Genetic Risk Loci and Familial Associations in Migraine: A Genome-Wide Association Study in the Han Chinese Population of Taiwan.

BACKGROUND AND PURPOSE: Migraine is a condition that is often observed to run in families, but its complex genetic background remains unclear. This study aimed to identify the genetic factors influencing migraines and their potential association with the family medical history. METHODS: We performed a comprehensive genome-wide association study of a cohort of 1,561 outpatients with migraine and 473 individuals without migraine in Taiwan, including Han Chinese individuals with or without a family history of migraine. By analyzing the detailed headache history of the patients and their relatives we aimed to isolate potential genetic markers associated with migraine while considering factors such as sex, episodic vs. chronic migraine, and the presence of aura. RESULTS: We revealed novel genetic risk loci, including rs2287637 in DEAD-Box helicase 1 and long intergenic non-protein coding RNA 1804 and rs12055943 in engulfment and cell motility 1, that were correlated with the family history of migraine. We also found a genetic location downstream of mesoderm posterior BHLH transcription factor 2 associated with episodic migraine, whereas loci within the ubiquitin-specific peptidase 26 exonic region, dual specificity phosphatase 9 and pregnancy-upregulated non-ubiquitous CaM kinase intergenic regions, and poly (ADP-ribose) polymerase 1 and STUM were linked to chronic migraine. We additionally identified genetic regionsassociated with the presence or absence of aura. A locus between LINC02561 and urocortin 3 was predominantly observed in female patients. Moreover, three different single-nucleotide polymorphisms were associated with the family history of migraine in the control group. CONCLUSIONS: This study has identified new genetic locations associated with migraine and its family history in a Han Chinese population, reinforcing the genetic background of migraine. The findings point to potential candidate genes that should be investigated further.

Naphthalene Diimide-Based Polycyclic Conjugated Molecule Composite CoFe2O4 Nanohybrids for Photoacoustic Imaging-Mediated Photo-/Sonic Therapy.

The complex and harsh tumor microenvironment imped the efficacy of single-modality tumor therapy. With the advantages of biosafety, organic/inorganic nanohybrids have attracted more and more interest of researchers, and it is critical to investigate the development of highly efficient nanohybrids for multimodality combination therapy of cancers. Herein, a naphthalene diimide-based polycyclic conjugated molecule (NDI-S) is designed and synthesized, which has broader light absorption in the near infrared (NIR) region, outstanding photothermal conversion ability, and excellent photostability. Inorganic CoFe2O4 is synthesized via a solvothermal technique, which can produce much more reactive oxygen species (ROS) as a sonosensitizer when activated by ultrasonic (US). NDI-S and CoFe2O4 are then nanoprecipitated to create the organic/inorganic nanohybrids, NDI-S@CoFe2O4. According to the results of in vitro and in vivo experiments, NDI-S@CoFe2O4 can serve as a multifunctional nanoplatform for multimodal treatment of tumors in combination with photothermal/photodynamic/sonodynamic- therapy under the guidance of photoacoustic imaging, which provides a new vision of the development of organic/inorganic nanohybrids for cancer theranostics.

Single-cell transcriptomic profiling unveils insights into ovarian fibrosis in obese mice.

BACKGROUND: Adiposity profoundly impacts reproductive health in both humans and animals. However, the precise subpopulations contributing to infertility under obese conditions remain elusive. RESULTS: In this study, we established an obese mouse model through an eighteen-week high-fat diet regimen in adult female mice. Employing single-cell RNA sequencing (scRNA-seq), we constructed a comprehensive single-cell atlas of ovarian tissues from these mice to scrutinize the impact of obesity on the ovarian microenvironment. ScRNA-seq revealed notable alterations in the microenvironment of ovarian tissues in obese mice. Granulosa cells, stromal cells, T cells, and macrophages exhibited functional imbalances compared to the control group. We observed heightened interaction strength in the SPP1-CD44 pairing within lgfbp7+ granulosa cell subtypes and Il1bhigh monocyte subtypes in the ovarian tissues of obese mice. Moreover, the interaction strength between Il1bhigh monocyte subtypes and Pdgfrb+ stromal cell subtypes in the form of TNF - TNFrsf1α interaction was also enhanced subsequently to obesity, potentially contributing to ovarian fibrosis pathogenesis. CONCLUSIONS: We propose a model wherein granulosa cells secrete SPP1 to activate monocytes, subsequently triggering TNF-α secretion by monocytes, thereby activating stromal cells and ultimately leading to the development of ovarian fibrosis. Intervening in this process may represent a promising avenue for improving clinical outcomes in fertility treatments for obese women.

Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. METHODS: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult-to-treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). RESULTS: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (-13.0 vs. -8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (-13.0 vs. -9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication-overuse headache (MOH) (-13.3 vs. -9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (-42.2 vs. -11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. CONCLUSIONS: In this multicenter, real-world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

A Bibliometric Analysis of the Spatial Transcriptomics Literature from 2006 to 2023.

In recent years, spatial transcriptomics (ST) research has become a popular field of study and has shown great potential in medicine. However, there are few bibliometric analyses in this field. Thus, in this study, we aimed to find and analyze the frontiers and trends of this medical research field based on the available literature. A computerized search was applied to the WoSCC (Web of Science Core Collection) Database for literature published from 2006 to 2023. Complete records of all literature and cited references were extracted and screened. The bibliometric analysis and visualization were performed using CiteSpace, VOSviewer, Bibliometrix R Package software, and Scimago Graphica. A total of 1467 papers and reviews were included. The analysis revealed that the ST publication and citation results have shown a rapid upward trend over the last 3 years. Nature Communications and Nature were the most productive and most co-cited journals, respectively. In the comprehensive global collaborative network, the United States is the country with the most organizations and publications, followed closely by China and the United Kingdom. The author Joakim Lundeberg published the most cited paper, while Patrik L. Ståhl ranked first among co-cited authors. The hot topics in ST are tissue recognition, cancer, heterogeneity, immunotherapy, differentiation, and models. ST technologies have greatly contributed to in-depth research in medical fields such as oncology and neuroscience, opening up new possibilities for the diagnosis and treatment of diseases. Moreover, artificial intelligence and big data drive additional development in ST fields.

Reverse Micelles Extraction of Prolamin from Baijiu Jiuzao: Impact of Isolation Process on Protein Structure and Morphology.

Prolamins, proteins derived from plants, have extensive applications in pharmaceutics and food science. Jiuzao is a byproduct of the Baijiu brewing industry, and is a great source of prolamin. Despite its importance, knowledge regarding the extraction techniques and the properties of prolamin derived from Baijiu Jiuzao (PBJ) remains limited. Reverse micelles (RMs) extraction offers an efficient and cost-effective method for purifying proteins. In the present study, prolamin was extracted from Baijiu Jiuzao using RMs extraction and subsequently characterized in terms of its secondary structure, morphology, and particle size distribution. Our findings indicate that the purified prolamin extracted using further RMs extraction possessed higher α-helix content (+13.25%), forming a large-scale protein network, and narrower particle size distributions compared to the crude prolamin obtained by NaOH-ethanol method. This research suggests that RMs extraction has potential applications in extracting prolamin from brewing industry byproducts, offering an environmentally friendly approach to Baijiu Jiuzao recycling.

Experimental Study on Vacuum Distillation Separation Characteristics of Tar Containing Solid Particles: Distributions of Light Components.

The impacts of the composition and properties of tar products on their utilization are of great importance, while the consequences of varying tar separation conditions on distillation fractions remain underexplored. Solid impurities in special tar products (e.g., subsurface in situ pyrolysis-derived tar-like substances) can contribute to the separation as well. In the present study, low-temperature coal tar (LTCT) was used as an analogue to pyrolysis product, mixed with semi-coke and coal dust, representing pyrolytic byproducts and nonpyrolytic substances, respectively. The LTCT mixtures were tested with vacuum distillation at various pressures and temperatures. The results revealed the role of pressure in fraction distribution across temperatures, with higher pressure concentrating fractions at lower temperatures. The impact of solid impurities on distillation primarily stemmed from adsorption. Minimal concentrations of solid impurities carried coal dust/semi-coke into the distillation, but higher levels retained them in the residue. The adsorption of coal dust was quite high at lower temperatures and waned as temperature increased, unlike semi-coke, which had consistent adsorption throughout the distillation. The present study can advance the understanding of vacuum distillation for tar products in the presence of solid impurities, offering a framework for the effective distillation/utilization of coal tar. By probing separation conditions, tar properties, and solid impurity effects, the present research will refine strategies for optimizing coal tar use, crucial for enhancing energy security and sustainable progress in China.

