Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

Machine learning-based autophagy-related prognostic signature for personalized risk stratification and therapeutic approaches in bladder cancer.

OBJECTIVE: Bladder cancer (BCa) is a highly lethal urological malignancy characterized by its notable histological heterogeneity. Autophagy has swiftly emerged as a diagnostic and prognostic biomarker in diverse cancer types. Nonetheless, the currently accessible autophagy-related signature specific to BCa remains limited. METHODS: A refined autophagy-related signature was developed through a 10-fold cross-validation framework, incorporating 101 combinations of machine learning algorithms. The performance of this signature in predicting prognosis and response to immunotherapy was thoroughly evaluated, along with an exploration of potential drug targets and compounds. In vitro and in vivo experiments were conducted to verify the regulatory mechanism of hub gene. RESULTS: The autophagy-related prognostic signature (ARPS) has exhibited superior performance in predicting the prognosis of BCa compared to the majority of clinical features and other developed markers. Higher ARPS is associated with poorer prognosis and reduced sensitivity to immunotherapy. Four potential targets and five therapeutic agents were screened for patients in the high-ARPS group. In vitro and vivo experiments have confirmed that FKBP9 promotes the proliferation, invasion, and metastasis of BCa. CONCLUSIONS: Overall, our study developed a valuable tool to optimize risk stratification and decision-making for BCa patients.

A novel lumen-apposing metal stent for endoscopic drainage of symptomatic pancreatic fluid collections: a retrospective study.

Background and Objectives: Previous studies showed that lumen-apposing metal stent (LAMS) provides a feasible route to perform direct endoscopic necrosectomy. However, the high risk of bleeding and migration induced by the placement of LAMS attracted attention. The aim of this study was to evaluate the safety and effectiveness of a novel LAMS. Methods: In this retrospective study, we enrolled patients with symptomatic pancreatic fluid collections (PFCs) to perform EUS-guided drainage with a LAMS in our hospital. Evaluation variables included technical success rate, clinical success rate, and adverse events. Results: Thirty-two patients with a mean age of 41.38 ± 10.72 years (53.1% males) were included in our study, and the mean size of PFC was 10.06 ± 3.03 cm. Technical success rate and clinical success rate reached 96.9% and 93.8%, respectively. Stent migration occurred in 1 patient (3.1%), and no stent-induced bleeding occurred. The outcomes of using LAMS in 10 patients with pancreatic pseudocyst and 22 patients with walled-off necrosis were comparable. Compared with pancreatic pseudocyst, walled-off necrosis needed more direct endoscopic necrosectomy times to achieve resolution (P = 0.024). Conclusions: Our study showed that the novel LAMS is effective and safe for endoscopic drainage of PFCs with a relatively low rate of adverse events. Further large-scale multicenter studies are needed to confirm the present findings.

Association of whole blood copper, zinc, calcium, magnesium, and iron with non-alcoholic fatty liver disease in overweight and obese children. / å ¨è¡€é“œã€é”Œã€é’™ã€é•ã€é“ä¸Žè¶ é‡è‚¥èƒ–å„¿ç«¥éžé ’ç²¾æ€§è„‚è‚ªè‚ç— çš„å ³è”.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder in overweight and obese children, and its etiology and pathogenesis remain unclear, lacking effective preventive and therapeutic measures. This study aims to explore the association between whole blood copper, zinc, calcium, magnesium and iron levels and NAFLD in overweight and obese children aged 6 to 17 years, providing a scientific basis for the prevention and intervention of early NAFLD in overweight and obese children. METHODS: A cross-sectional study design was used to collect relevant data from overweight and obese children who visited the Hunan Children's Hospital from January 2019 to December 2021 through questionnaire surveys. Fasting blood samples were collected from the subjects, and various indicators such as blood glucose, blood lipid, and mineral elements were detected. All children were divided into an overweight group (n=400) and a NAFLD group (n=202). The NAFLD group was divided into 2 subgroups according to the ALT level: A non-alcoholic fatty liver (NAFL) group and a non-alcoholic steatohepatitis (NASH) group. Logistic regression analysis was used to analyze the association between minerals (copper, zinc, calcium, magnesium, and iron) and NAFLD, NAFL and NASH. RESULTS: A total of 602 subjects were included, of whom 73.6% were male, with a median age of 10 (9, 11) years, and a body mass index (BMI) of 24.9 (22.7, 27.4) kg/m2. The intergroup comparison results showed that compared with the overweight group, the NAFLD group had higher levels of age, BMI, diastolic blood pressure (DBP), systolic blood pressure (SBP), triglyceride (TG), low density lipoprotein (LDL), alanine transaminase (ALT) and aspartate aminotransferase (AST), and lower level of high density lipoprotein (HDL). The NAFL group had higher levels of age, BMI, DBP, SBP, ALT, and AST, and lower levels of HDL compared with the overweight group. The levels of age, BMI, DBP, SBP, TG, LDL, ALT, and AST of NASH were higher than those in the overweight group, while the level of HDL was lower than that in overweight group (all P<0.017). After adjusting for a variety of confounders, the OR of NAFLD for the highest quantile of iron was 1.79 (95% CI 1.07 to 3.00) compared to the lowest quantile, and no significant association was observed between copper, zinc, calcium, and magnesium, and NAFLD. The subgroup analysis of NAFLD showed that the OR for the highest quantile of iron in children with NAFL was 2.21 (95% CI 1.26 to 3.88), while no significant association was observed between iron level and NASH. In addition, no significant associations were observed between copper, zinc, calcium, and magnesium levels and NAFL or NASH. CONCLUSIONS: High iron level increases the risk of NAFLD (more likely NAFL) in overweight and obese children, while copper, zinc, calcium, magnesium, and other elements are not associated with the risk of NAFLD in overweight and obese children.

