Combined Genetic Association and Differed Expression Analysis of UBE2L3 Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy.

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN. Methods: We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored. Results: The rs131654 showed the most significant association signal in UBE2L3 region (OR: 1.10, 95% CI: 1.04-1.16, p = 2.29 × 10-3), whose genotypes were also associated with the levels of Gd-IgA1 (p = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, p = 0.01) and lower eGFR (r = -0.28, p = 0.04), but also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1. Conclusion: In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.

Idiopathic young-onset Fahr's disease with schizophrenia-like presentation: a case report.

This case report describes an exceptionally rare case in which a prior diagnosis of schizophrenia was later determined to be early-onset Fahr's disease, linked to a genetic mutation in the SLC20A2 gene. Initially, the patient exhibited symptoms resembling schizophrenia, including aggression and hostility, and was highly susceptible to medication side effects such as restlessness and Parkinsonism. Despite maintaining independent activities of daily living, his neurological examinations revealed hidden weakness on the left side. Following adjustments to the medication regimen, stability was achieved with residual psychotic symptoms under treatment with Risperidone 1.5mg/day, Valproic acid 1500mg/day, and Quetiapine 37.5mg/day. This case underscores the importance of conducting comprehensive imaging studies at the time of initial psychiatric diagnosis, regardless of the apparent typicality of the presentation. Additionally, it emphasizes the need for patience and adherence to the "Start Low and Go Slow" approach in medication management to minimize the risk of exacerbating psychiatric symptoms and aggression.

Loss of Lipocalin2 confers cisplatin vulnerability through modulating NF-ĸB mediated ferroptosis via ferroportin.

Cisplatin is a widely used anti-cancer drug. Unfortunately, many cancers often develop resistance, which contributes to tumor recurrence and poorly prognosis. Growing knowledge has suggested the therapeutic potential of ferroptosis in cancer. Lipocalin2 (LCN2) is demonstrated to be a critical iron metabolic factor and implies in ferroptosis. Here, we aim to explore its role in chemotherapy resistance. The influence of LCN2 on colorectal cancer (CRC) cell chemoresistance and ferroptosis were evaluated by in vitro and in vivo approaches. The interaction between LCN2, NF-ĸB and ferroportin (FPN) was assessed by western blots, immunohistochemistry and dual luciferase reporter assays. Results showed that LCN2 was highly expressed in tumor regression grade 1 (TRG1) cases than that in TRG3 specimens. Loss of LCN2 contributed to resistance to cisplatin-induced ferroptosis. Mechanistically, loss of LCN2 inhibited cisplatin sensitivity and cisplatin-induced ferroptosis through elevating FPN expression which was regulated by NF-ĸB, subsequently reducing Fe2+ mediated Fenton reaction. Furthermore, FPN expression rate was much lower in TRG1 cases, and negative correlation between LCN2 and FPN expression was observed in clinical specimens. Collectively, low LCN2 expression enhances insensitivity of cisplatin to CRC cells via Fenton reaction mediated ferroptosis. LCN2/NF-ĸB/FPN pathway might be potentially utilized for chemoresistance strategy. LCN2 and FPN expression might be a promising biomarker of chemotherapy effect for CRC patients.

Generalized Confidence Intervals for Ratios of Standard Deviations Based on Log-Normal Distribution when Times Follow Weibull Distributions.

Modern anesthetic drugs ensure the efficacy of general anesthesia. Goals include reducing variability in surgical, tracheal extubation, post-anesthesia care unit, or intraoperative response recovery times. Generalized confidence intervals based on the log-normal distribution compare variability between groups, specifically ratios of standard deviations. The alternative statistical approaches, performing robust variance comparison tests, give P-values, not point estimates nor confidence intervals for the ratios of the standard deviations. We performed Monte-Carlo simulations to learn what happens to confidence intervals for ratios of standard deviations of anesthesia-associated times when analyses are based on the log-normal, but the true distributions are Weibull. We used simulation conditions comparable to meta-analyses of most randomized trials in anesthesia, n ≈ 25 and coefficients of variation ≈ 0.30 . The estimates of the ratios of standard deviations were positively biased, but slightly, the ratios being 0.11% to 0.33% greater than nominal. In contrast, the 95% confidence intervals were very wide (i.e., > 95% of P ≥ 0.05). Although substantive inferentially, the differences in the confidence limits were small from a clinical or managerial perspective, with a maximum absolute difference in ratios of 0.016. Thus, P < 0.05 is reliable, but investigators should plan for Type II errors at greater than nominal rates.

