Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis.

BACKGROUND: In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. PURPOSE: In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. METHODS: We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. RESULTS: Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. CONCLUSION: This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.

Constructing a disulfidptosis-related prognostic signature of hepatocellular carcinoma based on single-cell sequencing and weighted co-expression network analysis.

Hepatocellular carcinoma (HCC) ranks as the second leading cause of cancer-related deaths globally. Disulfidptosis is a newly identified form of regulated cell death that is induced by glucose starvation. However, the clinical prognostic characteristics of disulfidptosis-associated genes in HCC remain poorly understood. We conducted an analysis of the single-cell datasets GSE149614 and performed weighted co-expression network analysis (WGCNA) on the Cancer Genome Atlas (TCGA) datasets to identify the genes related to disulfidptosis. A prognostic model was constructed using univariate COX and Lasso regression. Survival analysis, immune microenvironment analysis, and mutation analysis were performed. Additionally, a nomogram associated with disulfidptosis-related signature was constructed to identify the prognosis of HCC patients. Patients with HCC in the TCGA and GSE14520 datasets were categorized using a disulfidptosis-related model, revealing significant differences in survival times between the high- and low-disulfidptosis groups. High-disulfidptosis patients exhibited increased expression of immune checkpoint-related genes, implying that immunotherapy and certain chemotherapies may be beneficial for them. Meanwhile, the ROC and decision curves analysis (DCA) indicated that the nomogram has satisfying prognostic efficacy. Moreover, the experimental results of GATM in this prognostic model indicated that GATM is low expressed in HCC tissues, and GATM knockdown promotes the proliferation and migration of HCC cells. By analyzing single-cell and bulk multi-omics sequencing data, we developed a prognostic signature related to disulfidptosis and explored the relationship between high- and low-disulfidptosis groups in HCC. This study offers a novel reference for gaining a deeper understanding of the role of disulfidptosis in HCC.

Bioassay-Guided and DeepSAT-Driven Precise Mining of Monoterpenoid Coumarin Derivatives with Antifeedant Effects from the Leaves of Ailanthus altissima.

Demand for the exploration of botanical pesticides continues to increase due to the detrimental effects of synthetic chemicals on human health and the environment and the development of resistance by pests. Under the guidance of a bioactivity-guided approach and HSQC-based DeepSAT, 16 coumarin derivatives were discovered from the leaves of Ailanthus altissima (Mill.) Swingle, including seven undescribed monoterpenoid coumarins, three undescribed monoterpenoid phenylpropanoids, and two new coumarin derivatives. The structure and configurations of these compounds were established and validated via extensive spectroscopic analysis, acetonide analysis, and quantum chemical calculations. Biologically, 5 exhibited significant antifeedant activity toward the Plutella xylostella. Moreover, tyrosinase being closely related to the growth and development of larva, the inhibitory potentials of 5 against tyrosinase was evaluated in vitro and in silico. The bioactivity evaluation results highlight the prospect of 5 as a novel category of botanical insecticide.

Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis.

Pathogens detected by metagenomic next-generation sequencing (mNGS) and the laboratory blood culture flask method were compared to understand the advantages and clinical significance of mNGS assays in the etiological diagnosis of peritoneal dialysis-associated peritonitis (PDAP). The study involved a total of 37 patients from the hospital's peritoneal dialysis centre, six of whom were patients with non-peritoneal dialysis-associated peritonitis. Peritoneal dialysis samples were collected from the 37 patients, who were divided into two groups. One group's samples were cultured using conventional blood culture flasks, and the other samples underwent pathogen testing using mNGS. The results showed that the positive rate of mNGS was 96.77%, while that of the blood culture flask method was 70.97% (p < 0.05). A total of 29 pathogens were detected by mNGS, namely 24 bacteria, one fungus, and four viruses. A total of 10 pathogens were detected using the bacterial blood culture method, namely nine bacteria and one fungus. The final judgment of the PDAP's causative pathogenic microorganism was made by combining the clinical condition, response to therapy, and the whole-genome sequencing findings. For mNGS, the sensitivity was 96.77%, the specificity was 83.33%, the positive predictive value was 96.77%, and the negative predictive value was 83.33%. For the blood culture flask method, the sensitivity was 70.97%, the specificity was 100%, the positive predictive value was 100%, and the negative predictive value was 0%. In conclusion, mNGS had a shorter detection time for diagnosing peritoneal dialysis-related peritonitis pathogens, with a higher positive rate than traditional bacterial cultures, providing significant advantages in diagnosing rare pathogens.

