Identification and validation of RNA-binding protein SLC3A2 regulates melanocyte ferroptosis in vitiligo by integrated analysis of single-cell and bulk RNA-sequencing.

BACKGROUND: The pathogenesis of vitiligo remains unclear. The genes encoding vitiligo-related RNA-binding proteins (RBPs) and their underlying pathogenic mechanism have not been determined. RESULTS: Single-cell transcriptome sequencing (scRNA-seq) data from the CNCB database was obtained to identify distinct cell types and subpopulations and the relative proportion changes in vitiligo and healthy samples. We identified 14 different cell types and 28 cell subpopulations. The proportion of each cell subpopulation significantly differed between the patients with vitiligo and healthy groups. Using RBP genes for unsupervised clustering, we obtained the specific RBP genes of different cell types in vitiligo and healthy groups. The RBP gene expression was highly heterogeneous; there were significant differences in some cell types, such as keratinocytes, Langerhans, and melanocytes, while there were no significant differences in other cells, such as T cells and fibroblasts, in the two groups. The melanocyte-specific RBP genes were enriched in the apoptosis and immune-related pathways in the patients with vitiligo. Combined with the bulk RNA-seq data of melanocytes, key RBP genes related to melanocytes were identified, including eight upregulated RBP genes (CDKN2A, HLA-A, RPL12, RPL29, RPL31, RPS19, RPS21, and RPS28) and one downregulated RBP gene (SLC3A2). Cell experiments were conducted to explore the role of the key RBP gene SLC3A2 in vitiligo. Cell experiments confirmed that melanocyte proliferation decreased, whereas apoptosis increased, after SLC3A2 knockdown. SLC3A2 knockdown in melanocytes also decreased the SOD activity and melanin content; increased the Fe2+, ROS, and MDA content; significantly increased the expression levels of TYR and COX2; and decreased the expression levels of glutathione and GPX4. CONCLUSION: We identified the RBP genes of different cell subsets in patients with vitiligo and confirmed that downregulating SLC3A2 can promote ferroptosis in melanocytes. These findings provide new insights into the pathogenesis of vitiligo.

Efficacy of SBAR combined with CICAR Communication Mode in Enhancing CT Hydration Effect and Nursing Satisfaction in Elderly Patients with Low Education.

Objective: To explore the effect of nurse-patient communication using the SBAR and CICAR communication mode on CT hydration effectiveness and nursing satisfaction in elderly patients with low education. Methods: From December 2020 to April 2023, 120 elderly patients with low education who underwent chest examinations in our hospital's imaging department were selected. Divide into an observation group and a control group using clinical randomized controlled trial design principles. Both groups of patients received the same diagnosis and treatment plan and nursing measures during hospitalization. The control group received traditional nursing care, while the observation group used the SBAR combined with CICAR communication template for nurse patient communication. After completing all intervention measures, the patient's state anxiety level and satisfaction with nursing work were re evaluated, and the enhanced CT examination status, enhanced CT examination knowledge awareness, psychological status, and their impact relationship were compared between the two groups of patients. Results: The heart rate, preparation time, examination time, anxiety score, depression score, and satisfaction of the observation group were better than those of the control group during examination, with statistical significance (P < .05); The scores related to the understanding of enhanced CT examination, preparation and precautions before the examination, proper posture during the examination, and post-examination precautions in the observation group were significantly higher than those in the control group (P < .05). The understanding of CT examination knowledge has a negative impact on the CT examination status and psychological state (P < .05), and the hydration effect of enhanced CT in patients (P < .05). Conclusion: Nurse-patient communication using the SBAR and CICAR communication mode improved CT hydration effectiveness and nursing satisfaction in elderly patients with low education. This mode enhanced patient understanding, preparation, and adherence to CT examination protocols, leading to better outcomes and reduced anxiety and depression levels.

A full-scale black soldier fly larvae (Hermetia illucens) bioconversion system for domestic biodegradable wastes to resource.