Naoxintong capsule for treating cardiovascular and cerebrovascular diseases: from bench to bedside.

Naoxintong Capsule (NXT), a renowned traditional Chinese medicine (TCM) formulation, has been broadly applied in China for more than 30 years. Over decades, accumulating evidences have proven satisfactory efficacy and safety of NXT in treating cardiovascular and cerebrovascular diseases (CCVD). Studies have been conducted unceasingly, while this growing latest knowledge of NXT has not yet been interpreted properly and summarized comprehensively. Hence, we systematically review the advancements in NXT research, from its chemical constituents, quality control, pharmacokinetics, to its profound pharmacological activities as well as its clinical applications in CCVD. Moreover, we further propose specific challenges for its future perspectives: 1) to precisely clarify bioactivities of single compound in complicated mixtures; 2) to evaluate the pharmacokinetic behaviors of NXT feature components in clinical studies, especially drug-drug interactions in CCVD patients; 3) to explore and validate its multi-target mechanisms by integrating multi-omics technologies; 4) to re-evaluate the safety and efficacy of NXT by carrying out large-scale, multicenter randomized controlled trials. In brief, this review aims to straighten out a paradigm for TCM modernization, which help to contribute NXT as a piece of Chinese Wisdom into the advanced intervention strategy for CCVD therapy.

DNMT1-Mediated the Downregulation of FOXF1 Promotes High Glucose-induced Podocyte Damage by Regulating the miR-342-3p/E2F1 Axis.

Podocyte damage plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Accumulating evidence suggests that dysregulation of transcription factors plays a crucial role in podocyte damage in DN. However, the biological functions and underlying mechanisms of most transcription factors in hyperglycemia-induced podocytes damage remain largely unknown. Through integrated analysis of data mining, bioinformatics, and RT-qPCR validation, we identified a critical transcription factor forkhead box F1 (FOXF1) implicated in DN progression. Moreover, we discovered that FOXF1 was extensively down-regulated in renal tissue and serum from DN patients as well as in high glucose (HG)-induced podocyte damage. Meanwhile, our findings showed that FOXF1 might be a viable diagnostic marker for DN patients. Functional experiments demonstrated that overexpression of FOXF1 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and fibrosis in HG-induced podocytes damage. Mechanistically, we found that the downregulation of FOXF1 in HG-induced podocyte damage was caused by DNMT1 directly binding to FOXF1 promoter and mediating DNA hypermethylation to block FOXF1 transcriptional activity. Furthermore, we found that FOXF1 inhibited the transcriptional expression of miR-342-3p by binding to the promoter of miR-342, resulting in reduced sponge adsorption of miR-342-3p to E2F1, promoting the expression of E2F1, and thereby inhibiting HG-induced podocytes damage. In conclusion, our findings showed that blocking the FOXF1/miR-342-3p/E2F1 axis greatly alleviated HG-induced podocyte damage, which provided a fresh perspective on the pathogenesis and therapeutic strategies for DN patients.

A Novel Classification System of Renal Hilar Tumors for Surgical Guidance: Technique, Outcome, and Safety.

