Clinical characteristics, genetic alterations, and prognosis of adult T-cell leukemia/lymphoma: an 11-year multicenter retrospective study in China.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis, and there is little data available from the Chinese population. This retrospective study included 115 patients diagnosed with ATLL who were treated across five hospitals in China from June 2011 to December 2022. The median age at diagnosis was 53 years. Several genes involved in T-cell receptor-induced nuclear factor κB (TCR-NF-κB) signaling were commonly mutated, including PLCG1, CIC, PRKCB, CARD11, and IRF4. Eighty-seven patients received chemotherapy. Of these, 13 received a hematopoietic stem cell transplant (HSCT) (allogeneic-HSCT, n=9; autologous-HSCT, n=4) after chemotherapy. Following initial multiagent chemotherapy using EPOCH/CHOEP and other regimens, the overall response rates were 80.6% (complete response [CR], 44.4%) and 42.8% (CR, 14.2%), respectively. The 4-year survival rates (median survival time in days) for EPOCH/CHOEP (n=43), HSCT (n=13), and CHOP-based regimens (n=31) were 12.7% (138), 30.8% (333), and 0% (66), respectively. Lymphadenopathy, EPOCH/CHOEP, and hematopoietic stem cell transplantation were independent prognostic protective factors in patients with aggressive ATLL. Chinese patients exhibit a higher incidence of aggressive-type ATLL, sharing similar genetic alterations with Japanese patients. Etoposide-based chemotherapy (EPOCH or CHOEP) remains the preferred choice for aggressive ATLL, and upfront allogeneic HSCT should be considered in all eligible patients.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation.

INTRODUCTION: Lung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear. METHODS: Firstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan-Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed. RESULTS: Firstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis. CONCLUSION: Our study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Comparative Analysis of Postoperative Sagittal Balance in Expansive Open-Door Laminoplasty versus Laminectomy with Fusion for Multilevel Ossification of Posterior Longitudinal Ligament: A Retrospective Study.

BACKGROUND This single-center study included 80 patients with multilevel cervical ossification of the posterior longitudinal ligament (OPLL) and aimed to compare postoperative sagittal balance following treatment with expansive open-door laminoplasty (LP) vs total laminectomy with fusion (LF). MATERIAL AND METHODS Data of 80 patients with multilevel OPLL treated with LP vs LF between January 2017 and January 2022 were retrospectively analyzed. The basic data, cervical sagittal parameters, and clinical outcomes of the patients were counted in the preoperative and postoperative periods, and complications were recorded. Forty patients underwent LP and 40 underwent LF. Cervical sagittal parameters were compared between and within the 2 groups. Clinical outcomes and complications were compared between the 2 groups. RESULTS At last follow-up, the postoperative C2-C7 Cobb angel, T1 slope (T1S), and C7 slope (C7S) were significantly higher in the LF group than in the LP group (P<0.001). C2-C7 SVA (cSVA) was slightly higher in the LF group (P>0.05) and significantly higher in the LP group (P<0.05). The incidence of postoperative complications in the LP group was significantly lower than in the LF group (P=0.02). The postoperative scores on the Visual Analog Scale (VAS), Neck Disability Index (NDI), and Japanese Orthopedic Association (JOA) were significantly improved in both groups (P<0.001). CONCLUSIONS Both procedures had good outcomes in neurological improvement. After posterior surgery, the cervical vertebrae all showed a tilting forward. Compared to LP, LF may change cervical balance in Cobb angel, T1S. LF has better efficacy in improving cervical lordosis compared with LP. Patients with high T1 slope after surgery may has more axial pain.

Treatment of Moderate-to-Severe Pain in Hepatocellular Carcinoma with Transcutaneous Electrical Acupoint Stimulation: A Randomized Controlled Trial.