Domestic biodegradable wastes (DBW) pose a threat to environmental quality and human health. Bioconversion via black soldier fly larvae (BSFL; Hermitia illucens L.) is an expedient way for converting 'waste to resource' (insect protein and biofertilizer). Although researches abounded in laboratory-reared experiments and bioconversion mechanisms were pertinent, the void of data from actual and full-scale operation restricts the intensification of BSFL technology and its global adoption. Hence, a full-scale BSFL bioconversion system lasting 4 years in Hangzhou (China) was investigated, and the feasibility and efficiency of 15 tonnes of DBW per day were studied. Through continuous technical optimization, the average production of fresh larvae was increased from 8.5% in 2017 to 15.3% in 2020, along with bioconversion rate of final vermicompost decreased from 35.4% to 14.5%. The total biomass reduction rate in 2020 was 68.7 ± 17.4 kg/(m3 d), equivalent to 0.735 ± 0.215 kg/(kg d) in the form of fresh larvae. Crude fat in fresh larvae accounted for 13.4%, and crude protein accounted for 16.2% in which the determined amino acid profile bore a strong resemblance to fish meal only except histidine and tyrosine. Its economic benefits proved the feasibility of this technology, and the profit reached up to 35.9 US$ per tonne of DBW in 2019. In conclusion, BSFL bioconversion system under current 'insect-farm' operation was a promising solution for DBW treatment with value-added waste recycling.

CAR-T cell therapy targeting B cell maturation antigen is effective for relapsed/refractory multiple myeloma, including cases with poor performance status.

In this open-label, single-arm, phase I/II clinical trial, we evaluated the efficacy of anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in 49 relapsed/refractory multiple myeloma (RRMM) patients, including 20 with Eastern Cooperative Oncology Group (ECOG) grade 3-4. After HDS269B infusion (9 × 106 CAR+ cells/kg), 17 patients (34.69%, 11 ECOG 0-2, 6 ECOG 3-4) developed cytokine release syndrome [grade 1-2: 14 patients (28.57%); grade 3: 3 patients (6.12%)]. The objective response rate (ORR) was 77%, with a complete response (CR) achieved in 47%. Ongoing response >12 months occurred in 15 patients, and was extended beyond 38 months in one patient. The median progression-free survival (PFS) and overall survival (OS) were 10 months (95% CI 5.3-14.7) and 29 months (95% CI 10.0-48.0), respectively. The PFS (12 months) and OS (18 months) rates were 41.64% and 62.76%, respectively. In patients with ECOG 0-2 and 3-4, ORR was 79.31% (23/29) and 75.0% (15/20) and PFS were 15 months (95% CI 5.4-24.6) and 4 months (95% CI 0-11.7), respectively. OS was not reached in ECOG 0-2 patients, but was 10.5 months (95% CI 0-22) in ECOG 3-4 patients. Single-cell sequencing indicated that treatment efficacy might be related to mTORC1 signaling. Thus, HDS269B therapy is safe and effective for RRMM patients, even those with ECOG 3-4.

A Novel Fluorescent Probe Based on Pyrazole-Pyrazoline for Fe (III) Ions Recognition.

Firstly, a novel pyrazole-pyrazoline fluorescent probe was developed and synthesized. The probe can be used to determine Fe3+ ions in a series of cations in tetrahydrofuran aqueous solution with high selectivity and high sensitivity. After the addition of iron ions, the fluorescence intensity is significantly reduced, Its structure was characterized by 1H NMR, 13C NMR and HR-ESI-MS. UV absorption spectra and Fluorescence spectroscopy were used to study the selective recognition of probe M on metal ions. The probe M can selectivity and sensitivity to distinguish the target ion from other ions through different fluorescence phenomena. In addition, the binding modes of M with Fe3+ were proved to be 1:1 stoichiometry in the complexes by Job's plot, IR results. The combination of probe M and iron ions is 1:1, and the detection limit is 3.9 × 10-10 M. The binding mode and sensing mechanism of M with Fe3+ was verified by theoretical calculations using Gaussian 09 based on B3LYP/6-31G(d) basis.

Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC. METHODS: Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases. RESULTS: ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients' survival as a prognostic signature. CONCLUSIONS: Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.

Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A.

BACKGROUND & AIMS: Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD. METHODS: Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named 'metabolitin (MTL)'. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function in NAFLD. RESULTS: We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5'AMP-activated protein kinase pathway. In addition, glucagon like peptide-1 secretion was induced by MTL treatment. CONCLUSIONS: Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD. LAY SUMMARY: A novel murine peptide hormone, herein named 'metabolitin', inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease.

