Imbalanced and Unchecked: The Role of Metal Dyshomeostasis in Driving COPD Progression.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterized by persistent inflammation and oxidative stress, which ultimately leads to progressive restriction of airflow. Extensive research findings have cogently suggested that the dysregulation of essential transition metal ions, notably iron, copper, and zinc, stands as a critical nexus in the perpetuation of inflammatory processes and oxidative damage within the lungs of COPD patients. Unraveling the intricate interplay between metal homeostasis, oxidative stress, and inflammatory signaling is of paramount importance in unraveling the intricacies of COPD pathogenesis. This comprehensive review aims to examine the current literature on the sources, regulation, and mechanisms by which metal dyshomeostasis contributes to COPD progression. We specifically focus on iron, copper, and zinc, given their well-characterized roles in orchestrating cytokine production, immune cell function, antioxidant depletion, and matrix remodeling. Despite the limited number of clinical trials investigating metal modulation in COPD, the advent of emerging methodologies tailored to monitor metal fluxes and gauge responses to chelation and supplementation hold great promise in unlocking the potential of metal-based interventions. We conclude that targeted restoration of metal homeostasis represents a promising frontier for ameliorating pathological processes driving COPD progression.

Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Major Depressive Disorder (MDD) emerges as a complex psychosomatic condition, notable for its considerable suicidality and mortality rates. Increasing evidence suggests the efficacy of Chinese herbal medicine in mitigating depression symptoms and offsetting the adverse effects associated with conventional Western therapeutics. Notably, clinical trials have revealed the adjunctive antidepressant potential of Kaiyu Zhishen Decoction (KZD) alongside Western medication. However, the standalone antidepressant efficacy of KZD and its underlying mechanisms merit in-depth investigation. AIM OF THE STUDY: This research aims to elucidate the impact of KZD on MDD and delineate its mechanistic pathways through integrated network pharmacological assessments and empirical in vitro and in vivo analyses. MATERIALS AND METHODS: To ascertain the optimal antidepressant dosage and mechanism of KZD, a Chronic Unpredictable Mild Stress (CUMS)-induced depression model in mice was established to evaluate depressive behaviors. High-Performance Liquid Chromatography (HPLC) and network pharmacological approaches were employed to predict KZD's antidepressant mechanisms. Subsequently, hippocampal samples were subjected to 4D-DIA proteomic sequencing and validated through Western blot, immunofluorescence, Nissl staining, and pathway antagonist applications. Additionally, cortisol-stimulated PC12 cells were utilized to simulate neuronal damage, analyzing protein and mRNA levels of MAPK-related signals and cell proliferation markers. RESULTS: The integration of network pharmacology and HPLC identified kaempferol and quercetin as KZD's principal active compounds for MDD treatment. Proteomic and network pharmacological KEGG pathway analyses indicated the MAPK signaling pathway as a critical regulatory mechanism for KZD's therapeutic effect on MDD. KZD was observed to mitigate CUMS-induced upregulation of p-ERK/ERK, CREB, and BDNF protein expressions in hippocampal cells by attenuating oxidative stress, thereby ameliorating neuronal damage and exerting antidepressant effects. The administration of PD98059 counteracted KZD's improvements in depression-like behaviors and downregulated p-ERK/ERK and BDNF protein expressions in the hippocampus. CONCLUSIONS: This investigation corroborates KZD's pivotal, dose-dependent role in antidepressant activity. Both in vivo and in vitro experiments demonstrate KZD's capacity to modulate the ERK-CREB-BDNF signaling pathway by diminishing ROS expression induced by oxidative stress, enhancing neuronal repair, and thus, manifesting antidepressant properties. Accordingly, KZD represents a promising herbal candidate for further antidepressant research.