Objective: Moderate-to-severe pain is the most common clinical symptom in patients with hepatocellular carcinoma (HCC).This trial aimed to analyze the clinical efficacy of Transcutaneous electrical acupoint stimulation (TEAS) in patients of HCC with severe pain and provide a reliable reference for optimizing the clinical diagnostic and therapeutic strategies of HCC. Methods: A total of 104 eligible patients were randomly allocated to experimental and control groups in a ratio of 1:1.The treatment was administered for 1 week continuously. Patients in both groups were followed up 1 week after the end of the treatment.The primary outcome measure was the Numerical Rating Scale (NRS) score, whereas the secondary outcome measures included Brief Pain Inventory BPI-Q3, Q4, Q5 scores, analgesic dose, frequency of opioid-induced gastrointestinal side effects, Karnofsky Performance Status (KPS), Quality of Life Scale - Liver Cancer (QOL-LC), and Brief Fatigue Inventory (BFI) scores. Results: The NRS scores of experimental group was significantly lower after treatment and at the follow-up than baseline (average P<0.01), there were also statistical differences between the groups at the above time points (average P<0.01). BPI-Q3, -Q4, and -Q5 scores in the experimental group were decreased after treatment when compared with those before treatment (average P<0.01). Furthermore, there were significant improvements of gastrointestinal side effects, KPS, QOL-LC and BPI in the experimental group after treatment, and the above results were statistically significant compared to the control group. Conclusion: 7-day TEAS treatment can significantly enhance the analgesic effect and maintain for the following week, also reduce the incidence of gastrointestinal side effects caused by opioids, and improve the quality of life of patients with moderate-to-severe HCC-related pain, which has reliable safety and certain clinical promotion value.

The value of surgery and the prognostic factors for patients with recurrent low-grade endometrial stromal sarcoma: a retrospective study of 38 patients.

OBJECTIVE: As an indolent malignant tumor, the long-term management of low-grade endometrial stromal sarcoma (LGESS) patients required awareness, especially the management of recurrences. Unfortunately, few studies focused on the treatment of recurrent LGESS. Our study aimed to investigate the prognostic factors and the value of recurrent surgery on recurrent LGESS. METHODS: This retrospective study consecutively recruited patients with pathologically diagnosed recurrent LGESS at our center from April 1, 2004 to April 1, 2020. RESULTS: After a median follow-up of 137.0 months (95% confidence interval=85.4-188.6), the 5-year cumulative survival rate of the cohort of 38 patients with recurrent LGESS was 71.1%. The median overall survival (OS) and post-recurrence survival (PRS) was 156 and 89.0 months. Survival analysis showed that patients with younger age, positive estrogen receptor (ER) and optimal abdominopelvic debulking in the first recurrent surgery had better prognosis (p<0.05). Multivariate analysis showed that optimal abdominopelvic debulking in the first recurrent surgery was the only independent prognostic factor for OS and PRS (OS=216.0/35.0 months, hazard ratio [HR]=5.319, p=0.034; PRS=not reached/4.0 months, HR=10.900, p=0.006). There was no significant difference in OS and PRS between patients recurred only once and those recurred at least twice (p>0.05). CONCLUSIONS: The prognosis of recurrent LGESS was favorable. Optimal debulking of no residual tumor in abdominal and pelvic cavity should be the first choice of treatment for recurrent patients, while preservation of ovary or fertility should not be recommended.

Identification of circRNAs expression profiles and functional networks in parotid gland of type 2 diabetes mouse.

BACKGROUND: Circular RNAs (circRNAs) are a novel kind of non-coding RNAs proved to play crucial roles in the development of multiple diabetic complications. However, their expression and function in diabetes mellitus (DM)-impaired salivary glands are unknown. RESULTS: By using microarray technology, 663 upregulated and 999 downregulated circRNAs companied with 813 upregulated and 525 downregulated mRNAs were identified in the parotid glands (PGs) of type2 DM mice under a 2-fold change and P < 0.05 cutoff criteria. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis of upregulated mRNAs showed enrichments in immune system process and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Infiltration of inflammatory cells and increased inflammatory cytokines were observed in diabetic PGs. Seven differently expressed circRNAs validated by qRT-PCR were selected for coding-non-coding gene co-expression (CNC) and competing endogenous RNA (ceRNA) networks analysis. PPAR signaling pathway was primarily enriched through analysis of circRNA-mRNA networks. Moreover, the circRNA-miRNA-mRNA networks highlighted an enrichment in the regulation of actin cytoskeleton. CONCLUSION: The inflammatory response is elevated in diabetic PGs. The selected seven distinct circRNAs may attribute to the injury of diabetic PG by modulating inflammatory response through PPAR signaling pathway and actin cytoskeleton in diabetic PGs.

Xylanase VmXyl2 is involved in the pathogenicity of Valsa mali by regulating xylanase activity and inducing cell necrosis.