Association of trimethylamine N-Oxide with cardiovascular and all-cause mortality in hemodialysis patients.

BACKGROUND: Trimethylamine-N-Oxide (TMAO) is a proatherogenic and prothrombotic metabolite. Our study examined the association of plasma TMAO level with cardiovascular and all-cause mortality in hemodialysis (HD) patients. METHODS: Patients who were at least 18 years-old and received HD for at least 6 months were enrolled within 6 months. Patients with coronary heart disease, congestive heart failure, arrhythmia, or stroke within 3 months before study onset were excluded. The primary endpoints were cardiovascular and all-cause death, and the secondary endpoint was cerebrovascular death. RESULTS: We recruited 252 patients and divided them into a high-TMAO group (>4.73 µg/mL) and a low-TMAO group (≤4.73 µg/mL). The median follow-up time was 73.4 months (interquartile range: 42.9, 108). A total of 123 patients died, 39 from cardiovascular disease, 19 from cerebrovascular disease, and 65 from other causes. Kaplan-Meier analysis indicated that the high-TMAO group had a greater incidence of cardiovascular death (Log-Rank: p = 0.006) and all-cause death (Log-Rank: p < 0.001). Cox regression analysis showed that high TMAO level was significantly associated with cardiovascular and all-cause mortality. After adjustment for confounding, this association remained significant for cardiovascular mortality (TMAO as a continuous variable: HR: 1.18, 95%CI: 1.07, 1.294, p < 0.001; TMAO as a dichotomous variable: HR: 3.44, 95%CI: 1.68, 7.08, p < 0.001) and all-cause mortality (TMAO as a continuous variable: HR: 1.14, 95%CI: 1.08, 1.21, p < 0.001; TMAO as a dichotomous variable: HR: 2.54, 95%CI: 1.71, 3.76, p < 0.001). CONCLUSIONS: High plasma TMAO level is significantly and independently associated with cardiovascular and all-cause mortality in HD patients.

Mesorhizobium carbonis sp. nov., isolated from coal bed water.

A Gram-stain negative, aerobic, motile, short rod-shaped bacterium, designated as B2.3T, was isolated from coal bed water collected from Jincheng, Shanxi Province, China. The strain was able to grow at 10-40 °C (optimum 28-30 °C), pH 4.0-10.0 (optimum 7.0), and in the presence of 0-5.0% NaCl (optimum 3.0%, w/v). Phylogenetic analysis based on the 16S rRNA and concatenated housekeeping gene recA, atpD and glnA sequences showed strain B2.3T belongs to the genus Mesorhizobium, with Mesorhizobium oceanicum B7T as the closely related type strain. Strain B2.3T exhibited ANI value of 77.5% and GGDC value of 21.5% to M. oceanicum B7T. The major fatty acids were identified as summed feature 8 (C18:1ω7c and/or C18:1ω6c) and 11-methyl C18:1ω7c. The major polar lipids were found to consist of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and an unidentified aminophospholipid. The predominant ubiquinone was identified as Quinone 10. Phenotypic and biochemical analysis results indicated that strain B2.3T can be distinguished from closely related type strains. On the basis of phenotypic, genotypic and chemotaxonomic characteristics, strain B2.3T is concluded to represent a novel species in the genus Mesorhizobium, for which the name Mesorhizobium carbonis sp. nov. is proposed. The type strain is B2.3T (=CGMCC 1.15730T = KCTC 52461T).

[Clinical effect of white noise combined with glucose in reducing the pain of retinopathy screening in preterm infants].

OBJECTIVE: To study the clinical effect of white noise combined with glucose in reducing the procedural pain of retinopathy screening in preterm infants. METHODS: A total of 396 preterm infants with a gestational age of 28-34 weeks and a birth weight of ≤2 000 g were randomly divided into 4 groups according to the intervention method for reducing pain in retinopathy screening: control group with 100 infants (no white noise or glucose intervention), white noise group with 96 infants, glucose group with 98 infants and white noise + glucose group with 102 infants. The Premature Infant Pain Profile (PIPP) was used to determine pain score during retinopathy screening, and the four groups were compared in terms of PIPP score before and after retinopathy screening. RESULTS: There were no significant differences in PIPP score, heart rate and blood oxygen saturation between the four groups at 3 minutes before screening (P>0.05). At 1 and 5 minutes after screening, the white noise, glucose and white noise + glucose groups had significantly lower heart rate and PIPP score but significantly higher blood oxygen saturation than the control group (P<0.05).The white noise + glucose group had significantly lower heart rate and PIPP score but significantly higher blood oxygen saturation than the white noise and glucose groups (P<0.05). CONCLUSIONS: White noise combined with glucose can reduce the procedural pain of retionopathy screening and keep vital signs stable in preterm infants.