Napex acupoint thread-embedding combined with metoprolol tartrate tablet for prophylactic treatment of migraine without aura: a randomized controlled trial. / æž•é¡¹éƒ¨åŸ‹çº¿æ³•è”åˆé ’çŸ³é ¸ç¾Žæ‰˜æ´›å°”ç‰‡é¢„é˜²æ€§æ²»ç–—æ— å ˆå †åå¤´ç—›ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the efficacy of napex acupoint thread-embedding combined with metoprolol tartrate tablet for prophylactic treatment of migraine without aura, and to compare its efficacy with simple napex acupoint thread-embedding and simple metoprolol tartrate tablet. METHODS: A total of 105 patients with migraine without aura were randomized into a combination group (35 cases, 5 cases dropped out), a thread-embedding group (35 cases, 4 cases dropped out) and a western medication group (35 cases, 2 cases dropped out). In the thread-embedding group, napex acupoint thread-embedding was applied at bilateral Fengchi (GB 20) and points of 1.5 cun nearby to the lower edge of spinous process of cervical 2. In the western medication group, metoprolol tartrate tablet was given orally, 12.5 mg a time, twice a day. In the combination group, napex acupoint thread-embedding combined with oral metoprolol tartrate tablet was delivered. The treatment of 8 weeks was required in the 3 groups. The days of headache attacks, frequency of headache attacks, headache severity (visual analogue scale [VAS] score) and the migraine specific quality of life questionnaire version 2.1 (MSQ) score were observed during baseline period (4 weeks before treatment to before treatment), observation period (1-4 weeks and 5-8 weeks in treatment) and follow-up period (1-4 weeks after treatment completion) respectively, the proportions of the days of headache attacks/frequency of headache attacks relieved by 50% were calculated, and the safety was evaluated in the 3 groups. RESULTS: During the observation period and the follow-up period, the days of headache attacks, frequency of headache attacks and headache VAS scores in the 3 groups were reduced compared with those of the baseline period (P<0.05). During the observation period and the follow-up period, the days of headache attacks and the frequency of headache attacks in the combination group were lower than those in the thread-embedding group and the western medication group (P<0.05); during the observation period (1-4 weeks in treatment), the headache VAS scores in the combination group and the thread-embedding group were lower than that in the western medication group (P<0.05); during the observation period (5-8 weeks in treatment) and the follow-up period, the headache VAS scores in the combination group were lower than those in the thread-embedding group and the western medication group (P<0.05). During the observation period and the follow-up period, the scores of role restriction, role prevention and emotion function of MSQ in the combination group were increased compared with those of the baseline period (P<0.05); during the observation period (5-8 weeks in treatment) and the follow-up period, the role prevention scores of MSQ in the thread-embedding group and the western medication group were increased compared with those of the baseline period (P<0.05); during the follow-up period, the emotion function scores of MSQ in the thread-embedding group and the western medication group were increased compared with those of the baseline period (P<0.05). During the observation period and the follow-up period, the scores of role restriction, role prevention and emotion function of MSQ in the combination group were higher than those in the thread-embedding group and the western medication group (P<0.05). There was no statistical difference in the proportions of the days of headache attacks/frequency of headache attacks relieved by 50% among the 3 groups (P>0.05), and there were no serious adverse reactions in the 3 groups. CONCLUSIONS: Napex acupoint thread-embedding combined with metoprolol tartrate tablet, simple napex acupoint thread-embedding and simple metoprolol tartrate tablet all can reduce the days of headache attacks and the frequency of headache attacks, relieve headache severity and improve the quality of life in patients with migraine without aura. Napex acupoint thread-embedding combined with metoprolol tartrate tablet has a better effect.

[Element relationship and extension path of clinical evidence knowledge map with Chinese patent medicine].

This study aims to construct the element relationship and extension path of clinical evidence knowledge map with Chinese patent medicine, providing basic technical support for the formation and transformation of the evidence chain of Chinese patent medicine and providing collection, induction, and summary schemes for massive and disorganized clinical data. Based on the elements of evidence-based PICOS, the conventional construction methods of knowledge graph were collected and summarized. Firstly, the data entities related to Chinese patent medicine were classified, and entity linking was performed(disambiguation). Secondly, the study associated and classified the attribute information of the data entity. Finally, the logical relationship between entities was constructed, and then the element relationship and extension path of the knowledge map conforming to the characteristics of clinical evidence of Chinese patent medicine were summarized. The construction of the clinical evidence knowledge map of Chinese patent medicine was mainly based on process design and logical structure, and the element relationship of the knowledge map was expressed according to the PICOS principle and evidence level. The extension path crossed three levels(model layer, data layer application, and new evidence application), and the study gradually explored the path from disease, core evaluation indicators, Chinese patent medicine, core prescriptions, syndrome and treatment rules, and medical case comparison(evolution law) to new drug research and development. In this study, the top-level design of the construction of the clinical evidence knowledge map of Chinese patent medicine has been clarified, but it still needs the joint efforts of interdisciplinary disciplines. With the continuous improvement of the map construction technology in line with the characteristics of TCM, the study can provide necessary basic technical support and reference for the development of the TCM discipline.

Effects of acupuncture and moxibustion on ulcerative colitis: An overview of systematic reviews.

Ulcerative colitis (UC) is a gastrointestinal disease with an unknown etiology that severely affects patients' quality of life. Acupuncture and moxibustion therapies are effective in the treatment of UC, but existing systematic reviews (SRs) and meta-analyses (MAs) on this subject have variable methodological and outcome quality. Therefore, this study aimed to summarize and evaluate the evidence of existing SRs and MAs to provide more reliable evidence for clinical practice. Data were extracted from seven databases through systematic search and evaluated in terms of the methodological quality, reporting quality, risk of bias, and quality of evidence using the AMSTAR-2, PRISMA, ROBIS, and GRADE systems, respectively. Ten studies were finally included, and all of them showed many problems with the overall design and quality of outcomes. Because of the lack of high-quality evidence to support the findings from the existing studies, we should take this conclusion with caution and strictly implement the registration, design, and implementation of trials based on evidence to provide high-quality results in future studies.

