogenesis of neurological diseases and causes a series of physiopathological changes, such as abnormal activation of glial cells, neuronal degeneration and death, and disruption of the blood‒brain barrier. Therefore, modulating inflammation may be an important therapeutic tool for treating neurological diseases. Mesenchymal stem cells (MSCs), as pluripotent stem cells, have great therapeutic potential for neurological diseases due to their regenerative ability, immunity, and ability to regulate inflammation. However, recent studies have shown that MSC-derived exosomes (MSC-Exos) play a major role in this process and play a key role in neuroprotection by regulating neuroglia. This review summarizes the recent progress made in regulating neuroinflammation by focusing on the mechanisms by which MSC-Exos are involved in the regulation of glial cells through signaling pathways such as the TLR, NF-κB, MAPK, STAT, and NLRP3 pathways to provide some references for subsequent research and therapy.

Icaritin and icariin reduce p-Tau levels in a cell model of Alzheimer's disease by downregulating glycogen synthase kinase 3ß.

This study aimed to explore the neuroprotective effect of icariin/icaritin (ICA/ICT) and the role of ICA/ICT in the treatment of Alzheimer's disease (AD). ICA and ICT were used to treat okadaic acid (OA)-induced Tau hyperphosphorylation in SH-SY5Y cells. We detected the relative changes in Tau, p-Tau, protein phosphatase 2A (PP2A), and glycogen synthase kinase 3ß (GSK-3ß) by Western blotting and enzyme-linked immunosorbent assay. At 40 nmol/L OA, the cell viability of the SH-SY5Y cells was significantly changed. We used different concentrations of ICA and IC to treat AD model cells and found that the effect of 2.5 µmol/L ICA and 1 µmol/L ICT was best after 48 H of treatment. After SH-SY5Y cell induction, the p-Tau levels were increased (P < 0.05); after the ICA/ICT treatment, the p-Tau and GSK-3ß levels were decreased (P < 0.05), although PP2A expression did not change (P > 0.05). We found that ICA and ICT exert an effect on AD model cells by decreasing the levels of GSK-3ß and p-Tau. The therapeutic effect of ICT is slightly better than that of ICA. Although these drugs were effective in the cell model, more studies are required to determine whether they are promising for the treatment and prevention of AD.

Dendrobium nobile Lindl. alkaloid decreases Tau hyperphosphorylation via regulating PI3K/Akt/GSK-3ß pathway in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANT: Dendrobium is a traditional and precious Chinese medicinal herb. The Compendium of Materia Medica describes its effects as "benefiting intelligence and dispelling shock, lightning the body and extending life". Dendrobium nobile Lindl. is a precious variety of Dendrobium. Our previous data showed Dendrobium nobile Lindl. alkaloid (DNLA) has significant neuroprotective effects and can improve cognitive dysfunction. However, the specific effects and mechanisms of action of its main active component, DNLA, on cognitive dysfunction caused by Tau hyperphosphorylation, are still unclear. AIM OF THE RESEARCH: This study aimed to determine the effects of DNLA on phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3ß (GSK-3ß) pathway, thus to explore the mechanisms of DNLA to inhibit Tau hyperphosphorylation. MATERIALS AND METHODS: We used wortmannin (WM) and GF-109203X (GFX)-induced hyperphosphorylation of Tau in N2a cells and rats to detect the protective mechanism of DNLA in vivo and in vitro. In vitro, the effect of modeling method on Tau hyperphosphorylation was screened and verified by Western Blotting (WB), and the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3ß pathway by different concentrations of DNLA was detected by WB. In vivo, MWM was used to detect the effect of DNLA on model rats, and then Nissl staining was used to detect the loss of neurons. Finally, WB was used to detect the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3ß pathway by different concentrations of DNLA. RESULTS: DNLA could rescue the abnormal PI3K/Akt/GSK-3ß pathway and reverse the hyperphosphorylation of Tau induced by WM and GFX in N2a cells. Furthermore, DNLA improved the learning and memory of WM and GFX-induced model rats. Moreover, DNLA regulated PI3K/Akt/GSK-3ß pathway and reduced the p-Tau and neuronal damage in the hippocampus of model rats. CONCLUSION: DNLA may be a promising candidate for reducing hyperphosphorylation of Tau.