Kv Channel S1-S2 Linker Working as a Binding Site of Human ß-Defensin 2 for Channel Activation Modulation.

Among the three extracellular domains of the tetrameric voltage-gated K(+) (Kv) channels consisting of six membrane-spanning helical segments named S1-S6, the functional role of the S1-S2 linker still remains unclear because of the lack of a peptide ligand. In this study, the Kv1.3 channel S1-S2 linker was reported as a novel receptor site for human ß-defensin 2 (hBD2). hBD2 shifts the conductance-voltage relationship curve of the human Kv1.3 channel in a positive direction by nearly 10.5 mV and increases the activation time constant for the channel. Unlike classical gating modifiers of toxin peptides from animal venoms, which generally bind to the Kv channel S3-S4 linker, hBD2 only targets residues in both the N and C termini of the S1-S2 linker to influence channel gating and inhibit channel currents. The increment and decrement of the basic residue number in a positively charged S4 sensor of Kv1.3 channel yields conductance-voltage relationship curves in the positive direction by ∼31.2 mV and 2-4 mV, which suggests that positively charged hBD2 is anchored in the channel S1-S2 linker and is modulating channel activation through electrostatic repulsion with an adjacent S4 helix. Together, these findings reveal a novel peptide ligand that binds with the Kv channel S1-S2 linker to modulate channel activation. These findings also highlight the functional importance of the Kv channel S1-S2 linker in ligand recognition and modification of channel activation.

Human α-defensins are immune-related Kv1.3 channel inhibitors: new support for their roles in adaptive immunity.

Defensins form a major family of antimicrobial peptides. Recently, human ß-defensin 2 and fungal plectasin were shown to be immune-related potassium voltage-gated channel subfamily A member 3 (Kv1.3) channel inhibitors. This work continued to show that the human α-defensins human neutrophil peptide (HNP) 1 and human defensin (HD) 5 are selective Kv1.3 channel inhibitors with 50% inhibition concentration values of 102.0 ± 30.3 nM and 2.2 ± 0.2 µM, respectively. Furthermore, HNP1 was found to inhibit Kv1.3 currents and IL-2 secretion in human CD3(+) T cells. Despite the structural similarity between HNP1 and HD5, HNP1 could simultaneously bind to the S1-S2 linker and the pore region of the Kv1.3 channel as both a toxinlike blocker and a novel modifier, whereas HD5 could only bind to the channel pore region as a toxinlike blocker. As a channel modifier, HNP1 could shift the conductance-voltage relationship curve of the Kv1.3 channel by ∼9.5 mV in the positive direction and could increase the time constant for channel activation through the electrostatic repulsion between the cationic HNP1 anchored in the S1-S2 linker and the positively charged S4 domain of the Kv1.3 channel. Together, these findings reveal that human α-defensins are novel endogenous inhibitors of Kv1.3 channels with distinct interaction mechanisms, which facilitates future research into their adaptive immune functions.

Endogenous animal toxin-like human ß-defensin 2 inhibits own K(+) channels through interaction with channel extracellular pore region.

Human potassium channels are widely inhibited by peptide toxins from venomous animals. However, no human endogenous peptide inhibitor has been discovered so far. In this study, we demonstrate for the first time using electrophysiological techniques, that endogenous human ß-defensin 2 (hBD2) is able to selectively and dose-dependently inhibit the human voltage-gated Kv1.3 channel at picomolar peptide concentration. The co-immunoprecipitation assays further supported the selective binding of hBD2 to Kv1.3 channel. Using mutagenesis experiments, we found that the outer pore domain of Kv1.3 channel was the binding site of hBD2, which is similar to the interacting site of Kv1.3 channel recognized by animal toxin inhibitors. The hBD2 was able to suppress IL-2 production through inhibition of Kv1.3 channel currents in human Jurkat cells, which was further confirmed by the lack of hBD2 activity on IL-2 production after Kv1.3 knockdown in these cells. More interestingly, hBD2 was also found to efficiently inhibit Kv1.3 channel currents and suppress IL-2 production in both human primary CD3(+) T cells and peripheral mononuclear cells from either healthy donors or psoriasis patients. Our findings not only evidenced hBD2 as the first characterized endogenous peptide inhibitor of human potassium channels, but also paved a promising avenue to investigate newly discovered function of hBD2 as Kv1.3 channel inhibitor in the immune system and other fields.