Effect of Kinesiology Taping on Breast Cancer-Related Lymphedema: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: The objective of this systematic review and meta-analysis was to evaluate the impact of kinesiology taping on individuals suffering from breast cancer-related lymphedema. METHODS AND METHODS: We conducted a comprehensive search in PubMed, Cochrane Library, and Embase databases, spanning from their inception date to December 20, 2023, to identify pertinent studies. Inclusion criteria comprised studies that (1) enrolled participants diagnosed with breast cancer-related lymphedema; (2) implemented kinesiology taping as the intervention; (3) incorporated either complete decongestive therapy, exercise, or sham taping as the control treatment; and (4) included clinical measurements such as the severity of lymphedema, upper limb function assessment, quality of life, and perceived comfort. RESULTS: Information was extracted from 14 randomized controlled trials (RCTs). The analyses demonstrated statistically significant improvement, indicating a preference for kinesiology taping in the outcomes of upper limb functional assessment (standardized mean difference [SMD] = -0.88, 95% confidence interval [CI]: [-1.22, -0.55]), quality of life (SMD = 0.50, 95% CI: [0.16, 0.84]), and perceived comfort (SMD = 0.85, 95% CI: [0.34, 1.36]). CONCLUSION: The findings suggest that kinesiology taping could be considered a viable option for individuals dealing with breast cancer-related lymphedema. Nevertheless, acknowledging certain limitations within this study, further confirmation of its benefits necessitates additional larger-scale and better-designed RCTs.

Gabapentinoids for chemotherapy-induced peripheral neuropathy: systematic review and meta-analysis.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) affects patients' quality of life and treatment effectiveness. Gabapentinoids, like gabapentin and pregabalin, are often used for CIPN treatment, but their efficacy and safety remain uncertain. This study reviews and analyses randomised controlled trial data on this topic. MATERIALS/METHODS: We searched PubMed, Embase and Cochrane CENTRAL until 29 August 2022 for studies on gabapentinoid use in CIPN. Meta-analysis was performed using RevMan V.5.4 and the Metafor package in R. Outcomes included pain scores, quality of life and adverse drug events. RESULTS: For the prevention setting, our meta-analysis shows that pregabalin did not significantly improve average pain (standardised mean difference (SMD) -0.14, 95% CI -0.51 to 0.23; I2=26% (95% CI 0% to >98%)) or quality of life (mean difference (MD) 2.5, 95% CI -4.67 to 9.67; p=0.49) in preventing CIPN compared with placebo. However, it showed a potential trend towards reducing the worst pain (SMD -0.28, 95% CI -0.57 to 0.01; I2=0% (95% CI 0% to 98%; p=0.06)). For the treatment setting, some studies have shown a potential therapeutic effect of gabapentinoids. However, the results are not consistent between studies. Given the studies' heterogeneity, a meta-analysis in treatment setting was not performed. CONCLUSION: There is limited evidence to support the use of gabapentinoids in CIPN. In prevention setting, gabapentinoids do not significantly prevent CIPN. In treatment setting, studies have been inconsistent in their conclusions, lacking definitive benefits over placebo. More comprehensive and higher quality research is needed in the future. PROSPERO REGISTRATION NUMBER: CRD42022361193.

TAF15 downregulation contributes to the benefits of physical training on dendritic spines and working memory in aged mice.