Effects of Supplementing Selenium-Enriched Cardamine violifolia to Laying Hens on Egg Quality and Yolk Antioxidant Capacity during Storage at 4 °C and 25 °C.

Oxidative stress occurs in the process of egg storage. Antioxidants as feed additives can enhance egg quality and extend the shelf life of eggs. Selenium-enriched Cardamine violifolia (SEC) has strongly antioxidant properties. The objective of this study was to assess the effects of dietary supplementation with SEC on egg quality and the yolk antioxidant capacity of eggs stored at 4 °C and 25 °C. Four hundred fifty 65-week-old, Roman hens that were similar in laying rate (90.79 ± 1.69%) and body weight (2.19 ± 0.23 kg) were divided into 5 groups. The birds were fed diets supplemented with 0 mg/kg selenium (Se) (CON), 0.3 mg/kg Se from sodium selenite (SS), 0.3 mg/kg Se from Se-enriched yeast (SEY), 0.3 mg/kg Se for selenium-enriched Cardamine violifolia (SEC) or 0.3 mg/kg Se from Se-enriched Cardamine violifolia and 0.3 mg/kg Se from Se-enriched yeast (SEC + SEY) for 8 weeks. The eggs were collected on the 8th week and were analyzed for egg quality and oxidative stability of yolk during storage at 4 °C or 25 °C for 0, 2, 4, or 6 weeks. Dietary SEC and SEC + SEY supplementation increased the Haugh unit (HU) and albumen foam stability in eggs stored at 4 °C and 25 °C (p < 0.05). SS and SEC supplementation increased the yolk index in eggs stored at 25 °C (p < 0.05). SEC or SEC + SEY slowed down an increase in albumen pH and gel firmness in eggs stored at 4 °C and 25 °C (p < 0.05). Moreover, SEC or SEC + SEY alleviated the increase in malonaldehyde (MDA), and the decrease in total antioxidant capacity (T-AOC) level and total superoxide dismutase (T-SOD) activity in yolks stored at 4 °C and 25 °C (p < 0.05). These results indicate that SEC mitigated egg quality loss and improved the antioxidant capacity of yolks during storage. SEC supplementation would be advantageous to extend the shelf life of eggs.

Polyethyleneimine in designed nanocomposite based magnetic halloysite nanotubes for extraction and determination of gallic acid in green tea.

An innovative and simple nanocomposite denoted as MHNTs@PEI was synthesized for gallic acid (GA) analytical sample pretreatment. Polyethyleneimine (PEI) functionalized was binded onto magnetic halloysite nanotubes (MHNTs) to inhence adsorption capacity. MHNTs@PEI was obtained only through two steps modification (amination and PEI modification). Characterizations showed that there are layers of synthetic PEI on the tubular structure of the material and magnetic spheres on its surface, both indicating successful synthesis of the nanocomposite. Furthermore, the adsorption isotherms and kinetic modeling showed that the Langmuir model and pseudo-first-order model fit the adsorption data, respectively. MHNTs@PEI achieved an adsorption capacity of 158 mg·g-1. Overall, the abundant adsorption sites significantly improved the adsorption performance of the MHNTs@PEI. Regeneration tests demonstrated that the MHNTs@PEI exhibits effective adsorption, even after undergoing five consecutive cycles. Optimization of key parameters (ratio, volume of elution, elution time and frequency) in the process of adsorption and desorption was also conducted. The limit of detection (LOD) and that of the quantification (LOQ) were 0.19 and 0.63 µg·mL-1, respectively, and the recoveries were 95.67-99.43 %. Finally, the excellent magnetism (43.5 emu·g-1) and the adsorption feature of MHNTs@PEI enabled its successful utilization in analytical sample pretreatment through the extraction of GA from green tea.

Combined effects of mulch film-derived microplastics and pesticides on soil microbial communities and element cycling.

