Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Relation of poverty with treatment-seeking behavior and antibiotic misuse among UTI patients in Pakistan.

Objective: The current study aimed to assess the relation between multi-dimension poverty, treatment-seeking behavior, and antibiotic misuse among urinary tract infection (UTI) patients. Method: A cross-sectional approach was utilized to recruit patients who had a history of UTI in the previous month from two provinces of Pakistan. The treatment-seeking behavior and antibiotic misuse data were collected on a self-developed questionnaire, whereas the poverty data were collected on a modified multi-dimension poverty index (MPI). Descriptive statistics were applied to summarize the data. The logistic regression analysis was carried out to assess the association of multi-dimension poverty with patient treatment-seeking behavior and antibiotic misuse. Results: A total of 461 participants who had UTI symptoms in the previous month were recruited. Most of the participants in the severely deprived stage treated the UTI (p < 0.001); however, there was a high proportion of the participants who consulted with friends and family for UTI treatment (p < 0.001). The patients with deprivation status (deprived and severely deprived) were less associated with formal consultation. The poorer subgroups were less likely to practice antibiotic course completion. Conclusion: The current study highlighted that poverty plays an important role in antibiotic misuse. Poorer subgroups were associated with informal consultations and the incompletion of the antibiotic course. Further studies are needed to explore the potential role of poverty in treatment-seeking behavior and antibiotic misuse.

Prevalence and clinical features of carotid artery web in patients undergoing endovascular thrombectomy for acute ischemic stroke.

PURPOSE: Carotid artery web (CaW) is a rare focal fibromuscular dysplasia that can lead to embolic strokes with large vessel occlusion. This condition can be effectively treated with endovascular thrombectomy (EVT). Our study aims to assess the prevalence of CaW among patients with acute ischemic stroke (AIS) who underwent EVT and to compare the clinical characteristics of CaW with other carotid artery pathologies. METHODS: We enrolled consecutive patients with AIS who underwent EVT at a single medical center and two regional teaching hospitals in Taiwan from September 2014 to December 2021. We compared CaW with carotid dissection (CaD) and carotid large artery atherosclerosis (CaLAA) in terms of patient demographics and thrombus histological findings. RESULTS: Of the 576 AIS patients who underwent EVT, four (mean age: 50 years) were diagnosed with CaW, resulting in a prevalence of 0.69%. Among these four patients, three experienced successful reperfusion after EVT and achieved functional independence (defined as a modified Rankin Scale score ≤2) three months post-stroke. Importantly, none of the CaW patients suffered a recurrent stroke within one year. Patients with CaW were younger than those with CaD or CaLAA, and exhibited fewer vascular risk factors. Additionally, CaW was associated with distal occlusion sites. The thrombus composition in CaW patients was similar to that in CaD patients. CONCLUSIONS: In conclusion, CaW is a rare finding among Asian patients with carotid artery disease who undergo for AIS. It is more prevalent in younger patients with a limited number of vascular risk factors.

Insights into the fish protein degradation induced by the fish-borne spoiler Pseudomonas psychrophila and Shewanella putrefaciens: From whole genome sequencing to quality changes.

The aim of this study is evaluating the protein degradation capacity of specific spoilage organisms (SSOs) Pseudomonas psychrophila and Shewanella putrefaciens in fish flesh during chilled storage and revealing the underlying genes by whole-genome sequencing (WGS). Biochemical and physical tests were performed on fish flesh inoculated with P. psychrophila and S. putrefaciens individually, including textural properties, myofibrillar fragmentation index, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) profiles, free amino acid composition, total volatile basic nitrogen (TVB-N), trichloroacetic acid (TCA) soluble peptides, and muscle microstructure. Results showed that P. psychrophila and S. putrefaciens exhibited a strong capacity for decomposing the fish protein, and the deterioration of fish flesh texture was primarily attributed to P. psychrophila. The genes from SSOs associated with the production of proteases were identified by whole genome sequencing and serine protease may be the primary enzyme secreted by SSOs involved in the degradation of fish protein. Therefore, the present study has shed light on the mechanisms of protein degradation induced by SSOs, thereby offering valuable insights for the development of effective quality control strategies.