Regulate the Solvation Structure and Interface by Nitrate in Phosphate-Based Electrolytes for 4.5 V-Class Ni-Rich Batteries.

Phosphate-based electrolyte propels the advanced battery system with high safety. Unfortunately, restricted by poor electrochemical stability, it is difficult to be compatible with advanced lithium metal anodes and Ni-rich cathodes. To alleviate these issues, the study has developed a phosphate-based localized high-concentration electrolyte with a nitrate-driven solvation structure, and the nitrate-derived N-rich inorganic interface shows excellent performance in stabilizing the LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode interface and modulating the lithium deposition morphology on the anode. The results show that the Li|| NCM811 cell has exceptional long-cycle stability of >80% capacity retention after 800 cycles at 4.3 V, 1 C. A more prominent capacity retention rate of 93.3% after 200 cycles can be reached with the high voltage of 4.5 V. While being compatible with the phosphate-based electrolyte with good flame retardancy and the good electrochemical stability of Ni-rich lithium metal battery (LMBs) systems, the present work expands the construction of anion-rich solvation structures, which is expected to promote the development of the high-performance LMBs with safety.

Characteristics of "do not resuscitate" orders among elderly patients receiving mechanical ventilation in the intensive care unit in Taiwan.

Objective: As patient life expectancy has increased and people are living longer than before, the rate of mechanical ventilation among elderly patients in the intensive care unit has increased. Older patients who receive mechanical ventilation and have multiple comorbidities are more likely to have a do not resuscitate order than are younger patients with fewer comorbidities. The aim of our study was to describe the patient characteristics and predictive factors of do not resuscitate orders during hospitalization among elderly patients who received ventilation in the intensive care unit. Methods: This was a retrospective review of the electronic medical records of patients in the intensive care unit of a teaching hospital in southern Taiwan. We enrolled patients admitted to the general intensive care unit from January 1, 2018, to September 31, 2020, and patients older than 80 years who experienced respiratory failure, were intubated and received mechanical ventilation. We analyzed patient demographics, disease severity during hospitalization and comorbidities. If a patient had multiple admissions to the intensive care unit, only the first admission was recorded. Results: Of the 305 patients over 80 years of age with respiratory failure who were intubated and placed on a ventilator, 66 were excluded because of incomplete data, and 13 were excluded because they had already signed a do not resuscitate order prior to admission to the hospital. Ultimately, 226 patients were included in this study. A higher acute physiology and chronic health evaluation II score (>30) was also associated with an increased likelihood of a do not resuscitate order (odds ratio (OR) = 3.85, 95% CI = 1.09-13.62, p = 0.0362). Patients who had acute kidney injury or cerebrovascular accident were more likely to have a do not resuscitate order (OR = 2.74, 95% CI = 1.03-7.28, p = 0.0428 and OR = 7.32, 95% CI = 2.02-26.49, p = 0.0024, respectively). Conclusion: Our study showed that older age, greater disease severity, and certain critical interventions were associated with a greater propensity for do not resuscitate orders, which is crucial for understanding patient preferences and guiding end-of-life care discussions. These findings highlight the importance of clinical severity and specific health events in predicting end-of-life care preferences in older patient groups.

Period measurement of a periodic structure by using a heterodyne grating interferometer.