Pesticides and microplastics (MPs) derived from mulch film in agricultural soil can independently impact soil ecology, yet the consequences of their combined exposure remain unclear. Therefore, the effects of simultaneous exposure to commonly used pesticides (imidacloprid and flumioxazin) and aged mulch film-derived MPs on soil microorganisms and element cycles in cotton fields were investigated. The combined exposure influenced soil microorganisms, alongside processes related to carbon, nitrogen, and phosphorus cycles, exhibiting effects that were either neutralized or enhanced compared to individual exposures. The impact of pesticides in combined exposure was notably more significant and played a dominant role than that of MPs. Specifically, combined exposure intensified changes in soil bacterial community and symbiotic networks. The combined exposure neutralized NH4+, NO3-, DOC, and A-P contents, shifting from 0.33 % and 40.23 % increase in MPs and pesticides individually to a 40.24 % increase. Moreover, combined exposure resulted in the neutralization or amplification of the nitrogen-fixing gene nifH, nitrifying genes (amoA and amoB), and denitrifying genes (nirS and nirK), the carbon cycle gene cbbLG and the phosphorus cycle gene phoD from 0.48 and 2.57-fold increase to a 2.99-fold increase. The combined exposure also led to the neutralization or enhancement of carbon and nitrogen cycle functional microorganisms, shifting from a 1.53-fold inhibition and 10.52-fold increase to a 6.39-fold increase. These findings provide additional insights into the potential risks associated with combined pesticide exposure and MPs, particularly concerning soil microbial communities and elemental cycling processes.

Suxiao Jiuxin Pill alleviates myocardial ischemia/reperfusion-induced autophagy via miR-193a-3p/ALKBH5 pathway.

BACKGROUND: Myocardial ischemia/reperfusion injury (MIRI) poses a formidable challenge to cardiac reperfusion therapy due to the absence of effective clinical interventions. Methylation of N6-methyladenosine (m6A), which is the most common post-transcriptional modifications occurring within mammalian mRNA, is believed to be involved in MIRI by modulating autophagy. MicroRNAs (miRNAs) play a crucial role in regulating gene expression at the post-transcriptional level and have been implicated in the regulation of m6A methylation. Suxiao Jiuxin Pill (SJP) is extensively used in China for the clinical treatment of angina pectoris and confers benefits to patients with acute coronary syndrome who have received percutaneous coronary intervention. However, the precise mechanisms underlying SJP intervention in MIRI remain unclear. PURPOSE: This study aimed to demonstrate, both in vivo and in vitro, that SJP could alleviate autophagy in MIRI by regulating miR-193a-3p to target and upregulate the demethylase ALKBH5. METHODS: An in vitro hypoxia/reoxygenation model was established using H9c2 cells, while an in vivo MIRI model was established using Wistar rats. A lentivirus harboring the precursor sequence of miR-193a-3p was employed for its overexpression. Adeno-associated viruses were used to silence both miR-193a-3p and ALKBH5 expressions. Cardiac function, infarct size, and tissue structure in rats were assessed using echocardiography, triphenyl tetrazolium chloride (TTC) staining, and HE staining, respectively. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was employed to detect the levels of apoptosis in rat cardiac tissue. m6A methylation levels were assessed using colorimetry. GFP-RFP-LC3B was used to monitor autophagic flux and transmission electron microscopy was used to evaluate the development of autophagosomes. Western Blot and qRT-PCR were respectively employed to assess the levels of autophagy-related proteins and miR-193a-3p. RESULTS: SJP alleviated autophagy, preserved cardiac function, and minimized myocardial damage in the hearts of MIRI rats. SJP attenuated autophagy in H/R H9C2 cells. Elevated levels of miR-193a-3p were observed in the cardiac tissues of MIRI rats and H/R H9C2 cells, whereas SJP downregulated miR-193a-3p levels in these models. ALKBH5, a target gene of miR-193, is negatively regulated by miR-193a-3p. Upon overexpression of miR-193a-3p or silencing of ALKBH5, m6A methylation decreased, and the autophagy-attenuating effects of SJP and its components, senkyunolide A and l-borneol, were lost in H/R H9C2 cells, whereas in MIRI rats, these effects were not abolished but merely weakened. Further investigation indicated that the METTL3 inhibitor STM2475, combined with the silencing of miR-193a-3p, similarly attenuated autophagy in the hearts of MIRI rats. This suggests that a reduction in m6A methylation is involved in autophagy alleviation. CONCLUSION: We demonstrated that SJP mitigates autophagy in MIRI by downregulating miR-193a-3p, enhancing ALKBH5 expression, and reducing m6A methylation, a mechanism potentially attributed to its constituents, senkyunolide A and l-borneol.

Application of Four-Dimensional Pelvic Floor Ultrasound in the Diagnosis of Postpartum Pelvic Floor Dysfunction and Evaluation of Curative Effect.