Strong cathode electroluminescence biosensor based on CeO2 functionalized PCN-222@Ag NPs for sensitive detection of p-Tau-181 protein.

Electrochemiluminescence (ECL) biosensors provide a convenient and high sensitivity method for early disease diagnosis. However, creating luminophore arrays relying on powerful ECL signals remains a daunting task. Porphyrin-centered metal organic frameworks (MOFs) exhibit remarkable potential in ECL sensing applications. In this paper, based on a simple one-pot synthesis method, PCN-222@Ag NPs doped with CeO2 was synthesized to enhance the ECL performance. Due to the strong catalytic ability of CeO2, the ECL signal strength of the new material PCN-222@CeO2@Ag NPs is much higher than that of the PCN-222@Ag NPs and PCN-222. The luminous properties of PCN-222@CeO2@Ag NPs become more intense and stable due to the excellent electronic conductivity of Ag NPs. Based on the fact that CuS@PDA composite can quench the ECL signal of PCN-222@CeO2@Ag NPs, we constructed a novel sandwich ECL immune sensor for the detection of phosphorylated Tau 181 (p-Tau-181) protein. The ECL sensor has a great linear relationship with p-Tau-181 protein concentration, ranging from 1 pg/mL to 100 ng/mL. The detection limit is as low as 0.147 pg/mL. This work provides new ideas for developing sensitive ECL sensors for the p-Tau-181 protein, the marker of Alzheimer's disease.

Necroptosis pathway emerged as potential diagnosis markers in spinal cord injury.

The present research focused on identifying necroptosis-related differentially expressed genes (NRDEGs) in spinal cord injury (SCI) to highlight potential therapeutic and prognostic target genes in clinical SCI. Three SCI-related datasets were downloaded, including GSE151371, GSE5296 and GSE47681. MSigDB and KEGG datasets were searched for necroptosis-related genes (NRGs). Differentially expressed genes (DEGs) and NRGs were intersected to obtain NRDEGs. The MCC algorithm was employed to select the first 10 genes as hub genes. A protein-protein interaction (PPI) network related to NRDEGs was developed utilizing STRING. Several databases were searched to predict interactions between hub genes and miRNAs, transcription factors, potential drugs, and small molecules. Immunoassays were performed to identify DEGs using CIBERSORTx. Additionally, qRT-PCR was carried out to verify NRDEGs in an animal model of SCI. Combined analysis of all datasets identified 15 co-expressed DEGs and NRGs. GO and KEGG pathway analyses highlighted DEGs mostly belonged to pathways associated with necroptosis and apoptosis. Hub gene expression analysis showed high accuracy in SCI diagnosis was associated with the expression of CHMP7 and FADD. A total of two hub genes, i.e. CHMP7, FADD, were considered potential targets for SCI therapy.

Ruxolitinib improves the inflammatory microenvironment, restores glutamate homeostasis, and promotes functional recovery after spinal cord injury.

JOURNAL/nrgr/04.03/01300535-202419110-00030/figure1/v/2024-03-08T184507Z/r/image-tiff The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury. Ruxolitinib, a JAK-STAT inhibitor, exhibits effectiveness in autoimmune diseases, arthritis, and managing inflammatory cytokine storms. Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma, the exact mechanism by which it enhances functional recovery after spinal cord injury, particularly its effect on astrocytes, remains unclear. To address this gap, we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury. Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury, restored EAAT2 expression, reduced glutamate levels, and alleviated excitatory toxicity. Furthermore, ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Additionally, in glutamate-induced excitotoxicity astrocytes, ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3, thereby reducing glutamate-induced neurotoxicity, calcium influx, oxidative stress, and cell apoptosis, and increasing the complexity of dendritic branching. Collectively, these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes, reduces neurotoxicity, and effectively alleviates inflammatory and immune responses after spinal cord injury, thereby promoting functional recovery after spinal cord injury.

[Characteristics of anion and cation in rhizosphere soil of saline grassland in North China under different nitrogen addition levels]. / ä¸åŒæ°´å¹³æ°®æ·»åŠ ä¸‹åŽåŒ—ç›æ¸åŒ–è‰åœ°æ ¹é™ åœŸå£¤é˜´é˜³ç¦»å­ç‰¹å¾.