This paper proposes an alternative method for grating period measurement based on heterodyne grating interferometry. The optical configurations for measuring the period of reflection/transmission gratings were demonstrated, and four commercially available gratings were used to evaluate the effectiveness of the proposed method. Based on the phase-lock technique, the grating period could be obtained immediately through the phase wrapped/unwrapped process. Under precise measurement conditions, the grating period measurement error of the proposed method was better than 1 nm, and the grating period difference between product specifications was less than 1%. In addition, the measurement results of the proposed method also exhibited high similarity with optical microscopy measurements.

High prevalence of exon-13 variants in USH2A-related retinal dystrophies in Taiwanese population.

BACKGROUND: Biallelic pathogenic variants in USH2A lead to Usher syndrome or non-syndromic retinitis pigmentosa, and shown to have geographical and ethnical distribution in previous studies. This study provided a deeper understanding of the detailed clinical features using multimodal imaging, genetic spectrum, and genotype-phenotype correlations of USH2A-related retinal dystrophies in Taiwan. RESULTS: In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset, which was referred to the onset of nyctalopia and/or visual field constriction, was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splicing variants, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T>G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and seemly poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T>G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference. CONCLUSIONS: This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A-related retinal dystrophies in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T>G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies.

Epitranscriptomic cytidine methylation of the hepatitis B viral RNA is essential for viral reverse transcription and particle production.

Epitranscriptomic RNA modifications have emerged as important regulators of the fate and function of viral RNAs. One prominent modification, the cytidine methylation 5-methylcytidine (m5C), is found on the RNA of HIV-1, where m5C enhances the translation of HIV-1 RNA. However, whether m5C functionally enhances the RNA of other pathogenic viruses remains elusive. Here, we surveyed a panel of commonly found RNA modifications on the RNA of hepatitis B virus (HBV) and found that HBV RNA is enriched with m5C as well as ten other modifications, at stoichiometries much higher than host messenger RNA (mRNA). Intriguingly, m5C is mostly found on the epsilon hairpin, an RNA element required for viral RNA encapsidation and reverse transcription, with these m5C mainly deposited by the cellular methyltransferase NSUN2. Loss of m5C from HBV RNA due to NSUN2 depletion resulted in a partial decrease in viral core protein (HBc) production, accompanied by a near-complete loss of the reverse transcribed viral DNA. Similarly, mutations introduced to remove the methylated cytidines resulted in a loss of HBc production and reverse transcription. Furthermore, pharmacological disruption of m5C deposition led to a significant decrease in HBV replication. Thus, our data indicate m5C methylations as a critical mediator of the epsilon elements' function in HBV virion production and reverse transcription, suggesting the therapeutic potential of targeting the m5C methyltransfer process on HBV epsilon as an antiviral strategy.

Combined Hounsfield units of hepatocellular carcinoma on computed tomography and PET as a noninvasive predictor of early recurrence after living donor liver transplantation: Time-to-recurrence survival analysis.

BACKGROUND: Liver transplantation is an effective treatment for preventing hepatocellular carcinoma (HCC) recurrence. This retrospective study aimed to quantitatively evaluate the attenuation in Hounsfield units (HU) on contrast-enhanced computed tomography (CECT) as a prognostic factor for hepatocellular carcinoma (HCC) following liver transplantation as a treatment. Our goal is to optimize its predictive ability for early tumor recurrence and compare it with the other imaging modality-positron emission tomography (PET). METHODS: In 618 cases of LDLT for HCC, only 131 patients with measurable viable HCC on preoperative CECT and preoperative positron emission tomography (PET) evaluations were included, with a minimum follow-up period of 6 years. Cox regression models were developed to identify predictors of postoperative recurrence. Performance metrics for both CT and PET were assessed. The correlation between these two imaging modalities was also evaluated. Survival analyses were conducted using time-dependent receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) to assess accuracy and determine optimized cut-off points. RESULTS: Univariate and multivariate analyses revealed that both arterial-phase preoperative tumor attenuation (HU) and PET were independent prognostic factors for recurrence-free survival. Both lower arterial tumor enhancement (Cut-off value = 59.2, AUC 0.88) on CT and PET positive (AUC 0.89) increased risk of early tumor recurrence 0.5-year time-dependent ROC. Composites with HU < 59.2 and a positive PET result exhibited significantly higher diagnostic accuracy in detecting early tumor recurrence (AUC = 0.96). CONCLUSION: Relatively low arterial tumor enhancement values on CECT effectively predict early HCC recurrence after LDLT. The integration of CT and PET imaging may serve as imaging markers of early tumor recurrence in HCC patients after LDLT.