Objective: To explore the application of four-dimensional pelvic floor ultrasound in the diagnosis of postpartum pelvic floor dysfunction (PFD) and evaluation of curative effect. Methods: A total of 100 patients with postpartum PFD undergoing vaginal delivery in the hospital were enrolled as the research objects between January 2020 and January 2023. A total of 100 postpartum women with good pelvic floor muscle function during the same period were enrolled as a control group. Both groups underwent four-dimensional pelvic floor ultrasound detection. The bladder neck descent (BND), retrovesical angle (RVA), urethral tilt angle (UTA), urethral rotation angle (ROT), levator ani thickness under rest state (LATr), levator ani thickness under Valsalva state (LATs), levator ani hiatus area under rest state (LHAr) and levator ani hiatus area under Valsalva state (LHAs) in both groups were compared. The patients in the study group were given Kegel training for pelvic floor muscle rehabilitation exercise and bio-feedback electrical stimulation. According to the clinical curative effect, patients in the study group were divided into a recovery group (n=87) and a non-recovery group (n=13). The value of four-dimensional pelvic floor ultrasound in the diagnosis of PFD and evaluation of curative effect was analyzed. Results: In the observation group, BND, RVA, UTA, ROT, LHAr, and LHAs were higher, while LATr and LATs were lower compared to the control group. (P < .05). The results of ROC curves analysis showed that the AUC of BND combined with RVA, UTA, ROT, LATr, LATs, LHAr, and LHAs in the diagnosis of PFD was 0.818, greater than that of the single index (0.728, 0.705, 0.680, 0.715, 0.677, 0.696, 0.719, 0.654; P < .05). BND, RVA, UTA, ROT, LHAr, and LHAs in the non-recovery group were higher than those in the recovery group, while LATr and LATs were lower than those in the recovery group (P < .05). The results of ROC curves analysis showed that the Area Under the Curve (AUC）of BND combined with RVA, UTA, ROT, LATr, LATs, LHAr, and LHAs for predicting the curative effect were 0.804, greater than that of a single index (0.725, 0.653, 0.651, 0.744, 0.733, 0.720, 0.661, 0.718; P < .05). Conclusion: Four-dimensional pelvic floor ultrasound can be applied to intuitively evaluate the structure and function of postpartum pelvic floor tissues, which can provide a reliable basis for the diagnosis of postpartum PFD and evaluation of curative effect.

Zhoushi Qi Ling decoction inhibits the progression of castration-resistant prostate cancer in vivo by regulating macrophage infiltration via IL6-STAT3 signaling.

Background and aim: Prostate cancer is a leading malignant tumor in men, associated with a high rate of mortality. Androgen deprivation therapy is commonly used to treat prostate cancer, which contributes to the progression of castration-resistant prostate cancer (CRPC). The current therapy has a low survival rate in patients with CRPC. Our study aims to develop a novel effective approach for CRPC treatment and improve survival benefits. Experimental procedure: CRPC cell line PC-3-Luc expressing luciferase and the CRPC cell line PC-3-IL6-Luc stably overexpressing IL-6 were used to establish the xenograft tumor mouse model. The tumor was monitored weekly using Bioluminescence imaging. Infiltrated macrophages were quantified by fluorescence-activated cell sorting using flow cytometry. IL6 mRNA level was determined using quantitative real-time PCR. The protein levels of total STAT3 and phosphorylated STAT3 were determined using Western blot. Results and conclusion: Zhoushi Qi Ling decoction (ZQD) treatment significantly reduced PC3 the xenograft tumor progression and the number of infiltrated macrophages when compared with saline treatment. IL6 mRNA level was remarkedly suppressed by ZQD treatment. Notably, the protein level of phosphorylated STAT3 was significantly decreased in PC3 the xenograft tumor treated with ZQD compared to saline treatment. Our findings demonstrated that ZQD treatment significantly reduced the progression of prostate cancer, evidenced by the reduced population of infiltrated macrophages and the inhibition of the IL6/STAT3 pathway.

Portable paper-based probe for on-site ratiometric fluorescence determination of total flavonol glycosides in plant extract using smartphone imaging.

A smartphone-assisted, paper-based ratio fluorescence probe is presented for the rapid, low-cost and on-site quantification of total flavonol glycosides in Ginkgo biloba extracts (GBE). The Al3+/Eu-MOF/paper-based probe utilizes lanthanide metal-organic framework (Ln-MOF) nanoparticles immobilized on Whatman filter paper along with Al3+ for detecting flavonols, which are the hydrolyzed products of flavonol glycosides. The color change of the paper-based fluorescence image from red to orange depends on the concentration of the target analyte in the sample solution. The smartphone equipped with a red, green, blue (RGB) color detector measured the fluorescence signal intensity on the paper substrate after adding flavonol. The analytical variables affecting the performance of the probe, including the addition sequence of the aluminum nitrate solution, its concentration, that of the Ln-MOF solution, the drying time of the paper probe, the reaction time and the sensitivity parameters of the mobile phone camera (ISO), were optimized. Under optimal conditions, the Al3+/Eu-MOF/paper-based probe has good linear response in the concentration range 7 ~ 80 µg mL- 1 and a lower detection limit of 2.07 µg mL- 1. The results obtained with the paper-based ratio fluorescence probe and smartphone combination were validated by comparing them with high-performance liquid chromatography (HPLC) measurements. This study provides a potential strategy for fabricating Al3+/Eu-MOF/paper-based probe used for total flavonol glycosides determination.