Role of NLRP3 in Parkinson's disease: Specific activation especially in dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder with motor symptoms like bradykinesia, tremors, and balance issues. The pathology is recognized by progressively degenerative nigrostriatal dopaminergic neurons (DANs) loss. Its exact pathogenesis is unclear. Numerous studies have shown that nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) contributes to the pathogenesis of PD. Previous studies have demonstrated that the over-activation of NLRP3 inflammasome in microglia indirectly leads to the loss of DANs, which can worsen PD. In recent years, autopsy analyses of PD patients and studies in PD models have revealed upregulation of NLRP3 expression within DANs and demonstrated that activation of NLRP3 inflammasome in neurons is sufficient to drive neuronal loss, whereas microglial activation occurs after neuronal death, and that inhibition of intraneuronal NLRP3 inflammasome prevents degeneration of DANs. In this review, we provide research evidence related to NLRP3 inflammasome in DANs in PD as well as focus on possible mechanisms of NLRP3 inflammasome activation in neurons, aiming to provide a new way of thinking about the pathogenesis and prevention of PD.

Neuroprotective effect of tanshinone IIA-modified mesenchymal stem cells in a lipopolysaccharide-induced neuroinflammation model.

In this study, the neuroprotective potential of tanshinone IIA (TIIA)-modified mesenchymal stem cells (MSC) were investigated using a murine model of lipopolysaccharide (LPS)-induced neuroinflammation. The cognitive performance of the mice was assessed using the Y-maze and Morris water maze tests, while immunofluorescence and Western blot analyses were employed to evaluate the hippocampal expression of pertinent markers and inflammatory factors, respectively. The results from the behavioral experiments demonstrated discernible differences in learning and memory abilities between the model group and the control group (P < 0.05), confirming the successful induction of neuroinflammation. Both the MSC and TIIA-MSC groups exhibited enhancements in the cognitive abilities of neuroinflammatory mice, with the TIIA-MSC group demonstrating a more pronounced improvement (P < 0.01). Immunofluorescence analysis revealed significant activation of microglia in the model group, while the MSC and TIIA-MSC groups exhibited a reduction in hippocampal microglial activation, with the TIIA-MSC group displaying a more substantial decrease. A statistically significant difference in the expression levels of IL-1, IL-6, and TNF-α was observed between the model and control groups (P < 0.05), indicating that IL-1, IL-6, and TNF-α were downregulated in both the MSC and TIIA-MSC groups. Notably, the downregulatory effect was more prominent in the TIIA-MSC group (P < 0.01). Compared to MSC treatment alone, the administration of TIIA-modified MSC demonstrated a superior protective effect against lipopolysaccharide-induced neuroinflammation. These findings underscore the potential therapeutic efficacy of TIIA-modified MSC in mitigating neuroinflammatory responses.

Possible opportunities and challenges for traditional Chinese medicine research in 2035.

The drug development process is poised for significant transformation due to the rapid advancement of modern biological and information technologies, such as artificial intelligence (AI). As these new technologies and concepts infiltrate every stage of drug development, the efficiency and success rate of research and development are expected to improve substantially. Traditional Chinese medicine (TCM), a time-honored therapeutic system encompassing herbal medicine, acupuncture, and qigong, will also be profoundly impacted by these advancements. Over the next decade, Traditional Chinese medicine research will encounter both opportunities and challenges as it integrates with modern technologies and concepts. By 2035, TCM is anticipated to merge with modern medicine through a more contemporary and open research and development model, providing substantial support for treating a broader spectrum of diseases.