We investigated the effects and mechanisms of nitrogen additions (0, 1, 2, 4, 8, 16, 24, 32 g N·m-2·a-1) on contents of anion and cation in rhizosphere soil, bulk soil, and mixed rhizosphere and bulk soil in the heavily salinized grassland in the agro-pastoral ecotone of North China. The results showed that pH of rhizosphere, mixed and bulk soils decreased significantly with the increases of nitrogen addition levels. Moreover, pH of three soil types under the 32 g N·m-2·a-1 treatment decreased by 1.2, 0.9, and 0.6, respectively, while pH of rhizosphere soil decreased by 0.44 compared with the bulk soil. Na+ content of rhizosphere, mixed and bulk soils significantly decreased, while the NO3- content significantly increased. The proportion of Na+ content in total soluble salt content in rhizosphere soil decreased by 14% and that in bulk soil decreased by 12% after the 32 g N·m-2·a-1 addition. NO3- content increased by 29% in rhizosphere soil and by 26% in bulk soil. There was significant negative correlation between pH and NO3- content, and significant positive correlation between pH and Na+ content. The total soluble salt content of rhizosphere soil under the 32 g N·m-2·a-1 treatment was significantly reduced by 31.5%. Collectedly, nitrogen deposition could reduce soil pH and total soluble salt content of rhizosphere soil and alleviate saline-alkali stress.

Fucoxanthin induces human melanoma cytotoxicity by thwarting the JAK2/STAT3/BCL-xL signaling axis.

Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes. Apoptosis is a primary reason for Fucoxanthin's melanoma cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk drastically abrogated Fucoxanthin-elicited clonogenicity blockage. Besides, Fucoxanthin downregulated tyrosine 705-phosphorylated STAT3 (p-STAT3 (Y705)), either inherently present in melanoma cells or inducible by interleukin 6 (IL-6) stimulation. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, abolished Fucoxanthin-elicited melanoma cell apoptosis and clonogenicity inhibition, supporting the pivotal role of STAT3 blockage in Fucoxanthin's melanoma cytotoxicity. Moreover, Fucoxanthin lowered BCL-xL levels by blocking STAT3 activation, while ectopic BCL-xL expression rescued melanoma cells from Fucoxanthin-induced killing. Lastly, Fucoxanthin was found to diminish the levels of JAK2 with dual phosphorylation at tyrosine residues 1007 and 1008 in melanoma cells, suggesting that Fucoxanthin impairs STAT3 signaling by blocking JAK2 activation. Collectively, we present the first evidence that Fucoxanthin is cytotoxic selectively against human melanoma cells while sparing normal melanocytes. Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.

Predictive value of bilirubin and serum γ-glutamyltranspeptidase levels in type-2 diabetes mellitus patients with acute coronary syndrome.

BACKGROUND: Cardiovascular disease is a major complication of diabetes mellitus (DM). Type-2 DM (T2DM) is associated with an increased risk of cardiovascular events and mortality, while serum biomarkers may facilitate the prediction of these outcomes. Early differential diagnosis of T2DM complicated with acute coronary syndrome (ACS) plays an important role in controlling disease progression and improving safety. AIM: To investigate the correlation of serum bilirubin and γ-glutamyltranspeptidase (γ-GGT) with major adverse cardiovascular events (MACEs) in T2DM patients with ACS. METHODS: The clinical data of inpatients from January 2022 to December 2022 were analyzed retrospectively. According to different conditions, they were divided into the T2DM complicated with ACS group (T2DM + ACS, n = 96), simple T2DM group (T2DM, n = 85), and simple ACS group (ACS, n = 90). The clinical data and laboratory indices were compared among the three groups, and the correlations of serum total bilirubin (TBIL) levels and serum γ-GGT levels with other indices were discussed. T2DM + ACS patients received a 90-day follow-up after discharge and were divided into event (n = 15) and nonevent (n = 81) groups according to the occurrence of MACEs; Univariate and multivariate analyses were further used to screen the independent influencing factors of MACEs in patients. RESULTS: The T2DM + ACS group showed higher γ-GGT, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1c) and lower TBIL and high-density lipoprotein cholesterol levels than the T2DM and ACS groups (P < 0.05). Based on univariate analysis, the event and nonevent groups were significantly different in age (t = 3.3612, P = 0.0011), TBIL level (t = 3.0742, P = 0.0028), γ-GGT level (t = 2.6887, P = 0.0085), LDL-C level (t = 2.0816, P = 0.0401), HbA1c level (t = 2.7862, P = 0.0065) and left ventricular ejection fraction (LEVF) levels (t=3.2047, P = 0.0018). Multivariate logistic regression analysis further identified that TBIL level and LEVF level were protective factor for MACEs, and age and γ-GGT level were risk factors (P < 0.05). CONCLUSION: Serum TBIL levels are decreased and γ-GGT levels are increased in T2DM + ACS patients, and the two indices are significantly negatively correlated. TBIL and γ-GGT are independent influencing factors for MACEs in such patients.