Astragaloside â £ negatively regulates Gpr97-TPL2 signaling to protect against hyperhomocysteine-exacerbated sepsis associated acute kidney injury.

BACKGROUND: Hyperhomocysteine (HHcy) plays an important role in promoting inflammation and cell death of tubular epithelial cells. However, the role of HHcy and Astragaloside IV (AS-IV) in sepsis associated acute kidney injury (S-AKI) remain unclear. PURPOSE: A significant aspect of this study aimed to elucidate the effect of AS-Ⅳ treatment on HHcy-exacerbated S-AKI and reveal its potential mechanism. METHODS: Male C57BL/6 J mice fed with specific diet containing 2% methionine were established as in vivo models, and AS-Ⅳ was orally administrated continuously for 3 weeks, and then LPS (10 mg·kg-1 bodyweight) was given by a single intraperitoneal injection. The renal morphological changes were evaluated by HE and PAS staining. RNA-sequencing analysis was applied to select key signaling. The NRK-52E cells exposed to Hcy or combined with LPS were used as in vitro models. The mRNA and protein expression levels of Gpr97-TPL2 signaling were examined by qRT-PCR and western blotting assays. RESULTS: In vivo, HHcy mice developed more severe renal injury and prevalent tubular inflammation after LPS injection. In vitro, the levels of NGAL, Gpr97 and TPL2 were significantly increased in NRK-52E cells induced by Hcy (1.6 mM) or in combination with LPS. Notably, the effects of Hcy on TPL2 signaling was abolished by transfecting TPL2 siRNA or treating TPL2 inhibitor, without alterations in Gpr97. However, the enhancement of Gpr97-TPL2 signaling induced by Hcy was counteracted by Gpr97 siRNA. Subsequently, our findings demonstrated that AS-Ⅳ treatment can improve renal function in HHcy-exacerbated S-AKI mice. Mechanistically, AS-Ⅳ alleviated renal tubular damage characterized by abnormal increases in KIM-1, NGAL, TPL2, Gpr97, Sema3A and TNF-α, and decreases in survivin in vivo and in vitro mainly through suppressing the activation of Gpr97-TPL2 signaling. CONCLUSION: The present study suggested that HHcy-exacerbated S-AKI was mediated mechanically by activation of Gpr97-TPL2 signaling for the first time. Furthermore, our research also illustrated that AS-Ⅳ protected against HHcy-exacerbated S-AKI by attenuating renal tubular epithelial cells damage through negatively regulating Gpr97-TPL2 signaling, proposing a natural product treatment strategy for HHcy-exacerbated S-AKI.

Prevalence of Unmet Rehabilitation Needs Among Canadians Living With Long-term Conditions or Disabilities During the First Wave of the COVID-19 Pandemic.

OBJECTIVE: We aimed to describe the prevalence of unmet rehabilitation needs among a sample of Canadians living with long-term conditions or disabilities during the first wave of the COVID-19 pandemic. DESIGN: Cross-sectional survey. SETTING: Individuals residing in Canada during the first wave of the COVID-19 pandemic. PARTICIPANTS: Eligible participants were Canadians living with long-term conditions or disabilities, 15 years or older living in 1 of the 10 provinces or 3 territories (n=13,487). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: We defined unmet rehabilitation needs as those who reported needing rehabilitation (ie, physiotherapy/massage therapy/chiropractic, speech, or occupational therapy, counseling services, support groups) but did not receive it because of the COVID-19 pandemic. We calculated the national, age, gender, and province/territory-specific prevalence and 95% confidence interval of unmet rehabilitation needs. RESULTS: During the first wave of the pandemic, the prevalence of unmet rehabilitation needs among Canadians with long-term conditions or disabilities was 49.3% (95% confidence interval [CI]; 48.3, 50.3]). The age-specific prevalence was higher among individuals 15-49 years old (55.6%; 95% CI [54.2, 57.1]) than those 50 years and older (46.0%; 95% CI [44.5, 47.4]). Females (53.7%; 95% CI [52.6, 54.9]) had higher unmet needs than males (44.1%; 95% CI [42.3, 45.9]). Unmet rehabilitation needs varied across provinces and territories. CONCLUSIONS: In this sample, almost 50% of Canadians living with long-term conditions or disabilities had unmet rehabilitation needs during the first wave of the COVID-19 pandemic. This suggests that a significant gap between the needs for and delivery of rehabilitation care existed during the early phase of the pandemic.