BACKGROUND: This study was designed to develop an innovative classification and guidance system for renal hilar tumors and to assess the safety and effectiveness of robot-assisted partial nephrectomy (RAPN) for managing such tumors. METHODS: A total of 179 patients undergoing RAPN for renal hilar tumors were retrospectively reviewed. A novel classification system with surgical techniques was introduced and the perioperative features, tumor characteristics, and the efficacy and safety of RAPN were compared within subgroups. RESULTS: We classified the tumors according to our novel system as follows: 131 Type I, 35 Type II, and 13 Type III. However, Type III had higher median R.E.N.A.L., PADUA, and ROADS scores compared with the others (all p < 0.001), indicating increased operative complexity and higher estimated blood loss [180.00 (115.00-215.00) ml]. Operative outcomes revealed significant disparities between Type III and the others, with longer operative times [165.00 (145.00-200.50) min], warm ischemia times [24.00 (21.50-30.50) min], tumor resection times [13.00 (12.00-15.50) min], and incision closure times [22.00 (20.00-23.50) min] (all p < 0.005). Postoperative outcomes also showed significant differences, with longer durations of drain removal (77.08 ± 18.16 h) and hospitalization for Type III [5.00 (5.00-6.00) d] (all p < 0.05). Additionally, Type I had a larger tumor diameter than the others (p = 0.009) and pT stage differed significantly between the subtypes (p = 0.020). CONCLUSIONS: The novel renal hilar tumor classification system is capable of differentiating the surgical difficulty of RAPN and further offers personalized surgical steps tailored to each specific classification. It provides a meaningful tool for clinical practice.

Exploring the Effects of Different Drying Methods on Related Differential Metabolites of Pleurotus citrinopileatus Singer Based on Untargeted Metabolomics.

Pleurotus citrinopileatus Singer (PCS) has attracted increasing attention as a raw material for medicine and food. Its quality is greatly affected by the accumulation of metabolites, which varies with the applied drying methods. In this study, we utilize an approach based on ultra-high-performance liquid chromatography/Q Exactive mass spectrometry (UHPLC-QE-MS) to reveal the metabolic profiles of PCS from three different drying methods (natural air-drying, NAD; hot-air-drying, HAD; vacuum freeze-drying, VFD). The results showed that lipids, amino acids and their derivatives were all important secondary metabolites produced during NAD, HAD and VFD treatments, with the key differential metabolites of PCS during drying including fifteen lipids and seven amino acids. Meanwhile, VFD was the best way for long-term preservation of dried PCS. Hot-drying methods, especially HAD, can improve the medicinal component of PCS. Furthermore, KEGG enrichment analysis highlighted 16 pathways and indicated that amino acid metabolism might be the key metabolite pathway for the PCS drying process. Our study elucidates the relationship between drying methods and metabolites or metabolic pathways of PCS to determine the mechanisms affecting the quality of PCS, and finally provides reference values for further development and application in functional food and medications.

Cell-Impermeable Buffering Fluorogenic Probes for Live-Cell Super-Resolution Imaging of Plasma Membrane Morphology Dynamics.

Super-resolution fluorescence imaging has emerged as a potent tool for investigating the nanoscale structure and function of the plasma membrane (PM). Nevertheless, the challenge persists in achieving super-resolution imaging of PM dynamics due to limitations in probe photostability and issues with cell internalization staining. Herein, we report assembly-mediated buffering fluorogenic probes BMP-14 and BMP-16 exhibiting fast PM labeling and extended retention time (over 2 h) on PM. The incorporation of alkyl chains proves effective in promoting the aggregation of BMP-14 and BMP-16 into nonfluorescent nanoparticles to realize fluorogenicity and regulate the buffering capacity to rapidly replace photobleached probes ensuring stable long-term super-resolution imaging of PM. Utilizing these PM-buffering probes, we observed dynamic movements of PM filopodia and continuous shrinkage, leading to the formation of extracellular vesicles (EVs) using structured illumination microscopy (SIM). Furthermore, we discovered two distinct modes of EV fusion: one involving fusion through adjacent lipids and the other through filamentous lipid traction. The entire process of EV fusion outside the PM was dynamically tracked. Additionally, BMP-16 exhibited a unique capability of inducing single-molecule fluorescence blinking when used for cell membrane staining. This property makes BMP-16 suitable for the PAINT imaging of cell membranes.