The association between lymphocyte-to-monocyte ratio and all-cause mortality in obese hypertensive patients with diabetes and without diabetes: results from the cohort study of NHANES 2001-2018.

Objective: Obesity, hypertension and diabetes are high prevalent that are often associated with poor outcomes. They have become major global health concern. Little research has been done on the impact of lymphocyte-to-monocyte ratio (LMR) on outcomes in these patients. Thus, we aimed to explore the association between LMR and all-cause mortality in obese hypertensive patients with diabetes and without diabetes. Methods: The researchers analyzed data from the National Health and Nutrition Examination Survey (2001-2018), which included 4,706 participants. Kaplan-Meier analysis was employed to compare survival rate between different groups. Multivariate Cox proportional hazards regression models with trend tests and restricted cubic splines (RCS) analysis and were used to investigate the relationship between the LMR and all-cause mortality. Subgroup analysis was performed to assess whether there was an interaction between the variables. Results: The study included a total of 4706 participants with obese hypertension (48.78% male), of whom 960 cases (20.40%) died during follow-up (median follow-up of 90 months). Kaplan-Meier curves suggested a remarkable decrease in all-cause mortality with increasing LMR value in patients with diabetes and non-diabetes (P for log-rank test < 0.001). Moreover, multivariable Cox models demonstrated that the risk of mortality was considerably higher in the lowest quartile of the LMR and no linear trend was observed (P > 0.05). Furthermore, the RCS analysis indicated a non-linear decline in the risk of death as LMR values increased (P for nonlinearity < 0.001). Conclusions: Increased LMR is independently related with reduced all-cause mortality in patients with obese hypertension, regardless of whether they have combined diabetes.

CD70-specific CAR NK cells expressing IL-15 for the treatment of CD19-negative B-cell malignancy.

ABSTRACT: Chimeric antigen receptor (CAR) natural killer (NK) cells can eliminate tumors not only through the ability of the CAR molecule to recognize antigen-expressed cancer cells but also through NK-cell receptors themselves. This overcomes some of the limitations of CAR T cells, paving the way for CAR NK cells for safer and more effective off-the-shelf cellular therapy. In this study, CD70-specific (a pan-target of lymphoma) fourth-generation CAR with 4-1BB costimulatory domain and interleukin-15 (IL-15) was constructed and transduced into cord blood-derived NK cells by Baboon envelope pseudotyped lentiviral vector. CD70-CAR NK cells displayed superior cytotoxic activity in vitro and in vivo against CD19-negative B-cell lymphoma when compared with nontransduced NK cells and CD19-specific CAR NK cells. Importantly, mice that received 2 doses of CD70-CAR NK cells showed effective eradication of tumors, accompanied by increased concentration of plasma IL-15 and enhanced CAR NK cell proliferation and persistence. Our study suggests that repetitive administration-based CAR NK-cell therapy has clinical advantage compared with a single dose of CAR NK cells for the treatment of B-cell lymphoma.

Shenyu ningshen tablet reduced neuronal damage in the hippocampus of chronic restraint stress model rat by inhibiting A1-reactive astrocytes.