Association between physical activity, body composition, and cognitive performance among female office workers.

Regular physical activity can potentially prevent cognitive decline. While most studies focused on the general decline of the elderly and child and adolescent population, aging is a gradual process and cognitive decline can commence in middle age. Other than the middle-aged working population, gender-specific nuances are another overlooked area regarding the relationship between physical activity and cognitive performance. Therefore, this study examines the associations and benefits of maintaining regular physical activity habits with cognitive function and body composition in middle-aged female office workers. The results show that middle-aged females exhibited age-related declines in working memory, while no significant age-related changes are observed in reaction time and executive function. However, the regular exercise group demonstrates the ability to maintain their cognitive performance across age, unlike the sedentary group, who experiences declines in reaction time and executive function with age. Our findings highlight the significant impact of age on specific cognitive functions in middle-aged females and the positive influence of regular exercise on cognitive performance. Furthermore, this study demonstrates the potential of "the Brain Gym" App for efficient cognitive function assessment. The findings underscore the importance of regular exercise for cognitive well-being in middle-aged females and provide valuable insights into the relationship between body composition and cognitive function.

Clinical Application of Polygenic Risk Score in IgA Nephropathy.

Genome-wide association studies (GWASs) have identified 30 independent genetic variants associated with IgA nephropathy (IgAN). A genetic risk score (GRS) represents the number of risk alleles carried and thus captures an individual's genetic risk. However, whether and which polygenic risk score crucial for the evaluation of any potential personal or clinical utility on risk and prognosis are still obscure. We constructed different GRS models based on different sets of variants, which were top single nucleotide polymorphisms (SNPs) reported in the previous GWASs. The case-control GRS analysis included 3365 IgAN patients and 8842 healthy individuals. The association between GRS and clinical variability, including age at diagnosis, clinical parameters, Oxford pathology classification, and kidney prognosis was further evaluated in a prospective cohort of 1747 patients. Three GRS models (15 SNPs, 21 SNPs, and 55 SNPs) were constructed after quality control. The patients with the top 20% GRS had 2.42-(15 SNPs, p = 8.12 × 10-40), 3.89-(21 SNPs, p = 3.40 × 10-80) and 3.73-(55 SNPs, p = 6.86 × 10-81) fold of risk to develop IgAN compared to the patients with the bottom 20% GRS, with area under the receiver operating characteristic curve (AUC) of 0.59, 0.63, and 0.63 in group discriminations, respectively. A positive correlation between GRS and microhematuria, mesangial hypercellularity, segmental glomerulosclerosis and a negative correlation on the age at diagnosis, body mass index (BMI), mean arterial pressure (MAP), serum C3, triglycerides can be observed. Patients with the top 20% GRS also showed a higher risk of worse prognosis for all three models (1.36, 1.42, and 1.36 fold of risk) compared to the remaining 80%, whereas 21 SNPs model seemed to show a slightly better fit in prediction. Collectively, a higher burden of risk variants is associated with earlier disease onset and a higher risk of a worse prognosis. This may be informational in translating knowledge on IgAN genetics into disease risk prediction and patient stratification. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00138-6.

Polymorphism of CYP3A4*18 is associated with anti-tuberculosis drug-induced hepatotoxicity.