Lymphocyte depletion and subset alteration correlate to renal function in chronic kidney disease patients.

BACKGROUND: It is widely accepted that chronic renal failure is associated with severe alterations of immune system. However, few studies looked into the immune alteration in earlier stage of chronic kidney disease (CKD) patients. To characterize immune defect in CKD patients, we performed lymphocyte subset analysis and explored its relationship to renal function in this population. METHODS: 472 CKD patients were enrolled in this study. Lymphocyte subsets (CD19(+), CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD56(+)CD16(+)) were determined by flow cytometry. Clinical and laboratory data were collected. Patterns of immune cells in different stages of CKD were compared. Multivariate linear regression was used to evaluate the relationship between lymphocyte subset group and renal function. Correlation analysis was used to assess the relationship between lymphocyte subset and other clinical and laboratory data. RESULTS: Decreased lymphocyte counts occurred long before the end stage of renal disease. Increased NK cell percentage was negatively related to estimated glomerular filtration rate (eGFR) (r = -0.259, p < 0.001) while B cell percentage was positively related to eGFR (r = 0.249, p < 0.001). Further multivariate linear regression showed increased B cell percentage (ß = 16.470, 95%CI [1.018-31.922], p = 0.037) and decreased NK cell percentage (ß = -10.659, 95%CI [-20.063 to -1.254], p = 0.026) were independently correlated with higher eGFR, respectively. Patients with lower NK cell percentage and higher B cell percentage tended to have the best renal function. CONCLUSIONS: Lymphocyte depletion and subset alteration occurred during the progress of CKD. Further studies are needed to clarify the role of immune system in CKD and to expand our knowledge about the effect of uremia on the structure and function of immune system.

Analysis of transplant urgency and benefit via multiple imputation.

Missing (censored) death times for lung candidates in urgent need of transplant are a signpost of success for allocation policy makers. However, statisticians analyzing these data must properly account for dependent censoring as the sickest patients are removed from the waitlist. Multiple imputation allows the creation of complete data sets that can be used for a variety of standard analyses in this setting. We propose an approach to multiply impute lung candidate outcomes that incorporates (i) time-varying factors predicting removal from the waitlist and (ii) estimates of transplant urgency via restricted mean models. The measures of transplant urgency and benefit for individual patient profiles are discussed in the context of lung allocation score modeling in the USA. Marginal survival estimates in the event that a transplant does not occur are also provided. Simulations suggest that the proposed imputation method gives attractive results when compared with existing methods.

Paired Electrolysis Enabled Trifluoromethylheteroaromatization of Alkenes and Alkyne with Trifluoromethyl Thianthrenium Triflate (TT-CF3+OTf-) as a Bifunctional Reagent.

We report a strategic exploitation of trifluoromethyl thianthrenium triflate (TT-CF3+OTf-) as both electromediator and CF3 radical precursors for paired electrolysis. Enabled by this strategy, the three-component trifluoromethylheteroaromatization of alkenes and alkynes was realized. The superiority of TT-CF3+OTf- to other electrophilic CF3 reagents is attributed to the cathodic generation of thianthrene (TT) as a mediator, which shifts the heterogeneous oxidation of interest to a homogeneous one.

Identification of active compounds in Vernonia anthelmintica (L.) willd by targeted metabolome MRM and kaempferol promotes HaCaT cell proliferation and reduces oxidative stress.