Global, regional, and national temporal trends of diet-related ischemic stroke mortality and disability from 1990 to 2019.

BACKGROUND: Stroke is the second leading cause of death and the third leading cause of disability in the general population worldwide. However, the changing trend of ischemic stroke burden attributable to various dietary risk factors has not been fully revealed and may contribute to a better understanding of stroke epidemiology. AIMS: Our article aimed to evaluate the temporal trend of diet-related ischemic stroke burden to inform future research and policy-making. METHODS: This analysis was based on the data from the Global Burden of Disease (GBD) Study 2019 (spanning years 1990 to 2019), and we used the joinpoint regression to model temporal trends in diet-related ischemic stroke burden across countries and regions of the world during the study period. Six specific dietary factors known to influence stroke risk, including sodium, red meat, fiber, vegetables, whole grains, and fruits, were evaluated in the GBD study to determine their individual and joint impact on ischemic stroke. The changing trend was primarily measured by the average annual percent change (AAPC). Age-standardized rates (ASRs) of mortality and years lived with disability (YLD) per 100,000 population were used to evaluate disease burden. Finally, the socioeconomic background, which was quantified as sociodemographic index (SDI), and its association with diet-related ischemic stroke burden were also explored with the Pearson correlation coefficient. RESULTS: During the study period, the ischemic stroke ASR of mortality attributable to overall dietary risk decreased by an average of 1.6% per year, while the ASR of YLD decreased by an average of 0.2% per year. High sodium diet was still a key driver of diet-related ischemic stroke, accounting for 8.4% and 11.0% of deaths and disabilities, respectively, in 2019. In addition, we found a negative association between temporal evolution of stroke burden and socioeconomic background (r = -0.6603 for mortality and r = -0.4224 for disability, P < 0.001), which suggested that the developing countries with weak social and economic foundation faced greater challenges from the ongoing burden of diet-related strokes compared with developed countries. CONCLUSIONS: Our study found declining trends and revealed the current status of diet-related ischemic stroke mortality and disability. Interdisciplinary countermeasures involving the development of effective food policies, evidence-based guidelines, and public education are needed in the future to combat this global epidemic. DATA ACCESS STATEMENT: The data used for analysis were open-access and can be obtained from https://vizhub.healthdata.org/gbd-results/.

Venetoclax plus daunorubicin and cytarabine in newly diagnosed acute myeloid leukemia patients: A propensity score-matched analysis.

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.

Antioxidant Agriculture for Stress-Resilient Crop Production: Field Practice.

Oxidative stress, resulting from the excessive production of reactive oxygen species, is a common and major cause of cellular damage in plants exposed to various abiotic stresses. To address this challenge, we introduce the concept of antioxidant agriculture as a comprehensive strategy to improve stress tolerance and thus crop productivity by minimizing oxidative stress levels in the field environment. This strategy encompasses a diverse range of approaches, including genetic engineering, the exogenous application of antioxidant agents, microbial inoculation, and agronomic practices, to reinforce the plant's intrinsic antioxidant defense system and mitigate oxidative stress. We present recent successful studies of antioxidant measures that have been validated in field conditions, along with our perspective on achieving antioxidant agriculture.

Proper C/N ratio enhances the effect of plant diversity on nitrogen removal and greenhouse effect mitigation in floating constructed wetlands.