Interpretable Data-Driven Descriptors for Establishing the Structure-Activity Relationship of Metal-Organic Frameworks Toward Oxygen Evolution Reaction.

The development of readily accessible and interpretable descriptors is pivotal yet challenging in the rational design of metal-organic framework (MOF) catalysts. This study presents a straightforward and physically interpretable activity descriptor for the oxygen evolution reaction (OER), derived from a dataset of bimetallic Ni-based MOFs. Through an artificial-intelligence (AI) data-mining subgroup discovery (SGD) approach, a combination of the d-band center and number of missing electrons in eg states of Ni, as well as the first ionization energy and number of electrons in eg states of the substituents, is revealed as a gene of a superior OER catalyst. The found descriptor, obtained from the AI analysis of a dataset of MOFs containing 3-5d transition metals and 13 organic linkers, has been demonstrated to facilitate in-depth understanding of structure-activity relationship at the molecular orbital level. The descriptor is validated experimentally for 11 Ni-based MOFs. Combining SGD with physical insights and experimental verification, our work offers a highly efficient approach for screening MOF-based OER catalysts, simultaneously providing comprehensive understanding of the catalytic mechanism.

China Anti-Cancer Association Guidelines for the diagnosis, treatment, and follow-up of thymic epithelial tumors (2023).

Background: Thymic epithelial tumors (TETs) are a relatively rare type of thoracic tumors with higher incidence in Asians. The diagnosis and treatment pattern has long been based mainly on clinical experience and expert consensus. In recent years, with an increasing number of TETs detected in physical examinations, there is an urgent need to develop the guidelines that apply to the Chinese population. Thus, we intend to develop a holistic integrative guideline for TETs. Methods: Under the leadership of the Chinese Anti-Cancer Association (CACA) Mediastinal Tumor Committee, a multidisciplinary guideline development group was established. Systemic literature review and two rounds of questionnaires regarding key clinical issues were carried out. The grading of recommendations assessment, development and evaluation (GRADE) approach was used to rate the quality of evidence and the strength of recommendations. Results: The CACA guideline provides recommendations for the clinical differential diagnosis of anterior mediastinal lesions, management of asymptomatic small anterior mediastinal nodules, pathological classification and staging systems of TETs, as well as principles of surgery, neoadjuvant and adjuvant therapies, systemic therapies for advanced TETs, and follow-up strategies after surgical resection. Conclusions: This guideline provides holistic integrative management strategies for TETs and would be a useful tool for clinicians on decision-making.

Unveiling the physical mechanisms driving delafossite crystal (ABX2) formation through interpretable machine learning.

A method integrating machine learning with first-principles calculations is employed to forecast the formation energy of delafossite crystals, facilitating the rapid identification of stable crystals. This approach identifies several stable candidates and highlights the importance of atomic ionization energy and electron affinity in the formation of delafossite crystals.

Thinning by cluster breaking: Active matter and shear flows share thinning mechanisms.

Among many unexpected phenomena of active matter is the recently observed superfluid-like thinning (viscosity drop) behavior of bacteria suspensions. Understanding this peculiar self-propelled thinning by active matter is of theoretical and practical importance. Here, we find that, although distinct in driving mechanisms, active matter and shear flows exhibit similar thinning behaviors upon the increase of self-propulsion and shear forces, respectively. Our structural characterizations reveal that they actually share the same cluster-breaking mechanism of thinning. How fast and how shattered the cluster is broken determines the (dis)continuity of the thinning. This explains why adding active particles to Newtonian fluids can cause thinning, in which rotation of active particles play a key role in breaking clusters. Our work proposes a mechanism of self-propelled thinning and further establishes the underlying connections between active matter and shear flows.

Self-assembled skin-like metamaterials for dual-band camouflage.

Skin-like soft optical metamaterials with broadband modulation have been long pursued for practical applications, such as cloaking and camouflage. Here, we propose a skin-like metamaterial for dual-band camouflage based on unique Au nanoparticles assembled hollow pillars (NPAHP), which are implemented by the bottom-up template-assisted self-assembly processes. This dual-band camouflage realizes simultaneously high visible absorptivity (~0.947) and low infrared emissivity (~0.074/0.045 for mid-/long-wavelength infrared bands), ideal for visible and infrared dual-band camouflage at night or in outer space. In addition, this self-assembled metamaterial, with a micrometer thickness and periodic through-holes, demonstrates superior skin-like attachability and permeability, allowing close attachment to a wide range of surfaces including the human body. Last but not least, benefiting from the extremely low infrared emissivity, the skin-like metamaterial exhibits excellent high-temperature camouflage performance, with radiation temperature reduction from 678 to 353 kelvin. This work provides a new paradigm for skin-like metamaterials with flexible multiband modulation for multiple application scenarios.