Periodontitis promotes the progression of diabetes mellitus by enhancing autophagy.

Objective: This study aims to identify the periodontitis factor that activates excessive autophagy in pancreatic ß cells, resulting in organic lesions of pancreatic islet tissues and diminished insulin secretion, thereby accelerating the progression of diabetes mellitus (DM). Methods: Sprague-Dawley (SD) rats were induced with periodontitis (PD), type 2 diabetes mellitus (T2DM), or the combination of T2DM and PD (DP) through a high-sugar/high-fat diet and ligation of the tooth neck with silk thread. Alveolar bone resorption was assessed using Micro-CT, blood glucose levels were measured with a blood glucose meter, pancreatic tissue pathology was examined through HE staining, and the expression of autophagy-related proteins Beclin1 and LC3II/LC3I was analyzed using Western blotting. Results: Micro-CT results revealed more pronounced alveolar bone resorption and root bifurcation exposure in the PD and DP groups compared to the control group, with the DP group exhibiting the most severe condition. HE staining demonstrated the formation of periodontal pockets, severe alveolar bone destruction, and abnormal pancreatic islet tissue morphology in the PD and DP groups. The serum levels of IL-6, TNF-α, and IL-1ß increased sequentially in the control, DM, PD, and DP groups (P < 0.05). Relative expressions of GCK and GLUT-2 mRNA decreased in the PD group compared to the control group (P > 0.05), while the mRNA expressions in the DP and DM groups increased (P < 0.05), with the DP group exhibiting higher levels than the DM group (P < 0.05). Western blot results indicated increased expression levels of autophagy proteins Beclin1 and LC3II/LC3I in the DM and DP groups compared to the control group (P < 0.05), with the DP group exhibiting higher levels than the DM group (P < 0.05). Conclusion: The findings demonstrate that periodontal inflammatory factors may promote the enhancement of pancreatic cell autophagy in diabetic rats.

Risk predict model using multi-drug resistant organism infection from Neuro-ICU patients: a retrospective cohort study.

The aim of this study was to analyze the current situation and risk factors of multi-drug-resistant organism (MDRO) infection in Neuro-intensive care unit (ICU) patients, and to develop the risk predict model. The data was collected from the patients discharged from Neuro-ICU of grade-A tertiary hospital at Guizhou province from January 2018 to April 2020. Binary Logistics regression was used to analyze the data. The model was examined by receiver operating characteristic curve (ROC). The grouped data was used to verify the sensitivity and specificity of the model. A total of 297 patients were included, 131 patients infected with MDRO. The infection rate was 44.11%. The results of binary Logistics regression showed that tracheal intubation, artery blood pressure monitoring, fever, antibiotics, pneumonia were independent risk factors for MDRO infection in Neuro-ICU (P < 0.05), AUC = 0.887. The sensitivity and specificity of ROC curve was 86.3% and 76.9%. The risk prediction model had a good predictive effect on the risk of MDRO infection in Neuro ICU, which can evaluate the risk and provide reference for preventive treatment and nursing intervention.

Meta-analysis of the effect of probiotics or synbiotics on the risk factors in patients with coronary artery disease.