Xylanase plays a key role in degrading plant cell wall during pathogenic fungi infection. Here, we identified a xylanase gene, VmXyl2 from the transcriptome of Valsa mali and examined its function. VmXyl2 has highly elevated transcript levels during the infection process of V. mali, with 15.02-fold increase. Deletion mutants of the gene were generated to investigate the necessity of VmXyl2 in the development and pathogenicity of V. mali. The VmXyl2 deletion mutant considerably reduced the virulence of V. mali in apple leaves and in twigs, accompanied by 41.22% decrease in xylanase activity. In addition, we found that VmXyl2 induces plant cell necrosis regardless of its xylanase activity, whereas promoting the infection of V. mali in apple tissues. The cell death-inducing activity of VmXyl2 dependent on BRI1-associated kinase-1 (BAK1) but not Suppressor of BIR1-1 (SOBIR1). Furthermore, VmXyl2 interacts with Mp2 in vivo, a receptor-like kinase with leucine-rich repeat. The results offer valuable insights into the roles of VmXyl2 in the pathogenicity of V. mali during its infection of apple trees.

PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton, modulating emotional behavior.

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders.

Analyzing the characteristics of respiratory microbiota after the placement of an airway stent for malignant central airway obstruction.

Malignant central airway stenosis is treated with airway stent placement, but post-placement microbial characteristics remain unclear. We studied microbial features in 60 patients post-stent placement, focusing on changes during granulation tissue proliferation. Samples were collected before stent (N = 29), after stent on day 3 (N = 20), and after granulation tissue formation (AS-GTF, N = 43). Metagenomic sequencing showed significant respiratory tract microbiota changes with granulation tissue. The microbiota composition, dominated by Actinobacteria, Firmicutes, and Proteobacteria, was similar among the groups. At the species level, the AS-GTF group exhibited significant differences, with Peptostreptococcus stomatis and Achromobacter xylosoxidans enriched. Analysis based on tracheoesophageal fistula presence identified Tannerella forsythia and Stenotrophomonas maltophilia as the main differential species, enriched in the fistula subgroup. Viral and fungal detection showed Human gammaherpesvirus 4 and Candida albicans as the main species, respectively. These findings highlight microbiota changes after stent placement, potentially associated with granulation tissue proliferation, informing stent placement therapy and anti-infective treatment optimization. IMPORTANCE: Malignant central airway stenosis is a life-threatening condition that can be effectively treated with airway stent placement. However, despite its clinical importance, the microbial characteristics of the respiratory tract following stent insertion remain poorly understood. This study addresses this gap by investigating the microbial features in patients with malignant central airway stenosis after stent placement, with a specific focus on microbial changes during granulation tissue proliferation. The findings reveal significant alterations in the diversity and structure of the respiratory tract microbiota following the placement of malignant central airway stents. Notably, certain bacterial species, including Peptostreptococcus stomatis and Achromobacter xylosoxidans, exhibit distinct patterns in the after-stent granulation tissue formation group. Additionally, the presence of tracheoesophageal fistula further influences the microbial composition. These insights provide valuable references for optimizing stent placement therapy and enhancing clinical anti-infective strategies.

Natural Antioxidants: An Effective Strategy for the Treatment of Alzheimer's Disease at the Early Stage.

The critical role of oxidative stress in Alzheimer's disease (AD) has been recognized by researchers recently, and natural antioxidants have been demonstrated to have anti-AD activity in animal models, such as Ginkgo biloba extract, soy isoflavones, lycopene, and so on. This paper summarized these natural antioxidants and points out that natural antioxidants always have multiple advantages which are help to deal with AD, such as clearing free radicals, regulating signal transduction, protecting mitochondrial function, and synaptic plasticity. Based on the available data, we have created a relatively complete pathway map of reactive oxygen species (ROS) and AD-related targets and concluded that oxidative stress caused by ROS is the core of AD pathogenesis. In the prospect, we introduced the concept of a combined therapeutic strategy, termed "Antioxidant-Promoting Synaptic Remodeling," highlighting the integration of antioxidant interventions with synaptic remodeling approaches as a novel avenue for therapeutic exploration.

The role of noncoding RNAs in beta cell biology and tissue engineering.