Treating wastewater with low carbon-to-nitrogen (C/N) ratios by constructed wetlands (CWs) is still problematic. Adding chemicals is costly and may cause secondary pollution. Configuring plant diversity in substrate-based CWs has been found to be a better way to treat low-C/N wastewater, but wastewater treatment in floating CWs needs to be studied. In this study, wastewater with C/N ratios of 5 and 10 were set in simulated floating CWs, and 9 combinations with plant species richness (SR) of 1, 3, and 4 were configured. The results showed that (1) increasing SR improved the total N mass removal (NMR) by 29% at a C/N ratio of 5 but not 10; (2) the presence of Oenanthe javanica in the microcosms increased the NMR by 13% and 20% with C/N ratios of 5 and 10, respectively; (3) increasing SR mitigated the net global warming potential (GWP) by 120% at a C/N ratio of 5 but not 10; and (4) a Hemerocallis fulva × O. javanica × Echinodorus parviflours × Iris hybrids mixture resulted in a high NMR and low net GWP. In summary, assembling plant diversity in floating CWs is an efficient and clean measure during the treatment of wastewater with a C/N ratio of 5.

Computationally defined and in vitro validated putative genomic safe harbour loci for transgene expression in human cells.

Selection of the target site is an inherent question for any project aiming for directed transgene integration. Genomic safe harbour (GSH) loci have been proposed as safe sites in the human genome for transgene integration. Although several sites have been characterised for transgene integration in the literature, most of these do not meet criteria set out for a GSH and the limited set that do have not been characterised extensively. Here, we conducted a computational analysis using publicly available data to identify 25 unique putative GSH loci that reside in active chromosomal compartments. We validated stable transgene expression and minimal disruption of the native transcriptome in three GSH sites in vitro using human embryonic stem cells (hESCs) and their differentiated progeny. Furthermore, for easy targeted transgene expression, we have engineered constitutive landing pad expression constructs into the three validated GSH in hESCs.

Association of long-term exposure to various ambient air pollutants, lifestyle, and genetic predisposition with incident cognitive impairment and dementia.

BACKGROUND: Long-term exposure to air pollution has been found to contribute to the development of cognitive decline. Our study aimed to assess the association between various air pollutants and cognitive impairment and dementia. Additionally, explore the modification effects of lifestyle and genetic predisposition. METHODS: The exposure levels to various air pollutants, including particulate matter (PM) with diameters ≤ 2.5 (PM2.5), ≤ 10 (PM10), and between 2.5 and 10 µm (PM2.5-10) and nitrogen oxides (NO and NO2) were identified. An air pollution score (APS) was calculated to evaluate the combined exposure to these five air pollutants. A genetic risk estimate and healthy lifestyle score (HLS) were also generated. The Cox regression model adjusted by potential confounders was adopted to access the association between pollution exposure and cognitive decline, and several sensitivity analyses were additionally conducted to test the robustness. RESULTS: The combined exposure to air pollutants was associated with an increased risk of incident cognitive decline. Compared with the low exposure group, the hazard ratio (HR) and 95% confidence interval (CI) for all-cause dementia, Alzheimer's dementia, vascular dementia, and mild cognitive impairment (MCI) in those exposed to the highest levels of air pollutants were respectively 1.07 (95% CI: 1.04 to 1.09), 1.08 (95% CI: 1.04 to 1.12), 1.07 (95% CI: 1.02 to 1.13), and 1.19 (95% CI: 1.12 to 1.27). However, the modification effects from genetic predisposition were not widely observed, while on the contrary for the healthy lifestyle. Our findings were proven to be reliable and robust based on the results of sensitivity analyses. CONCLUSIONS: Exposure to air pollution was found to be a significant contributing factor to cognitive impairment and dementia, and this association was not easily modified by an individual's genetic predisposition. However, adopting a healthy lifestyle may help to manage the risk of cognitive decline related to air pollution.

pH and redox dual response nano-suppository for the treatment of ulcerative colitis.