Aim: The association between cytochrome P450 (CYP) gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity (ATDH) was investigated in patients with or without pre-existing liver diseases (PLD). Materials & methods: We followed 164 tuberculosis subjects, 58 with PLD and 106 without PLD. Polymorphisms in CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 were analyzed using the TaqMan® SNP genotyping assay. Results: The CYP3A4*18 heterozygous genotype was associated with ATDH (OR: 3.24, 95% CI: 1.06-9.86) regardless of PLD presence. Among subjects without PLD, CYP3A4*18 heterozygotes had significantly higher ATDH risk (OR: 9.10, 95% CI: 1.56-53.16). Conversely, in the PLD group, CYP3A4*18 heterozygotes had lower ATDH risk (OR: 0.21, 95% CI: 0.05-0.98). Conclusion: CYP3A4*18 genotype is linked to ATDH in tuberculosis patients, with differential effects based on PLD presence.

[Box: see text].

Integrated multi-omics analyses revealed the association between rheumatoid arthritis and colorectal cancer: MYO9A as a shared gene signature and an immune-related therapeutic target.

BACKGROUND: Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC). METHODS: Mendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors. RESULTS: MR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01-1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers. CONCLUSION: RA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.

Corrigendum: Distinct characteristics and prognosis of IgA nephropathy patients with nephrotic syndrome: a propensity score-matched cohort study.

[This corrects the article DOI: 10.3389/fmed.2024.1344219.].

Enlarged perivascular spaces in alcohol-related brain damage induced by dyslipidemia.

Perivascular spaces (PVSs) as the anatomical basis of the glymphatic system, are increasingly recognized as potential imaging biomarkers of neurological conditions. However, it is not clear whether enlarged PVSs are associated with alcohol-related brain damage (ARBD). We aimed to investigate the effect of long-term alcohol exposure on dyslipidemia and the glymphatic system in ARBD. We found that patients with ARBD exhibited significantly enlargement of PVSs in the frontal cortex and basal ganglia, as well as a notable increased levels of total cholesterol (TC) and triglycerides (TG). The anatomical changes of the glymphatic drainage system mentioned above were positively associated with TC and TG. To further explore whether enlarged PVSs affects the function of the glymphatic system in ARBD, we constructed long alcohol exposure and high fat diet mice models. The mouse model of long alcohol exposure exhibited increased levels of TC and TG, enlarged PVSs, the loss of aquaporin-4 polarity caused by reactive astrocytes and impaired glymphatic drainage function which ultimately caused cognitive deficits, in a similar way as high fat diet leading to impairment in glymphatic drainage. Our study highlights the contribution of dyslipidemia due to long-term alcohol abuse in the impairment of the glymphatic drainage system.

A Self-Delivery Nanodrug Simultaneously Inhibits COX-2/PGE2 Mediated Inflammation and Downregulates PD-L1 to Boost Photoimmunotherapy.

Phototherapy promotes anti-tumor immunity by inducing immunogenic cell death (ICD), However, the accompanying inflammatory responses also trigger immunosuppression, attenuating the efficacy of photo-immunotherapy. Herein, they co-assembled a cell-membrane targeting chimeric peptide C16-Cypate-RRKK-PEG8-COOH (CCP) and anti-inflammatory diclofenac (DA) to develop a nanodrug (CCP@DA) that both enhances the immune effect of phototherapy and weakens the inflammation-mediated immunosuppression. CCP@DA achieves cell membrane-targeting photodynamic and photothermal synergistic therapies to damage programmed death ligand 1 (PD-L1) and induce a strong ICD to activate anti-tumor response. Simultaneously, the released DA inhibits the cycoperoxidase-2 (COX-2)/prostaglandin E2 (PGE2) pathway in tumor cells to inhibit pro-tumor inflammation and further down-regulate PD-L1 expression to relieve the immunosuppressive microenvironment. CCP@DA significantly inhibited tumor growth and inflammation both in vitro and in vivo, while maintaining a potent anti-tumor immune response. Additionally, it exhibits excellent anti-metastatic capabilities and prolongs mouse survival time with a single dose and low levels of near-infrared (NIR) light exposure. This work provides a valuable strategy to control the therapy-induced inflammation for high-efficiency photoimmunotherapy.