The loss or dysfunction of pancreatic ß-cells, which are responsible for insulin secretion, constitutes the foundation of all forms of diabetes, a widely prevalent disease worldwide. The replacement of damaged ß-cells with regenerated or transplanted cells derived from stem cells is a promising therapeutic strategy. However, inducing the differentiation of stem cells into fully functional glucose-responsive ß-cells in vitro has proven to be challenging. Noncoding RNAs (ncRNAs) have emerged as critical regulatory factors governing the differentiation, identity, and function of ß-cells. Furthermore, engineered hydrogel systems, biomaterials, and organ-like structures possess engineering characteristics that can provide a three-dimensional (3D) microenvironment that supports stem cell differentiation. This review summarizes the roles and contributions of ncRNAs in maintaining the differentiation, identity, and function of ß-cells. And it focuses on regulating the levels of ncRNAs in stem cells to activate ß-cell genetic programs for generating alternative ß-cells and discusses how to manipulate ncRNA expression by combining hydrogel systems and other tissue engineering materials. Elucidating the patterns of ncRNA-mediated regulation in ß-cell biology and utilizing this knowledge to control stem cell differentiation may offer promising therapeutic strategies for generating functional insulin-producing cells in diabetes cell replacement therapy and tissue engineering.

Gray matter volume and corresponding covariance connectivity are biomarkers for major depressive disorder.

The major depressive disorder (MDD) is a common and severe mental disorder. To identify a reliable biomarker for MDD is important for early diagnosis and prevention. Given easy access and high reproducibility, the structural magnetic resonance imaging (sMRI) is an ideal method to identify the biomarker for depression. In this study, sMRI data of first episode, treatment-naïve 66 MDD patients and 54 sex-, age-, and education-matched healthy controls (HC) were used to identify the differences in gray matter volume (GMV), group-level, individual-level covariance connections. Finally, the abnormal GMV and individual covariance connections were applied to classify MDD from HC. MDD patients showed higher GMV in middle occipital gyrus (MOG) and precuneus (PCun), and higher structural covariance connections between MOG and PCun. In addition, the Allen Human Brain Atlas (AHBA) was applied and revealed the genetic basis for the changes of gray matter volume. Importantly, we reported that GMV in MOG, PCun and structural covariance connectivity between MOG and PCun are able to discriminate MDD from HC. Our results revealed structural underpinnings for MDD, which may contribute towards early discriminating for depression.

Improvement of skin wound healing by giant salamander skin mucus gel wrapped with bone marrow mesenchymal stem cells via affecting integrin family molecules.

BACKGROUND: Traditional bandages, gauze, and cotton balls are increasingly insufficient for addressing complex war injuries characterized by severe bleeding and diverse wound conditions. The giant salamander, a species of high medical value, secretes a unique mucus when stimulated, which has potential applications in wound care. MATERIALS: Giant salamander skin mucus gel dressing wrapped with bone marrow mesenchymal stem cells (BMSCs-GSSM-gel) was prepared and validated. Skin wound injury of rabbit and mouse models were established. Hematoxylin and Eosin, Masson's trichrome, and Sirius red staining were performed. The platelet aggregation rate and coagulation items were measured. Transcriptome sequencing was performed to find potential differential expression genes. RESULTS: Preparation and characterization of BMSCs-GSSM-gel were performed, and BMSCs-GSSM-gel particles with a diameter of about 200 nm were obtained. BMSCs-GSSM-gel accelerated wound healing in both rabbit and mouse models. BMSCs-GSSM-gel significantly promoted hemostasis via increasing platelet aggregation rate and fibrinogen, but decreasing activated partial thromboplastin time, thrombin time, and prothrombin time. BMSCs-GSSM-gel treatment significantly impacted several genes associated with cell adhesion, inflammatory response, collagen-containing extracellular matrix, and the positive regulation of cell migration based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Integrin Subunit Beta 4 (ITGB4), Integrin Subunit Alpha 3 (ITGA3), and Laminin Subunit Beta 3 (LAMB3) might be involved in the wound healing process by BMSCs-GSSM-gel. CONCLUSIONS: We proved the BMSCs-GSSM-gel greatly improved the skin wound healing, and it might play a crucial role in the application fields of skin damage repair.