To improve treatment compliance and reach sustained and controlled drug release in the colon, we developed a hollow mesoporous silica nano-suppository that responded to both pH and redox stimuli. Firstly, we prepared hollow mesoporous silica nanoparticles containing disulfide bonds (HMSN-SS) and loaded them with 5-ASA. Secondly, we modified the surface of HMSN-SS with polydopamine (PDA) and chitosan (CS) and molded the suppository, which we named 5-ASA@HMSN-SS-PDA-CS (5-ASA@HSPC). By administering 5-ASA@HSPC rectally, it acted directly on the affected area. CS helped the nanoparticles adhere to the colon's surface, while PDA dissociates from HMSN-SS due to protonation in the acidic environment of the ulcerative colon. The disulfide bonds were destroyed by the reducing environment of the colon, leading to a stable and slow release of encapsulated 5-ASA from the pores of HMSN. Finally, in vitro release experiments and in vivo pharmacokinetic and pharmacodynamic experiments had demonstrated that 5-ASA@HSPC exhibited a slow and steady action at the colonic site, with an excellent safety profile. This novel approach showed great potential in the treatment of ulcerative colitis.

The efficacy of tofacitinib combined with bDMARDs in the treatment of ankylosing spondylitis patients with inadequate response to bDMARDs: a retrospective study.

INTRODUCTION: Ankylosing spondylitis(AS) is a chronic inflammatory rheumatic disease primarily affecting the spine and sacroiliac joints. While biologic disease-modifying antirheumatic drugs(bDMARDs) and targeted synthetic DMARDs(tsDMARDs) are popular treatments for AS, there is limited research on their combined use. This study examined a cohort of AS patients who demonstrated inadequate response to bDMARDs and subsequently initiated combination therapy with tofacitinib in conjunction with bDMARDs, assessing both the efficacy and safety profile of this therapeutic approach. METHODS: In this study, we retrospectively collected the electronic medical records (EMR) of 15 adult patients with AS who were admitted to the Fourth Affiliated Hospital Zhejiang University School of Medicine between January 2018 and June 2022. All patients had received at least one bDMARD treatment for more than three months and still exhibited moderate to high disease activity. Tofacitinib 5 mg bid was added to their original biological treatment. Treatment was continued for a minimum of 12 weeks following the initiation of combination therapy. Changes in ASDAS-CRP and BASDAI scores at week 12 were collected and analyzed from baseline, while changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at weeks 4, 8, and 12 were also collected and analyzed. RESULTS: After 12 weeks of treatment, the overall ASDAS-CRP score decreased significantly from a baseline of 3.82 ± 1.47 (2.83 ~ 4.99) to 1.47 ± 0.48 (0.75 ~ 2.44), with remission achieved by 7 patients (46.7%) and low disease activity achieved by 5 patients (33.3%). The overall BASDAI score also showed significant improvement, decreasing from a baseline of 5.11 ± 1.42 (3.25 ~ 7 0.75) to 1.28 ± 0.70(0.20 ~ 2.55). Additionally, both ESR and CRP levels decreased significantly during the course of treatment without any reported adverse events leading to discontinuation. CONCLUSION: To a certain extent, our findings provide some evidence supporting the efficacy and safety of the combination of bDMARD and JAK inhibitor tofacitinib in AS patients with inadequate response to bDMARD monotherapy. It effectively controls disease activity while maintaining a relatively low and manageable incidence of adverse events. Further prospective randomized controlled trials with large sample sizes are anticipated to provide evidence-based medical support.

The relationship between circulating metabolites and prostate hyperplasia: a Mendelian randomization study.

BACKGROUND: Circulating metabolites (CM) play a pivotal role in our overall health, yet the current evidence concerning the involvement of diverse CM in benign prostatic hyperplasia (BPH) remains limited. Mendelian randomization (MR) offers a promising avenue to explore the potential impact of CM on BPH. METHODS: In a forward MR analysis, a cohort of 249 circulating metabolites was employed as exposures to investigate their potential associations with BPH risk. Conversely, in a reverse MR analysis, BPH was employed as an exposure to assess its effects on CM. RESULTS: The forward MR analysis discerned a linkage between six metabolites and BPH, with careful consideration to excluding heterogeneity and pleiotropy. Subsequently, the reverse MR analysis unveiled that nine metabolic compounds, mainly comprising phospholipids and triglycerides, potentially exhibit elevated levels in BPH patients. CONCLUSION: Bidirectional MR analysis furnishes genetic insight into the interplay between CM and BPH. The prominence of lipids and triglycerides emerges as significant factors intricately linked to BPH risk.