Objective: The objective of this study was to study the effect of probiotics or synbiotics on the risk factors for coronary artery disease (CAD) in the context of conventional drug therapy for CAD. Methods: The literature on probiotics or synbiotics for the treatment of CAD was collected from PubMed, Scopus, Web of Science, Embase, and Cochrane Library. The search period was conducted on November 5, 2022, and the search covered all literature before November 5, 2022. The included literature consisted of randomized controlled trials of probiotics or synbiotics for CAD, and a meta-analysis was performed using Stata 14 software and RevMan 5.4 software. Results: The meta-analysis explored the effect of probiotics or synbiotics on the risk factors for coronary artery lesions in a treatment setting with conventional medications for CAD. After a rigorous literature screening process, 10 studies were finally included for data consolidation to objectively evaluate the effect of probiotics or synbiotics on coronary lesions. The results of this study showed that the addition of probiotics or synbiotics to conventional medications for CAD reduced the levels of low-density lipoprotein cholesterol [weighted mean difference (WMD) -9.13 (-13.17, -5.09)], fasting glucose (FPG) [WMD -13.60 (-23.57, -3.62)], and hypersensitive C-reactive protein (hs-CRP) [standardized mean difference (SMD) -0.60 (-0.83, -0.37)] and increased the levels of high-density lipoprotein cholesterol (HDL-C) [WMD 1.94 (0.32, 3.57)], nitric oxide (NO) [WMD 5.38 (3.23, 7.54)] but did not affect the triglyceride (TG) level [WMD -13.41 (-28.03, 1.21)], systolic blood pressure (SBP) [WMD -0.88 (-3.72, 1.96)], or diastolic blood pressure (DBP) [WMD -0.21 (-2.19, 1.76)]. Conclusion: Adding probiotics or synbiotics to conventional medications for CAD may improve patient prognosis. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022362711.

China's drug clinical trial institution record-keeping system: Qualification requirements for PI are the key.

It has been 3 years since China implemented new management regulations for drug clinical trial institutions in December 2019, the most important of which is to change the qualification recognition of drug clinical trial institutions into record-keeping system. The original intention of the institution record-keeping system was to solve the shortage of clinical trial resources in China, effectively expand the number of clinical trial institutions, and effectively alleviate the contradiction between medical treatment and scientific research. After implementing the record-keeping system, although these goals have been achieved to a certain extent, there are still areas worthy of optimization and improvement. Therefore, we evaluated the new process, in particular the requirements, in order to see what possible barriers in the record-keeping system of institutions. We find that the requirements for principal investigator (PI) qualifications are the key to the record-keeping system. This reflects the shift of Chinese regulators' supervision of clinical trials to supervision of the ability to conduct clinical trials. However, the ambiguity of the definition of PI qualification has hindered implementation of the record-keeping system and reduced the release of clinical trial resources.

The role of TREM2 in Alzheimer's disease: from the perspective of Tau.

Triggering receptor expressed on myeloid cells 2 (TREM2), a pattern recognition receptor abundantly expressed on microglia, has been identified as one of the risk factors for Alzheimer's disease (AD). Several studies have already demonstrated the relationship between TREM2 and Tau. TREM2 mutations and altered expression play an important role in Tau phosphorylation. Furthermore, the level of Tau phosphorylation is correlated with soluble TREM2 (sTREM2). However, in different stages of AD, TREM2 seems to have varying effects on Tau pathology. The explicit interaction between TREM2 and Tau, as well as how they affect AD pathology, remains unclear, and there is much evidence to the contrary that requires rational interpretation. Reviewing the dual roles of TREM2 in AD will help identify a more appropriate development strategy for targeting TREM2 to treat AD. Therefore, this review focuses on the interplay between Tau and TREM2 in relation to AD.

Epiglottic Cyst With Slurred Speech Misdiagnosed as Acute Cerebral Infarction: A Case Report.

INTRODUCTION: Epiglottic cysts are cysts that occur under the mucosa of the epiglottis. Patients with severe cysts may have difficulty in breathing. Slurred speech usually occurs in cerebrovascular diseases, especially with slurred speech as the starting symptom. CASE REPORT: We describe the case of a patient with slurred speech as the first symptom. The patient was a 53-year-old man with slurred speech as the first symptom, and he was initially considered to have an acute cerebral infarction. However, the results of the cranial magnetic resonance imaging examination did not support the diagnosis. The possibility of neck tumor recurrence was considered based on past medical history. The findings of a computed tomography examination of the neck suggested an epiglottic cyst. The effect of anti-inflammatory and surgical treatment was significant, and speech returned to normal. CONCLUSION: This case emphasizes that neurologists need to be vigilant when dealing with patients with slurred speech, which may be one of the clinical manifestations of epiglottic cysts.