Context: Shenyu Ningshen (SYNS) tablet is the first pure Chinese medicinal small compound preparation approved for clinical trials for the treatment of depression in China. Clinical experiments confirmed that the formulation had a significant Improvement effect against depression due to the deficiency of both qi and yin. It has been shown to exhibit noticeable anti-inflammatory effect in an animal model of depression. Our previous study showed that SYNS could effectively inhibit the inflammatory response in a depression model. Aim of the study: The purpose of this study was to investigate the protective effects of SYNS on neurons and explore whether the underlying mechanism was associated with A1s. Materials and methods: The depression model of solitary raising-chronic restraint stress (CRS) rats was established; body weight examination, sugar water preference test, open field test, and histological analysis were performed to preliminarily verify the efficacy of the formulation. Subsequently, neuronal nucleus (NeuN) and synaptic-associated proteins (MAP2 and PSD95) were labeled, and the protective effect of SYNS on hippocampal neurons was observed based on the fluorescence intensity of the above indicators. Western blotting, histological examination, and immunofluorescence were used to evaluate the inhibitory effects of SYNS on neuroinflammation and activation of A1s in CRS depression model. Results: SYNS improved behavioral indicators such as weight loss, pleasure loss, and reduced exercise volume in CRS rat model. SYNS restored the CRS-induced histopathological changes in the hippocampus. SYNS showed a certain degree of protective effect on synapses. Further, SYNS inhibited the activation of A1s by inhibiting neuroinflammatory factors in the hippocampus. Conclusion: Our results showed that SYNS had a certain degree of neuroprotective effect, which might be related to its inhibition of the inflammatory response and A1s.

Identification and functional activity of Nik related kinase (NRK) in benign hyperplastic prostate.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is common in elder men. The current study aims to identify differentially expressed genes (DEGs) in hyperplastic prostate and to explore the role of Nik related kinase (NRK) in BPH. METHODS: Four datasets including three bulk and one single cell RNA-seq (scRNA-seq) were obtained to perform integrated bioinformatics. Cell clusters and specific metabolism pathways were analyzed. The localization, expression and functional activity of NRK was investigated via RT-PCR, western-blot, immunohistochemical staining, flow cytometry, wound healing assay, transwell assay and CCK-8 assay. RESULTS: A total of 17 DEGs were identified by merging three bulk RNA-seq datasets. The findings of integrated single-cell analysis showed that NRK remarkably upregulated in fibroblasts and SM cells of hyperplasia prostate. Meanwhile, NRK was upregulated in BPH samples and localized almost in stroma. The expression level of NRK was significantly correlated with IPSS and Qmax of BPH patients. Silencing of NRK inhibited stromal cell proliferation, migration, fibrosis and EMT process, promoted apoptosis and induced cell cycle arrest, while overexpression of NRK in prostate epithelial cells showed opposite results. Meanwhile, induced fibrosis and EMT process were rescued by knockdown of NRK. Furthermore, expression level of NRK was positively correlated with that of α-SMA, collagen-I and N-cadherin, negatively correlated with that of E-cadherin. CONCLUSION: Our novel data identified NRK was upregulated in hyperplastic prostate and associated with prostatic stromal cell proliferation, apoptosis, cell cycle, migration, fibrosis and EMT process. NRK may play important roles in the development of BPH and may be a promising therapeutic target for BPH/LUTS.

Effect of Zusanli Acupoint Injection with Anisodamine on Postoperative Recovery Quality of Patients Undergoing Bariatric Surgery.

PURPOSE: To evaluate the influence of anisodamine injection at the Zusanli (ST36) on early postoperative recovery quality in patients who have undergone laparoscopic sleeve gastrectomy. MATERIALS AND METHODS: 141 patients undergoing laparoscopic sleeve gastrectomy were randomly divided into the control group (group C), the normal saline group (group S) and the anisodamine group (group A). Acupuncture point injections were administered after induction of general anesthesia. The quality of recovery-40 questionnaire (QoR-40) scores were documented preoperatively (D0) and on the 1st (D1), 3rd (D3) and 7th (D7) days postoperatively. Additional metrics included: the numerical rating scale (NRS) for pain, postoperative nausea and vomiting (PONV), assessment and analgesic consumption 24-h post-extubation and the initial postoperative times for ambulation and anal exhaust. Substance P (SP), ß-endorphin (ß-EP), motilin (MTL) and gastrin (GAS) were quantified at 24-h post-surgery. RESULTS: Compared with group C, group A demonstrated an elevation in QoR-40 scores and physical comfort dimensions during D1-3, and an increased pain scores during D1-7; group S exhibited an augmentation in QoR-40 scores and pain scores on D1 (p < 0.05). Compared with group S, group A improved QoR-40 scores on D1 and pain scores during D1-3 (p < 0.05). SP, ß-EP, MTL and GAS presented significant variances among the groups 24-h post-surgery (p < 0.05). There were significant differences between the groups in NRS pain scores and PONV scores at 24-h postoperatively, dosage of dizocin on the first postoperative day, and time to first anal defecation (p < 0.05). CONCLUSION: The administration of anisodamine via ST36 acupoint injections has been demonstrated to facilitate the recuperation of gastrointestinal functionality, to alleviate postoperative pain and nausea, and substantially to enhance the quality of early postoperative recovery.