A lower eGFRcystatin C/eGFRcreatinine ratio is associated with greater cardiovascular risk (higher Framingham Risk Score) in Chinese patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients. Shrunken pore syndrome (SPS) is defined as eGFRcystatin C/eGFRcreatinine ratio <0.70 and predicts high CVD mortality. The Framingham Risk Score (FRS) is used to estimate an individual's 10-year CVD risk. This study investigated the association between FRS and eGFRcystatin C/eGFRcreatinine ratio in T2DM patients. METHODS: Patients aged 18-80 years who were newly diagnosed with T2DM were included in this retrospective study. Ordinal logistic regression analysis was used to investigate the association between risk factors of T2DM and FRS. A Generalized Linear Model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: There were 270 patients included in the study. Only 27 patients (10%) met the diagnostic criteria of SPS. Ordinal logistic regression analysis showed that SPS was not correlated with FRS risk (OR = 1.99, 95%CI = 0.94-4.23, p = 0.07), whereas eGFRcystatin C/eGFRcreatinine (OR = 0.86, 95%CI = 0.77-0.97, p = 0.01) showed a significant negative association with FRS risk. Compared with eGFRcystatin C/eGFRcreatinine>0.85, eGFRcystatin C/eGFRcreatinine≤0.85 increased FRS risk (OR = 1.95, 95%CI = 1.18-3.21, p < 0.01). After adjustment for confounding factors, increased eGFRcystatin C/eGFRcreatinine ratio was associated with decreased FRS risk when considered as a continuous variable (OR = 0.87, 95%CI = 0.77-0.99, p = 0.03). The FRS risk in patients with eGFRcystatin C/eGFRcreatinine≤0.85 is 1.86 times higher than that in patients with eGFRcystatin C/eGFRcreatinine>0.85 (OR = 1.86, 95%CI = 1.08-3.21, p = 0.03). CONCLUSIONS: In the current study, no significant association between SPS and FRS was identified. However, lower eGFRcystatin C/eGFRcreatinine and eGFRcystatin C/eGFRcreatinine≤0.85 were associated with a significantly increased CVD risk in T2DM.

The effect of ß-Glucan induced intestinal trained immunity against Trichinella spiralis infection.

Parasitic helminth Trichinella spiralis (Ts) induce mixed Th1/Th2 response with predominant type 2 immune responses, with protective immunity mediated by interleukin (IL)-4, IL-5, and IL-13. ß-Glucan (BG) has been shown to have the ability to induce trained immunity, confers non-specific protection from secondary infections. However, whether BG-induced trained immunity played a role in protective type 2 immunity against Ts infection is unclear. In this study, BG was administered five days before Ts infection to induce trained immunity. Our findings demonstrate that BG pretreatment effectively reduced the number of T. spiralis adults and muscle larvae, whereas inhibition of trained immunity abolished the effect of BG. Additionally, we observed a significant increase in goblet cells and mucus production as evidenced by Alcian blue periodic acid-Schiff staining. Furthermore, quantitative real-time PCR analysis revealed a significant upregulation of IL-4, IL-5, and IL-13 expression in response to BG. Conversely, the inhibitor of trained immunity reversed these effects, suggesting that BG-induced trained immunity confers strong protection against Ts infection. In conclusion, these findings suggest that BG-induced trained immunity may play a role in protection against infections caused by other helminths.

Relieving metabolic burden to improve robustness and bioproduction by industrial microorganisms.

Metabolic burden is defined by the influence of genetic manipulation and environmental perturbations on the distribution of cellular resources. The rewiring of microbial metabolism for bio-based chemical production often leads to a metabolic burden, followed by adverse physiological effects, such as impaired cell growth and low product yields. Alleviating the burden imposed by undesirable metabolic changes has become an increasingly attractive approach for constructing robust microbial cell factories. In this review, we provide a brief overview of metabolic burden engineering, focusing specifically on recent developments and strategies for diminishing the burden while improving robustness and yield. A variety of examples are presented to showcase the promise of metabolic burden engineering in facilitating the design and construction of robust microbial cell factories. Finally, challenges and limitations encountered in metabolic burden engineering are discussed.