Clinical antidiabetic medication used in Alzheimer's disease: From basic discovery to therapeutics development.

Alzheimer's disease (AD) is a common neurodegenerative disease. Type 2 diabetes mellitus (T2DM) appears to increase and contributing to the risk of AD. Therefore, there is increasing concern about clinical antidiabetic medication used in AD. Most of them show some potential in basic research, but not in clinical research. So we reviewed the opportunities and challenges faced by some antidiabetic medication used in AD from basic to clinical research. Based on existing research progress, this is still the hope of some patients with special types of AD caused by rising blood glucose or/and insulin resistance.

Breast milk jaundice affects breastfeeding: From the perspective of intestinal flora and SCFAs-GPR41/43.

Breast milk jaundice (BMJ) is one of the main factors leading to interruption or early termination of breastfeeding. Interrupting breastfeeding to treat BMJ may increase the adverse consequences for infant growth and disease prevention. The Intestinal flora and metabolites are increasingly recognized as a potential therapeutic target in BMJ. First, dysbacteriosis can lead to a decrease in the metabolite short-chain fatty acids. At the same time, SCFA can act on specific G protein-coupled receptors 41 and 43 (GPR41/43), and a decrease in SCFA downregulates the GPR41/43 pathway, leading to a diminished inhibition of intestinal inflammation. In addition, intestinal inflammation leads to a decrease in intestinal motility and a large amount of bilirubin enters the enterohepatic circulation. Ultimately, these changes will result in the development of BMJ. In this review, we will describe the underlying pathogenetic mechanism of the intestinal flora effects on BMJ.

Natural bioactive compounds in Alzheimer's disease: From the perspective of type 3 diabetes mellitus.

There is a close relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the link between the two is often referred to as type 3 diabetes mellitus (T3DM). Many natural bioactive compounds have shown the potential to treat AD and diabetes. We mainly review the polyphenols represented by resveratrol (RES) and proanthocyanidins (PCs) and alkaloids represented by berberine (BBR) and Dendrobium nobile Lindl. alkaloids (DNLA) from the perspective of T3DM to review the neuroprotective effects and molecular mechanisms of natural compounds in AD.

Case Report: Transcatheter treatment of aortic coarctation in a 58-year-old patient with LACHT syndrome and left lung agenesis.

LACHT (Lung Agenesis, Congenital Heart, and Thumb anomalies) syndrome is an extremely rare congenital anomaly and presents significant challenges in adults due to its poor survival rates. Herein, we report a case of late diagnosis and successful transcatheter treatment of aortic coarctation in a 58-year-old male patient with LACHT syndrome, medically resistant arterial hypertension, and left lung agenesis. Baseline CT angiography showed isthmic aortic coarctation and left lung agenesis, with compensatory right pulmonary artery and vein thickenings. The patient underwent balloon dilation and subsequent implantation of a covered NuMED 45 mm 8-ZIG CP stent with satisfactory outcomes. The pressure gradient decreased from 43 to 23 mmHg. The arterial pressures normalized during the follow-up with fewer medications. Genetic testing identified a heterozygous mutation (c.6583C > T) in the FBN2, supporting the diagnosis of variant Marfan syndrome.

NELL2 as a potential marker of outcome in the cerebrospinal fluid of patients with tuberculous meningitis: preliminary results from a single-center observational study.