Moderate physical training has been shown to hinder age-related memory decline. While the benefits of physical training on hippocampal memory function are well-documented, little is known about its impact on working memory, which is linked to the prelimbic cortex (PrL), one major subdivision of the prefrontal cortex. Here, we examined the effects of physical training on spatial working memory in a well-established animal model of physical training, starting at 16 months of age and continuing for 5 months (running wheel 1 h/day and 5 days/week). This training strategy improved spatial working memory in aged mice (22-month-old), which was accompanied by an increased spine density and a lower TAF15 expression in the PrL. Specifically, physical training affected both thin and mushroom-type spines on PrL pyramidal cells, and prevented age-related loss of spines on selective segments of apical dendritic branches. Correlation analysis revealed that increased TAF15-expression was detrimental to the dendritic spines. However, physical training downregulated TAF15 expression in the PrL, preserving the dendritic spines on PrL pyramidal cells and improving working memory in trained aged mice. When TAF15 was overexpressed in the PrL via a viral approach, the benefits of physical training on the dendritic spines and working memory were abolished. These data suggest that physical training at a moderate pace might downregulate TAF15 expression in the PrL, which favors the dendritic spines on PrL pyramidal cells, thereby improving spatial working memory.

Longitudinal assessment of plasma biomarkers for early detection of cognitive changes in subjective cognitive decline.

Background: Individuals experiencing subjective cognitive decline (SCD) are at an increased risk of developing mild cognitive impairment and dementia. Early identification of SCD and neurodegenerative diseases using biomarkers may help clinical decision-making and improve prognosis. However, few cross-sectional and longitudinal studies have explored plasma biomarkers in individuals with SCD using immunomagnetic reduction. Objective: To identify plasma biomarkers for SCD. Methods: Fifty-two participants [38 with SCD, 14 healthy controls (HCs)] underwent baseline assessments, including measurements of plasma Aß42, Aß40, t-tau, p-tau, and α-synuclein using immunomagnetic reduction (IMR) assays, cognitive tests and the Mini-Mental State Examination (MMSE). Following initial cross-sectional analysis, 39 individuals (29 with SCD, 10 HCs) entered a longitudinal phase for reassessment of these biomarkers and the MMSE. Biomarker outcomes across different individual categories were primarily assessed using the area under the receiver operating characteristic (ROC) curve. The SCD subgroup with an MMSE decline over one point was compared to those without such a decline. Results: Higher baseline plasma Aß1-42 levels significantly discriminated participants with SCD from HCs, with an acceptable area under the ROC curve (AUC) of 67.5% [95% confidence interval (CI), 52.7-80.0%]. However, follow-up and changes in MMSE and IMR data did not significantly differ between the SCD and HC groups (p > 0.05). Furthermore, lower baseline plasma Aß1-42 levels were able to discriminate SCD subgroups with and without cognitive decline with a satisfied performance (AUC, 75.0%; 95% CI, 55.6-89.1%). At last, the changes in t-tau and Aß42 × t-tau could differentiate between the two SCD subgroups (p < 0.05). Conclusion: Baseline plasma Aß42 may help identify people with SCD and predict SCD progression. The role of plasma Aß42 levels as well as their upward trends from baseline in cases of SCD that progress to mild cognitive impairment and Alzheimer's disease require further investigation.

Signatures of Adaptation and Purifying Selection in Highland Populations of Dasiphora fruticosa.

High mountains harbor a considerable proportion of biodiversity, but we know little about how diverse plants adapt to the harsh environment. Here we finished a high-quality genome assembly for Dasiphora fruticosa, an ecologically important plant distributed in the Qinghai-Tibetan Plateau and lowland of the Northern Hemisphere, and resequenced 592 natural individuals to address how this horticulture plant adapts to highland. Demographic analysis revealed D. fruticosa underwent a bottleneck after Naynayxungla Glaciation. Selective sweep analysis of two pairs of lowland and highland populations identified 63 shared genes related to cell wall organization or biogenesis, cellular component organization, and dwarfism, suggesting parallel adaptation to highland habitats. Most importantly, we found that stronger purging of estimated genetic load due to inbreeding in highland populations apparently contributed to their adaptation to the highest mountain. Our results revealed how plants could tolerate the extreme plateau, which could provide potential insights for species conservation and crop breeding.