Unraveling the immunogenic cell death pathways in gastric adenocarcinoma: A multi-omics study.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal (GI) system. However, the lack of reliable biomarkers has made its diagnosis, prognosis, and treatment challenging. Immunogenic cell death (ICD) is a type of programmed cell death that is strongly related to the immune system. However, its function in GC requires further investigation. METHOD: We used multi-omics and multi-angle approaches to comprehensively explore the prognostic features of ICD in patients with stomach adenocarcinoma (STAD). At the single-cell level, we screened genes associated with ICD at the transcriptome level, selected prognostic genes related to ICD using weighted gene co-expression network analysis (WGCNA) and machine learning, and constructed a prognostic model. In addition, we constructed nomograms that incorporated pertinent clinical features and provided effective tools for prognostic prediction in clinical settings. We also investigated the sensitivity of the risk subgroups to both immunotherapy and drugs. Finally, in addition to quantitative real-time polymerase chain reaction, immunofluorescence was used to validate the expression of ICD-linked genes. RESULTS: Based on single-cell and transcriptome WGCNA analyses, we identified 34 ICD-related genes, of which 11 were related to prognosis. We established a prognostic model using the least absolute shrinkage and selection operator (LASSO) algorithm and identified dissimilarities in overall survival (OS) and progression-free survival (PFS) in risk subgroups. The nomograms associated with the ICD-related signature (ICDRS) demonstrated a good predictive value for clinical applications. Moreover, we detected changes in the tumor microenvironment (TME), including biological functions, mutation landscapes, and immune cell infiltration, between the high- and low-risk groups. CONCLUSION: We constructed an ICD-related prognostic model that incorporated features related to cell death. This model can serve as a useful tool for predicting the prognosis of GC, targeted prevention, and personalized medicine.

Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell death mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced neuronal death has not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization in cerebral I/R could mitigate neuroinflammation-mediated neuronal death, it remains unknown whether microglial polarization influences PANoptotic neuronal death triggered by cerebral I/R. Our prior study demonstrated that curcumin (CUR) preconditioning could boost the neuroprotective properties of olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) in intracerebral hemorrhage. Yet, the potential neuroprotective capacity of curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing PANoptotic neuronal death during cerebral I/R injury through modulating microglial polarization is uncertain. METHODS: To mimic cerebral I/R injury, We established in vivo models of reversible middle cerebral artery occlusion (MCAO) in C57BL/6 mice and in vitro models of oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 neurons and BV2 microglia. RESULTS: Our findings indicated that cerebral I/R injury caused PANoptotic neuronal death and triggered microglia to adopt an M1 (pro-inflammatory) phenotype both in vivo and in vitro. Curcumin pretreatment enhanced the proliferation and anti-inflammatory capacity of OM-MSCs. The CUR-OM-MSCs group experienced a more pronounced reduction in PANoptotic neuronal death and a better recovery of neurological function than the OM-MSCs group. Bioinformatic analysis revealed that microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated in CUR-OM-MSCs compared to OM-MSCs. CUR-OM-MSCs treatment induced the switch to an M2 (anti-inflammatory) phenotype in microglia by releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), an upstream regulator of NF-kappaB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, to attenuate PANoptotic neuronal death resulting from cerebral I/R. CONCLUSION: This results provide the first demonstration of the existence of PANoptotic neuronal death in cerebral I/R conditions. Curcumin preconditioning enhanced the ameliorating effect of OM-MSCs on neuroinflammation mediated by microglia polarization via upregulating the abundance of miRNA-423-5p. This intervention effectively alleviates PANoptotic neuronal death resulting from cerebral I/R. The combination of curcumin with OM-MSCs holds promise as a potentially efficacious treatment for cerebral ischemic stroke in the future.

F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.

BACKGROUND: Diabetes is accompanied by a high prevalence of hyposalivation, causing severe damage to oral and systemic health. Mitochondrial dynamics play important roles in the pathogenesis of various diabetic complications; however, little is known about their roles in diabetic hyposalivation. MATERIALS AND METHODS: A diabetic mouse model and a high glucose (HG)-induced diabetic submandibular gland (SMG) cell model were employed. RESULTS: More mitochondria surrounded by autophagosomes and higher expression of mitophagy-related proteins were detected in the SMGs of diabetic mice and HG-treated SMG cells. In diabetic SMGs, dynamin-related protein 1 (DRP1) was upregulated, whereas mitofusin-2 was downregulated both in vivo and in vitro. Shortened mitochondria and impaired mitochondrial functions were observed in the HG group. A DRP1-specific inhibitor, mdivi-1, suppressed mitochondrial fission and mitophagy, as well as restored mitochondrial functions in the HG condition. Moreover, the interaction of F-actin and DRP1 was enhanced in the diabetic group. Inhibiting F-actin with cytochalasin D repaired the injured effects of HG on mitochondrial dynamics and functions. Conversely, the F-actin-polymerization-inducer jasplakinolide aggravated mitochondrial fission and dysfunction. CONCLUSIONS: F-actin contributes to HG-evoked mitochondrial fission by interacting with DRP1, which induces mitophagy and impairs mitochondrial function in SMG cells, ultimately damaging the SMG.

Reliable detection of generalized convulsive seizures using an off-the-shelf digital watch: A multisite phase 2 study.