Introduction: Vernonia anthelmintica (L.) Willd. is a traditional treatment for vitiligo in Xinjiang. However, its therapeutic mechanism remains unclear owing to its complex composition and limited research on its chemical profile. Methods: We employed a targeted metabolome approach, combining selective reaction monitoring/multiple response monitoring (SRM/MRM) with high-performance liquid chromatography and MRM mass spectrometry to quantitatively analyze the flavonoid constituents of Vernonia anthelmintica. We also used network pharmacology and molecular docking to identify potential vitiligo-linked compounds and targets of V. anthelmintica seeds. Additionally, we assessed HaCaT cell proliferation by AAPH-induced, alongside changes in SOD activity and MDA content, following treatment with V. anthelmintica components. Finally, flow cytometry was used to detect apoptosis and ROS levels. Results and Discussion: We identified 36 flavonoid compounds in V. anthelmintica seeds, with 14 compounds exhibiting druggability. AKT1, VEGFA, ESR1, PTGS2, and IL2 have been identified as key therapeutic target genes, with PI3K/AKT signaling being an important pathway. Notably, kaempferol, one of the identified compounds, exhibited high expression in network pharmacology analysis. Kaempferol exhibited a strong binding affinity to important targets. Further, kaempferol enhanced HaCaT cell viability, inhibited apoptosis, reduced MDA levels, suppressed ROS activity, and upregulated SOD activity, increase the expression of cellular antioxidant genes, including HO-1, GCLC, GCLM, Nrf2, NQO1 and Keap1, providing significant protection against oxidative stress damage in vitro. Here, we present the first comprehensive study integrating SRM/MRM approaches and network analysis to identify active flavonoid compounds within V. anthelmintica (L.) Willd. Moreover, we revealed that its active ingredient, kaempferol, offers protection against AAPH-induced damage in keratinocytes, highlighting its potential as a clinical resource.

A five-year follow-up clinical study of the B cell maturation antigen chimeric antigen receptor-T cell therapy HDS269B in patients with relapsed or refractory multiple myeloma.

PURPOSE: This study aimed to report the five-year clinical outcomes of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in relapsed/refractory multiple myeloma (RRMM) patients, including those with poor performance status (Eastern Cooperative Oncology Group [ECOG] 3-4), and to identify factors influencing long-term outcomes. METHODS: Forty-nine RRMM patients enrolled from 2016 to 2020 received HDS269B (9×106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS: With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months (95% confidence interval [CI], 5.01-13.99) and 20.0 months (95% CI, 11.26-28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%-36.7%) and 34.1% (95% CI, 22.7%-51.3%), respectively. Patients with ECOG 0-2 had marked longer survival, with a median PFS of 11.0 months and median OS of 41.8 months. Early minimal residual disease negativity, and higher and persistent CAR-T cell expansion and absence of extramedullary disease were associated with better survival outcomes. No new CAR-T cell therapy associated toxicities were observed. Importantly, ECOG 0-2, prior therapy lines <4, and CAR-T cell persistence at ≥6 months were independently associated with longer OS. CONCLUSIONS: HDS269B is effective and safe, especially for patients with ECOG 0-2. Early CAR-T cell intervention may improve prognosis in patients with RRMM.

CD8(+) T cell-mediated cytotoxicity toward Schwann cells promotes diabetic peripheral neuropathy.

BACKGROUND: Damage to Schwann cells has been reported in the development of diabetic peripheral neuropathy (DPN), but how Schwann cells are damaged has not been elucidated. METHODS: The highly expressed proteins in the PBMC of DPN patients were identified through MALDI-TOF/TOF and SELDI protein chip technology. The expression levels of CXCR3 were detected by qPCR and flow cytometric analysis. Transwell migration assay was to investigate the migration of CD8(+) T cells. Western-blot analysis was to detect the levels of p38 MAP kinases pathway related proteins and TNF-α, FasL, and PDL1. RESULTS: Two highly expressed proteins, CXCR3 and p38, were identified. Under high glucose conditions, CXCR3 was elevated in CD8(+) T cells via the activation of p38 MAP kinases. Moreover, CXCL9, CXCL10, and CXCL11 expression were induced in Schwann cells, leading to the recruitment and infiltration of CD8(+) T cells into DPN tissues. Further study demonstrated that Schwann cells promoted activation of CD8(+) T cells and induced expression of TNF-α, FasL, and PDL1 on CD8(+) T cells, in return, CD8(+) T cells induced obvious apoptosis of Schwann cells. CONCLUSION: Our study indicates that CD8(+) T cells mediate cytotoxicity toward Schwann cells and play an important role in the development of DPN.