Oncogenic functions and therapeutic potentials of targeted inhibition of SMARCAL1 in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by high frequency loss-of-function mutations in tumor suppressors with a lack of targeted therapy due to absence of high frequency gain-of-function abnormalities in oncogenes. SMARCAL1 is a member of the ATP-dependent chromatin remodeling protein SNF2 family that plays critical roles in DNA damage repair and genome stability maintenance. Here, we showed that SMARCAL1 was overexpressed in SCLC patient samples and was inversely associated with overall survival of the patients. SMARCAL1 was required for SCLC cell proliferation and genome integrity. Mass spectrometry revealed that PAR6B was a downstream SMARCAL1 signal molecule which rescued inhibitory effects caused by silencing of SMARCAL1. By screening of 36 FDA-approved clinically available agents related to DNA damage repair, we found that an aza-anthracenedione, pixantrone, was a potent SMARCAL1 inhibitor which suppressed the expression of SMARCAL1 and PAR6B at protein level. Pixantrone caused DNA damage and exhibited inhibitory effects on SCLC cells in vitro and in a patient-derived xenograft mouse model. These results indicated that SMARCAL1 functions as an oncogene in SCLC, and pixantrone as a SMARCAL1 inhibitor bears therapeutic potentials in this deadly disease.

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease.

BACKGROUND: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. METHODS: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). RESULTS: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased ß-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). CONCLUSIONS: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

The value of urinary exosomal microRNA-21 in the early diagnosis and prognosis of bladder cancer.

Bladder cancer (BC) poses high morbidity and mortality, with urinary exosomal microRNA (miR)-21 showing potential value in its diagnosis and prognosis, and we probed its specific role. We prospectively selected 116 BC patients and 116 healthy volunteers as the BC and control groups, respectively. BC urinary exosomal miR-146a-5p, miR-93-5p, miR-663b, miR-21, and miR-4454 relative expression levels were assessed. The correlations between clinical indexes and urinary exosomal miR-21, prognostic value of miR-21, and diagnostic value of the five candidate miRNAs, urine cytology, and miRNA joint diagnostic panel for BC and urinary exosomal miR-21, miR-4454, and urine cytology for Ta-T1 and T2-T4 stage BC were analyzed. Urinary exosomal miR-146a-5p, miR-93-5p, miR-663b, miR-21, and miR-4454 were highly expressed in BC patients. miR-146a-5p, miR-93-5p, miR-663b, miR-21, miR-4454, miRNA combined diagnostic panel, and urine cytology had certain diagnostic value for BC, with miR-21, miR-4454, and miRNA co-diagnostic panel showing the highest diagnostic value. Collectively, urinary exosomal miR-21 was closely related to Tumor-Node-Metastasis staging and grading in BC patients. Urinary exosomal miR-21 had high diagnostic value for BC and Ta-T1 and T2-T4 stage BC, and had high predictive value for BC poor prognosis, providing an effective indicator for the occurrence, development, and prognostic assessment of BC.

Stereoscopic Polymer Network for Developing Mechanically Robust Flexible Perovskite Solar Cells with an Efficiency Approaching 25.

Flexible perovskite solar cells (pero-SCs) have the potential to overturn the application scenario of silicon photovoltaic technology. However, their mechanical instability severely impedes their practical applicability, and the corresponding intrinsic degradation mechanism remains unclear. In this study, the degradation behavior of flexible pero-SCs is systematically analyzed under mechanical stress and it is observed that the structural failure first occurs in the polycrystal perovskite film, then extend to interfaces. To suppress the structural failure, pentaerythritol triacrylate, a crosslinked molecule with three stereoscopic crosslink sites, is employed to establish a 3D polymer network in both the interface and bulk perovskite. This network reduced the Young's modulus of the perovskite and simultaneously enhanced the interfacial toughness. As a result, the formation of cracks and delamination, which occur under a high mechanical stress, is significantly suppressed in the flexible pero-SC, which consequently retained 92% of its initial power conversion efficiency (PCE) after 20 000 bending cycles. Notably, the flexible device also shows a record PCE of 24.9% (certified 24.48%).