Association between thiamine intake and depression: A national cross-sectional study.

BACKGROUND: Recent years have seen increasing attention to improving depressive symptoms through dietary intakes, yet the association between thiamine intake and depression remains unclear. The present study aimed to explore this association using data from an American cross-sectional study. METHODS: We explored the association of covariates, exposure, and outcome with logistic regression equations. Multivariable regression models were performed to further exclude confounding factors. To investigate nonlinear relationships, we employed restricted cubic splines. Recursive algorithms were utilized to identify inflection points. Additionally, we conducted stratified analyses by age and sex to uncover differences among subgroups. RESULTS: When all covariates were adjusted, the association between thiamine intake and depression was not statistically significant [0.93 (0.82, 1.07)]. In the linear trend test using Q1 as the reference, the ORs (95%CI) for Q2, Q3, and Q4 were 0.87 (0.73, 1.04), 0.83 (0.68, 1.00), and 0.92 (0.73, 1.16), which suggested that the association might be nonlinear. We then confirmed this nonlinear relationship with a restricted cubic spline, and the inflection point of 1.35 mg/day was calculated. Before the inflection point, the effect value of the relationship was 0.68 (0.53, 0.89). After the inflection point, no significant association was found [1.10 (0.92, 1.31)]. Stratified analyses revealed that this nonlinear relationship was consistent among women and individuals aged <60 years. DISCUSSION: In this cross-sectional study among American general adults, we found a nonlinear association between thiamine intake and depression and further observed differences by age and sex.

Effect of preoperative oral carbohydrates on insulin resistance in patients undergoing laparoscopic cholecystectomy: a randomized controlled trial.

PURPOSE: The present research seeks to clarify the consequences of two specific preoperative oral carbohydrate (POC) amounts on insulin resistance (IR) and stomach evacuation in laparoscopic cholecystectomy (LC) patients. METHODS: A total of 129 patients set for elective LC procedures were randomly assigned to a control group (C, n = 45), a 200 mL POC group (P1, n = 42), and a 400 mL POC group (P2, n = 42). The C group was fasted from midnight until surgery, whereas the P1 and P2 groups received their respective carbohydrate volumes 2-4 h before anesthesia. Fasting blood glucose, insulin, and glucagon concentrations were measured at three junctures. IR metrics were derived by employing the homeostasis model assessment. Gastric volume was measured before anesthesia using gastric ultrasound. Inter-group comparisons included IR indicators, subjective comfort scores, and hemodynamic data. RESULTS: At T2, the C group exhibited reduced glucose concentrations compared to the P2 group (4.73 ± 0.64 vs. 5.26 ± 1.02 mmol/L, p < 0.05). The Perlas grading indicated that grade 1 was more prevalent in the P2 group than in the P1 and C groups (18 [42.9%] vs. 6 [14.3%] and 1 [2.2%], p < 0.05). Additionally, thirst and hunger metrics for the P2 group were notably reduced compared to the C group at both T2 and T3. CONCLUSION: Administering either 200 mL or 400 mL of carbohydrates 2-4 h pre-surgery had no detectable impact on IR or gastric volume in LC patients. TRIAL REGISTRATION: ChiCTR, ChiCTR2200065648. Registered January 13, 2023, http://www.chictr.org.cn .

Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study.

OBJECTIVE: This study was designed to assess the efficacy and safety of cadonilimab monotherapy, a first-in-class, bi-specific PD-1/CTLA-4 antibody, in patients with previously treated recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). PATIENTS AND METHODS: This multicenter, open-label, single-arm, phase II clinical trial enrolled patients with R/M-NPC who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy, and immunotherapy-naive. Patients received cadonilimab for 6 mg/kg once every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) in full analysis set (FAS) assessed by investigators according to RECIST v.1.1. The secondary endpoint included progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR) and safety. RESULTS: A total of 23 patients were assessed. The median time from first dose to data cutoff was 16.56 (range, 0.8-25.2) months. ORR was 26.1 % (95 %CI:10.2-48.4). The ORR were 44.4 % (95 %CI: 13.7-78.8) and 14.3 % (95 %CI:1.8-42.8) in patients with tumor PD-L1 expression ≥50 % and <50 %, respectively. ORR was achieved in 40.0 % (95 %CI:12.2-73.8) of patients with EBV-DNA level <4000 IU/ml (n = 10) and 15.4 % (95 %CI:1.9-45.4) of those with ≥4000 IU/ml. The median PFS was 3.71 months (95 %CI: 1.84-9.30). respectively. Median OS was not reached, and the 12-month OS rate was 79.7 % (95 % CI:54.5-91.9). Only two patients (8.3 %) experienced Grade ≥3 treatment-related adverse events (TRAEs) with hypothyroidism (30.4 %), rash (21.7 %) and pruritus (21.7 %) being the most prevalent TRAEs. CONCLUSION: Cadonilimab monotherapy demonstrated a promising efficacy and manageable toxicity in patients with previously treated R-M/NPC and provide an efficacious salvage treatment option.

Surgical treatment and outcome of haematomyelia with a traumatic cause in a dog and a cat.

Two surgically treated haematomyelia cases were documented. One dog and one cat were presented for acute progressive paraplegia following a fall from height incident. Neurological examinations suggested a L4-S3 myelopathy in both cases. Radiography and magnetic resonance imaging in both cases revealed no fracture or subluxation of the spine, but well-defined intramedullary mass lesions in lower lumbar regions compatible with haemorrhage and haematoma formation. Exploratory surgeries were performed over the lesions. Dark-red friable masses were removed via myelotomy. Histopathological examinations revealed organizing haematomas at the acute to subacute stage. Postoperatively, both cases improved and regained ambulation. The dog walked normally but remained urinary and faecal incontinent 9 months after the surgery. The cat was continent and ambulatory with a paraparetic gait 5 months after the surgery. In both cases, the outcomes and the patients' quality of life were considered satisfactory by the owners.

The Effect of Characteristics of Patient Communication on Physician Feedback in Online Health Communities: An Observational Cross-Sectional Study.

With the rapid development of e-health and telemedicine, previous studies have explored the relationship between physician-patient communication and patient satisfaction; however, there is a paucity of research on the influence of the characteristics of patient communication on the characteristics of physician feedback. Based on the communication accommodation theory, as well as the computer-mediated communication theory and media richness theory, this study aimed to explore how characteristics of patient communication influence characteristics of physician feedback in online health communities. We employed a crawler software to download the communication data between 1652 physicians and 105,325 patients from the Good Doctor platform, the biggest online health community in China. We built an empirical model using this data and employed a multilevel model to test our hypotheses using Stata and Python software. The results indicate that the amount of patients' rendered information positively influences the physicians' text (α = 0.123, t = 33.147, P < .001) and voice feedback (ß = 0.201, t = 40.011, P < .001). Patients' hope for help signals and the provision of their electronic health records weaken the effect of the amount of patients' rendered information on physicians' text feedback (α = -0.040, t = -24.857, P < .001; α = -0.048, t = -15.784, P < .001), whereas, it strengthened the effect of the amount of patients' rendered information on physicians' voice feedback (ß = 0.033, t = 14.789, P < .001; ß = 0.017, t = 4.208, P < .001). Moreover, the occurrence of high-privacy diseases strengthened the effect of the amount of patients' presented information on physicians' text and voice feedback (α = 0.023, t = 4.870, P < .001; ß = 0.028, t = 4.282, P < .001). This research contributes to the development of computer-mediated communication theories and sheds light on service delivery in the online health community.