Increased Long-Term Risk of Dementia in Patients With Carbon Monoxide Poisoning: A Systematic Review and Meta-Analysis of Cohort Studies.

OBJECTIVE: To assess whether carbon monoxide (CO) poisoning increases the incidence of dementia. METHODS: We searched the Cochrane Library, PubMed, and EMBASE from inception to 14 August 2022. Two authors independently selected studies, assessed the quality of included studies, and extracted data. Any disagreement was resolved by discussion with a third author. Only cohort study with an enough follow-up period was included for systematic reviews and meta-analysis. RESULTS: Thirty-three full texts were initially searched, but only three studies met our inclusion criteria, and they were comprised of 134,563 participants who were initially free of dementia. The follow-up period ranged from 9 to 12 years. We found that CO poisoning increased the risk of dementia incidence (adjusted hazard ratio 2.61, 95% confidence interval 1.56 to 4.36, p=0.0003). Subgroup analysis showed that the increased dementia risk was significant in males but not in females, and the highest risk was in young age group, followed by in middle age group, but not in the old one. CONCLUSION: Overall the evidence from prospective cohort studies supported a link between CO exposure and an increased dementia risk, although all the included studies were limited to Taiwanese population.

Role of Exercise on Inflammation Cytokines of Neuropathic Pain in Animal Models.

Neuropathic pain (NP) resulting from a lesion or disease of the somatosensory system can lead to loss of function and reduced life quality. Neuroinflammation plays a vital role in the development and maintenance of NP. Exercise as an economical, effective, and nonpharmacological treatment, recommended by clinical practice guidelines, has been proven to alleviate chronic NP. Previous studies have shown that exercise decreases NP by modifying inflammation; however, the exact mechanisms of exercise-mediated NP are unclear. Therefore, from the perspective of neuroinflammation, this review mainly discussed the effects of exercise on inflammatory cytokines in different parts of NP conduction pathways, such as the brain, spinal cord, dorsal root ganglion, sciatic nerve, and blood in rat/mice models. Results suggested that exercise training could modulate neuroinflammation, inhibit astrocyte glial cell proliferation and microglial activation, alter the macrophage phenotype, reduce the expression of proinflammatory cytokines, increase anti-inflammatory cytokine levels, and positively modulate the state of the immune system, thereby relieving NP.

Oral administration of Lactobacillus delbrueckii subsp. lactis LDL557 attenuates airway inflammation and changes the gut microbiota in a Der p-sensitized mouse model of allergic asthma.

BACKGROUND: Lactic acid bacteria may be used as probiotics to prevent or treat various diseases, and Lactobacillus delbrueckii has an inhibitory effect on the development of atopic diseases. OBJECTIVE: This study explored the effects of L. delbrueckii subsp. lactis strain LDL557 administration on a mouse asthma model resulting from Dermatophoides pteronyssinus (Der p) sensitization and investigated the associated gut microbiota. METHODS: Der p-sensitized and challenged BALB/c mice were orally administered with three different doses of live (low, 107 colony-forming units (CFU); medium, 108 CFU; high, 109 CFU) and heat-killed (109 cells) LDL557 in 200 µL of PBS daily, starting 2 weeks before Der p sensitization and lasting 4 weeks. After the allergen challenge, airway responsiveness to methacholine and the influx of inflammatory cells to the lungs were assessed. The gut microbiome was obtained by sequencing the V3-V4 region of the 16S rRNA gene from mice stool samples. RESULTS: LDL557 in the live (109 CFU) and heat-killed (109 cells) conditions reduced the airway hyper-responsiveness after stimulation with methacholine, inflammatory cell infiltration, and mucus production. These effects were similar to those in groups treated with dexamethasone. No significant change in the gut microbiota was observed after LDL557 treatment, except for the tendency of heat-killed LDL557 to change the gut microbial profile to a greater extent than live LDL557. CONCLUSION: In summary, we found that live and heat-killed LDL557 had the beneficial effect of preventing Der p-induced allergic inflammation in a mouse model of asthma.