Characterization of the Endophytic Bacillus subtilis KRS015 Strain for Its Biocontrol Efficacy Against Verticillium dahliae.

Endophytes play important roles in promoting plant growth and controlling plant diseases. Verticillium wilt is a vascular wilt disease caused by Verticillium dahliae, a widely distributed soilborne pathogen that causes significant economic losses on cotton each year. In this study, an endophyte KRS015, isolated from the seed of the Verticillium wilt-resistant Gossypium hirsutum 'Zhongzhimian No. 2', was identified as Bacillus subtilis by morphological, phylogenetic, physiological, and biochemical analyses. The volatile organic compounds (VOCs) produced by KRS015 or its cell-free fermentation extract had significant antagonistic effects on various pathogenic fungi, including V. dahliae. KRS015 reduced Verticillium wilt index and colonization of V. dahliae in treated cotton seedlings significantly; the disease reduction rate was ∼62%. KRS015 also promoted plant growth, potentially mediated by the growth-related cotton genes GhACL5 and GhCPD-3. The cell-free fermentation extract of KRS015 triggered a hypersensitivity response, including reactive oxygen species (ROS) and expression of resistance-related plant genes. VOCs from KRS015 also inhibited germination of conidia and the mycelial growth of V. dahliae, and were mediated by growth and development-related genes such as VdHapX, VdMcm1, Vdpf, and Vel1. These results suggest that KRS015 is a potential agent for controlling Verticillium wilt and promoting growth of cotton.

CMAUP database update 2024: extended functional and association information of useful plants for biomedical research.

Knowledge of the collective activities of individual plants together with the derived clinical effects and targeted disease associations is useful for plant-based biomedical research. To provide the information in complement to the established databases, we introduced a major update of CMAUP database, previously featured in NAR. This update includes (i) human transcriptomic changes overlapping with 1152 targets of 5765 individual plants, covering 74 diseases from 20 027 patient samples; (ii) clinical information for 185 individual plants in 691 clinical trials; (iii) drug development information for 4694 drug-producing plants with metabolites developed into approved or clinical trial drugs; (iv) plant and human disease associations (428 737 associations by target, 220 935 reversion of transcriptomic changes, 764 and 154121 associations by clinical trials of individual plants and plant ingredients); (v) the location of individual plants in the phylogenetic tree for navigating taxonomic neighbors, (vi) DNA barcodes of 3949 plants, (vii) predicted human oral bioavailability of plant ingredients by the established SwissADME and HobPre algorithm, (viii) 21-107% increase of CMAUP data over the previous version to cover 60 222 chemical ingredients, 7865 plants, 758 targets, 1399 diseases, 238 KEGG human pathways, 3013 gene ontologies and 1203 disease ontologies. CMAUP update version is freely accessible at https://bidd.group/CMAUP/index.html.

The protective effects of icariin against testicular dysfunction in type 1 diabetic mice Via AMPK-mediated Nrf2 activation and NF-κB p65 inhibition.

BACKGROUND: Owing to the early suffering age and the rising incidence of type 1 diabetes (T1D), the resulting male reproductive dysfunction and fertility decline have become a disturbing reality worldwide, with no effective strategy being available. Icariin (ICA), a flavonoid extracted from Herba Epimedium, has been proved its promising application in improving diabetes-related complications including diabetic nephropathy, endothelial dysfunction and erectile dysfunction. Ensuring the future reproductive health of children and adolescents with T1D is crucial to improve global fertility. However, its roles in the treatment of T1D-induced testicular dysfunction and the potential mechanisms remain elusive. PURPOSE: The purpose of this present study was to investigate whether ICA ameliorates T1D-induced testicular dysfunction as well as its potential mechanisms. METHODS: T1D murine model was established by intraperitoneal injection of STZ with or without treated with ICA for eleven weeks. Morphological, pathological and serological experiments were used to determine the efficacy of ICA on male reproductive function of T1D mice. Western blotting, Immunohistochemistry analysis, qRT-PCR and kit determination were performed to investigated the underlying mechanisms. RESULTS: We found that replenishment of ICA alleviated testicular damage, promoted testosterone production and spermatogenesis, ameliorated apoptosis and blood testis barrier impairment in streptozotocin-induced T1D mice. Functionally, ICA treatment triggered adenosine monophosphate protein kinase (AMPK) activation, which in turn inhibited the nuclear translocation of nuclear factor kappa B p65 (NF-κB p65) to reduce inflammatory responses in the testis and activated nuclear factor erythroid 2-related factor 2(Nrf2), thereby enhancing testicular antioxidant capacity. Further studies revealed that supplementation with the AMPK antagonist Compound C or depletion of Nrf2 weakened the beneficial effects of ICA on testicular dysfunction of T1D mice. CONCLUSION: Collectively, these results demonstrate the feasibility of ICA in the treatment of T1D-induced testicular dysfunction, and reveal the important role of AMPK-mediated Nrf2 activation and NF-κB p65 inhibition in ICA-associated testicular protection during T1D.

Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice.

BACKGROUND: Delayed emergence from general anaesthesia poses a significant perioperative safety hazard. Subanaesthetic doses of ketamine not only deepen anaesthesia but also accelerate recovery from isoflurane anaesthesia; however, the mechanisms underlying this phenomenon remain elusive. Esketamine exhibits a more potent receptor affinity and fewer adverse effects than ketamine and exhibits shorter recovery times after brief periods of anaesthesia. As the paraventricular thalamus (PVT) plays a pivotal role in regulating wakefulness, we studied its role in the emergence process during combined esketamine and isoflurane anaesthesia. METHODS: The righting reflex and cortical electroencephalography were used as measures of consciousness in mice during isoflurane anaesthesia with coadministration of esketamine. The expression of c-Fos was used to determine neuronal activity changes in PVT neurones after esketamine administration. The effect of esketamine combined with isoflurane anaesthesia on PVT glutamatergic (PVTGlu) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVTGlu neuronal activity. RESULTS: A low dose of esketamine (5 mg kg-1) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg-1) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVTGlu neurones (0.03 [1.7]% vs 6.9 [3.4]%, P=0.002) during isoflurane anaesthesia (1.9 [5.7]% vs -5.1 [5.3]%, P=0.016) and emergence (6.1 [6.2]% vs -1.1 [5.0]%, P=0.022). Chemogenetic suppression of PVTGlu neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P<0.001). CONCLUSIONS: Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVTGlu neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine.

Selenium-Enriched Cardamine violifolia Alleviates LPS-Induced Hepatic Damage and Inflammation by Suppressing TLR4/NODs-Necroptosis Signal Axes in Piglets.

Selenium-enriched Cardamine violifolia (SEC), a cruciferous plant, exerts excellent antioxidant and anti-inflammatory capacity, but its effect on hepatic function is unclear. This study investigated the effect and potential mechanism of SEC on hepatic injury induced by lipopolysaccharide (LPS). Twenty-four weaned piglets were randomly allotted to treatment with SEC (0.3 mg/kg Se) and/or LPS (100 µg/kg). After 28 days of the trial, pigs were injected with LPS to induce hepatic injury. These results indicated that SEC supplementation attenuated LPS-induced hepatic morphological injury and reduced aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities in plasma. SEC also inhibited the expression of pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) after the LPS challenge. In addition, SEC improved hepatic antioxidant capacity via enhancing glutathione peroxidase (GSH-Px) activity and decreasing malondialdehyde (MDA) concentration. Moreover, SEC downregulated the mRNA expression of hepatic myeloid differentiation factor 88 (MyD88) and nucleotide-binding oligomerization domain proteins 1 (NOD1) and its adaptor molecule receptor interacting protein kinase 2 (RIPK2). SEC also alleviated LPS-induced hepatic necroptosis by inhibiting RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) expression. These data suggest that SEC potentially mitigates LPS-induced hepatic injury via inhibiting Toll-like receptor 4 (TLR4)/NOD2 and necroptosis signaling pathways in weaned piglets.

Characteristics of Canadians Living With Long-Term Health Conditions or Disabilities Who Had Unmet Rehabilitation Needs During the First Wave of the COVID-19 Pandemic: A Cross-sectional Study.

OBJECTIVE: This study aimed to describe the characteristics associated with unmet rehabilitation needs in a sample of Canadians with long-term health conditions or disabilities during the first wave of the COVID-19 pandemic. DESIGN: We used data from the Impacts of COVID-19 on Canadians Living With Long-Term Conditions and Disabilities, a national cross-sectional survey with 13,487 respondents. Unmet needs were defined as needing rehabilitation (ie, physiotherapy/massage/chiropractic, speech therapy, occupational therapy, counseling services, or support groups) but not receiving due to the pandemic. We used multivariable modified Poisson regression to examine the association between demographic, socioeconomic, and health-related characteristics and unmet rehabilitation needs. RESULTS: More than half of the sample were 50 years and older (52.3%), female (53.8%), and 49.3% reported unmet rehabilitation needs. Those more likely to report unmet needs were females, those with lower socioeconomic status (receiving disability benefits or social assistance, job loss, increased work hours, decreased household income or earnings), and those with lower perceived general health or mental health status. CONCLUSIONS: Among Canadians with disabilities or chronic health conditions, marginalized groups are more likely to report unmet rehabilitation needs. Understanding the systemic and upstream determinants is necessary to develop strategies to minimize unmet rehabilitation needs and facilitate the delivery of equitable rehabilitation services.