OBJECTIVE: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy. METHODS: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of (1) leave-one-patient-out cross-validation (LOPO CV) on GCS patients, (2) false alarm rate (FAR) testing on nonseizure patients, and (3) "fixed-and-frozen" prospective testing on a prospective patient cohort. Balanced accuracy, precision, sensitivity, and FAR were used to quantify the performance of the algorithm. Seizure onsets and offsets were determined by using video-electroencephalographic (EEG) monitoring. Feature importance was calculated as the mean decrease in Gini impurity during the LOPO CV testing. RESULTS: LOPO CV results showed balanced accuracy of .93 (95% confidence interval [CI] = .8-.98), precision of .68 (95% CI = .46-.85), sensitivity of .87 (95% CI = .62-.96), and FAR of .21/24 h (interquartile range [IQR] = 0-.90). Testing the algorithm on patients without seizure resulted in an FAR of .28/24 h (IQR = 0-.61). During the "fixed-and-frozen" prospective testing, two patients had three GCS, which were detected by the algorithm, while generating an FAR of .25/24 h (IQR = 0-.89). Feature importance showed that heart rate-based features outperformed accelerometer/gyroscope-based features. SIGNIFICANCE: Commercially available wearable digital watches that reliably detect GCS, with minimum false alarm rates, may overcome usage adoption and other limitations of custom-built devices. Contingent on the outcomes of a prospective phase 3 study, such devices have the potential to provide non-EEG-based seizure surveillance and forecasting in the clinical setting.

Effect of Mechanical Damage in Green-Making Process on Aroma of Rougui Tea.

Rougui Tea (RGT) is a typical Wuyi Rock Tea (WRT) that is favored by consumers for its rich taste and varied aroma. The aroma of RGT is greatly affected by the process of green-making, but its mechanism is not clear. Therefore, in this study, fresh leaves of RGT in spring were picked, and green-making (including shaking and spreading) and spreading (unshaken) were, respectively, applied after sun withering. Then, they were analyzed by GC-TOF-MS, which showed that the abundance of volatile compounds with flowery and fruity aromas, such as nerolidol, jasmine lactone, jasmone, indole, hexyl hexanoate, (E)-3-hexenyl butyrate and 1-hexyl acetate, in green-making leaves, was significantly higher than that in spreading leaves. Transcriptomic and proteomic studies showed that long-term mechanical injury and dehydration could activate the upregulated expression of genes related to the formation pathways of the aroma, but the regulation of protein expression was not completely consistent. Mechanical injury in the process of green-making was more conducive to the positive regulation of the allene oxide synthase (AOS) branch of the α-linolenic acid metabolism pathway, followed by the mevalonate (MVA) pathway of terpenoid backbone biosynthesis, thus promoting the synthesis of jasmonic acid derivatives and sesquiterpene products. Protein interaction analysis revealed that the key proteins of the synthesis pathway of jasmonic acid derivatives were acyl-CoA oxidase (ACX), enoyl-CoA hydratase (MFP2), OPC-8:0 CoA ligase 1 (OPCL1) and so on. This study provides a theoretical basis for the further explanation of the formation mechanism of the aroma substances in WRT during the manufacturing process.

Detection of uridine diphosphate glucuronosyltransferase 1A1 for pancreatic cancer imaging and treatment via a "turn-on" fluorescent probe.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is expressed ubiquitously in cancer cells and can metabolize exogenous substances. Studies show higher UGT1A1 levels in pancreatic cancer cells than normal cells. Therefore, we need a method to monitor the activity level of UGT1A1 in pancreatic cancer cells and in vivo. Here, we report a fluorescent probe, BCy-panc, for UGT1A1 imaging in cells and in vivo. Compared with other molecular probes, this probe is readily prepared, with high selectivity and sensitivity for the detection of UGT1A1. Our results show that BCy-panc rapidly detects UGT1A1 in pancreatic cancer. In addition, there is an urgent need for evidence to clarify the relationship between UGT1A1 and pancreatic cancer development. The present investigation found that the increase of UGT1A1 by chrysin was effective in inducing apoptosis in pancreatic cancer cells. These results indicate that the synergistic effect of chrysin and cisplatin at the cellular level is superior to that of cisplatin alone. The UGT1A1 level may be a biomarker for early diagnosis of cancer. Meanwhile, UGT1A1 plays a crucial role in pancreatic cancer, and the combination of chrysin and cisplatin may provide effective ideas for pancreatic cancer treatment.