Mucus Impaction Related to Postoperative Anastomosis Site Obstruction: A Rare Case.

Anastomotic stricture has an incidence rate of 6-10% and typically manifests three to six months after colorectal surgery. Immediate postoperative stricture is exceedingly rare and underreported in the literature. The possible etiology includes poor circulation, leakage, local inflammation, or infection. We report a rare case of a patient with total obstruction by mucus on the anastomosis site on postoperation day two. We used a sigmoidoscope to remove mucus material, following which the patient recovered well.

Hyperbaric Lidocaine Aggravates Diabetic Neuropathic Pain by Targeting p38 MAPK/ERK and PINK1/Parkin-Mediated Mitophagy Signaling Pathway.

BACKGROUND: Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP. METHODS: The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively. RESULTS: PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy. CONCLUSION: In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.

Injection therapy for carpal tunnel syndrome: A systematic review and network meta-analysis of randomized controlled trials.

Various injectants are available for the treatment of carpal tunnel syndrome. This systematic review and network meta-analysis was conducted to investigate the effectiveness of different injection therapies in alleviating the symptoms of carpal tunnel syndrome. Various databases were searched for relevant studies from inception until May 10, 2023. Eligible studies were identified using the patient (P), intervention (I), comparison (C), and outcomes (O) model, which involved (P) participants with carpal tunnel syndrome, (I) an intervention based on injection therapy, (C) the use of placebo or another injectant as a control treatment, and (O) the measurement of clinical and electrodiagnostic outcomes of interest. A total of 18 studies were included in the analysis. The network meta-analysis revealed that platelet-rich plasma is effective in the treatment of carpal tunnel syndrome in terms of symptom and pain relief and functional improvement in both the short and long term, whereas steroids are effective only in the short term. Additionally, injections of dextrose solution may offer long-term pain relief as well as short- and long-term symptom alleviation and functional improvement. The study findings suggest that platelet-rich plasma should be used as the first-line treatment for carpal tunnel syndrome, with dextrose and steroids serving as alternative treatment options.

Photodynamic therapy inhibits cancer progression and induces ferroptosis and apoptosis by targeting P53/GPX4/SLC7A11 signaling pathways in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a malignant tumor with a poor prognosis. The specific mechanism of photodynamic therapy (PDT) in treating CCA remains unclear. This study aims to investigate the mechanisms of PDT in the treatment of CCA and try to improve the therapeutic effect of PDT by intervening associated signaling pathways. METHODS: The Cell Counting Kit-8 (CCK-8) was used to examine the cytotoxicity of CCA cell lines following PDT. Apoptosis and reactive oxygen species (ROS) levels were measured by flow cytometry. A transmission electron microscope was used to study the changes in cell mitochondria after PDT. The levels of glutathione (GSH), malondialdehyde (MDA), ferrous iron (Fe2+), lactate dehydrogenase (LDH), and lipid peroxide (LPO) were determined. Changes in the expression of apoptosis and ferroptosis-related proteins were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Xenograft tumor models were developed to investigate the effects of PDT on tumor proliferation, apoptosis, and ferroptosis in vivo. RESULTS: PDT inhibited tumor proliferation and induced apoptosis both in vivo and in vitro. This treatment led to swelling and damage of the mitochondria in affected cells. Furthermore, ROS levels rose, accompanied by an increase in the proportion of apoptotic-positive cells. The expressions of Bax and Caspase-3 were upregulated, while the Bcl-2 was downregulated. Meanwhile, PDT triggered ferroptosis, marked by decreased expressions of GPX4 and SLC7A11, and reduced GSH levels. This was accompanied by upregulation of P53 expression and heightened levels of Fe2+, LPO, MDA, and LDH. After inducing the ferroptosis pathway, the therapeutic effect of PDT was enhanced, the tumor tissue was further reduced, and the degree of malignancy was reduced. CONCLUSION: PDT promotes apoptosis and ferroptosis of cholangiocarcinoma cells by activating the P53/SLC7A11/GPX4 signaling pathway and inhibits the growth of cholangiocarcinoma. Inducing ferroptosis can enhance the effectiveness of photodynamic therapy.