OBJECTIVE: To detect the changes in Nel-like 2 (NELL2) in cerebrospinal fluid (CSF) in the outcome of tuberculous meningitis (TBM) patients and to initially evaluate its potential as a marker. METHODS: We collected the clinical data of patients with suspected TBM in the First People's Hospital of Zunyi from November 2017 to January 2021 and retained their CSF. According to the selection and exclusion criteria, the TBM group (11 cases) and the control group (18 cases) were obtained. Western blotting (WB) was used to detect the level of NELL2 in the CSF of the two groups, especially the change in NELL2 before and after treatment in TBM patients. RESULTS: The level of NELL2 in the TBM group was lower than that in the control group (P < 0.05), and the level of NELL2 showed an increasing trend after anti-tuberculosis treatment in the TBM group. CONCLUSIONS: NELL2 in the CSF of TBM patients decreased significantly. Anti-tuberculosis treatment can improve the level of NELL2, which may become one of the potential markers of outcome in the cerebrospinal fluid of patients with tuberculous meningitis.

Effect of icaritin on autophagy-related protein expression in TDP-43-transfected SH-SY5Y cells.

Objective: To study the protective effect and mechanism of icaritin (ICT) in a SH-SY5Y cells with virus-loaded TAR DNA-binding domain protein 43(TDP-43) by examining the effect of ICT on the expression of autophagy-related proteins in TDP-43-infected SH-SY5Y cells. Methods: A TDP-43-induced neuronal cell injury model was established by transfecting well-growing SH-SY5Y cells with virus loaded with the TDP-43 gene. The changes in cell viability were detected by the CCK-8 method. After successful transfection, the establishment of the model was verified by real-time quantitative PCR (qPCR) and Western blot methods. After the cells were subjected to drug intervention with ICT, the changes in the expression levels of TDP-43, cleaved Caspase-3, LC3 II/I, Beclin-1 and p62 were detected by Western blotting. Results: After ICT intervention, it was found that compared with that of the TDP-43 group, the cell viability of the TDP-43+ICT group increased, the expression level of TDP-43 decreased, and the expression levels of the apoptotic protein cleaved Caspase-3, autophagy protein Beclin-1, and LC3-II/I decreased, while the expression level of the autophagy protein p62 increased. Conclusion: ICT has a protective effect on the SH-SY5Y cell injury model transfected with TDP-43. This protective effect may be related to reducing the protein expression of TDP-43 and inhibiting autophagy.

Misdiagnosis of HIV With Toxoplasmosis Encephalopathy With Progressive Memory Loss as the Initial Symptom: A Case Report.

Toxoplasmosis encephalopathy (TE) is a kind of encephalopathy parasitic disease caused by Toxoplasma gondii. It is the most common opportunistic for central system infection in patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus. Without early diagnosis and proper treatment, this opportunistic infection can be life-threatening. The common clinical manifestations of the disease include altered mental state, epilepsy, cranial nerve damage, paresthesia, cerebellar signs, meningitis, motor disorders, and neuropsychiatry. The most common presentation in about 75% of cases is a subacute episode of focal neurological abnormalities such as hemiplegia, personality changes, or aphasia. Imaging needs to be differentiated from multiple sclerosis, lymphoma, and metastases. We report a case of acquired immune deficiency syndrome complicated with toxoplasma encephalopathy with rapid progressive memory loss as the initial symptom and misdiagnosed as multiple sclerosis. Through the comprehensive analysis of the clinical symptoms and imaging examination of this disease, we hope to enhance the confidence of clinicians in the diagnosis of this disease.

Endoscope ear pick: An emerging but neglected medical device.

Earwax (cerumen), a normal bodily secretion, can become a problem when it obstructs the ear canal. Earwax removal is a difficult task for specialists because of the ear's unique location and the ear canal's intricate structure. Using ear scoops or cotton swabs to dig out ear wax in daily life is like "a blind man walking on a cliff." Improper operation may damage the ear canal or the eardrum. Thus, we need a pair of visible "eyes," otoscopes, to help us see earwax intuitively. As opposed to traditional otoscopes, which only serve as a visual aid, the endoscopic ear pick allows us to not only view the ear canal but also remove wax or other obstructions from the ear. In this review, we discussed endoscope ear pick pros and cons and discussed their future role.