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma.

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106-4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

Adipose knockout of H-ferritin improves energy metabolism in mice.

OBJECTIVE: Ferritin, the principal iron storage protein, is essential to iron homeostasis. How iron homeostasis affects the adipose tissue is not well understood. We investigated the role of ferritin heavy chain in adipocytes in energy metabolism. METHODS: We generated adipocyte-specific ferritin heavy chain (Fth, also known as Fth1) knockout mice, herein referred to as FthAKO. These mice were analyzed for iron homeostasis, oxidative stress, mitochondrial biogenesis and activity, adaptive thermogenesis, insulin sensitivity, and metabolic measurements. Mouse embryonic fibroblasts and primary mouse adipocytes were used for in vitro experiments. RESULTS: In FthAKO mice, the adipose iron homeostasis was disrupted, accompanied by elevated expression of adipokines, dramatically induced heme oxygenase 1(Hmox1) expression, and a notable decrease in the mitochondrial ROS level. Cytosolic ROS elevation in the adipose tissue of FthAKO mice was very mild, and we only observed this in the brown adipose tissue (BAT) but not in the white adipose tissue (WAT). FthAKO mice presented an altered metabolic profile and showed increased insulin sensitivity, glucose tolerance, and improved adaptive thermogenesis. Interestingly, loss of ferritin resulted in enhanced mitochondrial respiration capacity and a preference for lipid metabolism. CONCLUSIONS: These findings indicate that ferritin in adipocytes is indispensable to intracellular iron homeostasis and regulates systemic lipid and glucose metabolism.

Toripalimab plus capecitabine in the treatment of patients with residual nasopharyngeal carcinoma: a single-arm phase 2 trial.

Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma.

Mutational profiling of mitochondrial DNA reveals an epithelial ovarian cancer-specific evolutionary pattern contributing to high oxidative metabolism.

BACKGROUND: Epithelial ovarian cancer (EOC) heavily relies on oxidative phosphorylation (OXPHOS) and exhibits distinct mitochondrial metabolic reprogramming. Up to now, the evolutionary pattern of somatic mitochondrial DNA (mtDNA) mutations in EOC tissues and their potential roles in metabolic remodelling have not been systematically elucidated. METHODS: Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC-specific evolutionary pattern of mtDNA mutations and investigated its biological implication. RESULTS: Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non-cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near-complete absence of mtCTR non-hypervariable segment (non-HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region-specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT-CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non-cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients. CONCLUSIONS: Our study presents a comprehensive delineation of EOC-specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.

Association between triglyceride glucose index and depression in hypertensive population.

Growing evidence suggests that hypertensive individuals have a greater risk of developing depression, and depression can also increase the incidence of hypertension. In the hypertensive population, the association between triglyceride glucose (TyG) index and depression remains unclear. This study aimed to assess the association between TyG index and depression in hypertensive people through the cross-sectional study of the National Health and Nutrition Examination Survey (2007-2018). To assess the relationship between TyG index and depression in hypertensive population, we conducted weighted multiple logistic regression models and used a generalized additive model to probe for nonlinear correlations. In addition, we employed a recursive algorithm to determine the inflection point and established a two-piece linear regression model. This study enrolled 5897 individuals. In the model adjusted for all covariates, the ORs (95% CI) for the relationship between TyG index and depression in hypertensive population were 1.32 (1.12-1.54). A nonlinear association was found between TyG index and depression, with an inflection point at 8.7. After the inflection point, the ORs (95% CI) were 1.44 (1.15-1.79). Only the interaction with the obese population was statistically significant. Our study highlighted a nonlinear association between TyG index and depression in American hypertensive adults.