20S-Ginsenoside Rh2, the major bioactive saponin in Panax notoginseng flowers, ameliorates cough by inhibition of NaV1.7 and TRPV1 channel currents and downregulation of TRPV1 expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng flowers, which are the buds of the traditional Chinese medicinal herb Sanqi, are widely used in China for their cough-ameliorating properties, with demonstrated therapeutic effects in the treatment of both acute and chronic coughs. However, both the antitussive mechanism and active compound basis of P. notoginseng flowers remain poorly understood. AIM OF THE STUDY: We investigated the antitussive effects of P. notoginseng flowers, identified the bioactive constituents responsible for alleviating cough symptoms, and elucidated the underlying pharmacological mechanisms. MATERIALS AND METHODS: We analyzed the major chemical constituents of aqueous extracts of P. notoginseng flowers using liquid chromatography-mass spectrometry and quantitatively analyzed the key component, 20S-ginsenoside Rh2, using high-performance liquid chromatography. Using a cough reflex model in healthy mice and an ovalbumin-induced, highly sensitive guinea pig cough model, we verified the suppressive effects of P. notoginseng flowers and their saponin constituents on coughing. Furthermore, we explored the mechanisms of action of the key ion channels, NaV1.7 and TRPV1, using whole-cell patch-clamp techniques and molecular docking. Finally, the therapeutic mechanisms of P. notoginseng flowers on pathological cough were revealed using hematoxylin and eosin staining, immunohistochemistry, and western blotting. RESULTS: The active components of P. notoginseng flowers were primarily protopanaxadiol-type saponins, among which 20S-ginsenoside Rh2 had the highest content (51.46 mg/g). In the mouse model, P. notoginseng flowers exhibited antitussive effects comparable to those of pentoxyverine citrate. Although its main saponin component, 20S-ginsenoside Rh2, showed slightly weaker effects, it still demonstrated concentration-dependent inhibition of channel activity. The whole-cell patch-clamp technique and virtual molecular docking showed that Rh2 might exert its effects by directly binding to the NaV1.7 and TRPV1 channels. In the guinea pig model, P. notoginseng flowers and their saponin components not only reduced cough frequency and prolonged the latency period before cough onset, but also significantly inhibited tracheal and pulmonary inflammation and the overexpression of TRPV1. CONCLUSIONS: 20S-Ginsenoside Rh2, the major bioactive saponin in P. notoginseng flowers, exhibits potent antitussive effects. The potential mechanism of action of 20S-Ginsenoside Rh2 in the treatment of cough may involve inhibiting NaV1.7 and TRPV1 channel currents through direct binding to core protein active sites and downregulating TRPV1 expression.

Study of a precise treatment protocol for patients with consciousness disorders based on the brain network analysis of functional magnetic resonance imaging.

Objective: How to conduct objective and accurate individualized assessments of patients with disorders of consciousness (DOC) and carry out precision rehabilitation treatment technology is a major rehabilitation problem that needs to be solved urgently. Methods: In this study, a multi-layer brain network was constructed based on functional magnetic resonance imaging (fMRI) to analyze the structural and functional brain networks of patients with DOC at different levels and to find regulatory targets (imaging markers) with recovery potential for DOC. Then repeated transcranial magnetic stimulation (rTMS) was performed in DOC patients to clinically validate. Results: The brain network connectivity of DOC patients with different consciousness states is different, and the most obvious brain regions appeared in the olfactory cortex and precuneus. rTMS stimulation could effectively improve the consciousness level of DOC patients and stimulate the occipital lobe (specific regions found in this study) and the dorsolateral prefrontal cortex (DLPFC), and both parts had a good consciousness recovery effect. Conclusion: In clinical work, personalized stimulation regimen treatment combined with the brain network characteristics of DOC patients can improve the treatment effect.

Apoptotic vesicles (apoVs) derived from fibroblast-converted hepatocyte-like cells effectively ameliorate liver fibrosis.

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs.

bSSFP Phase Contrast (PC-SSFP) at 0.55T Applied to Aortic Flow.

BACKGROUND: There is a growing interest in the development and application of mid-field (0.55T) for cardiac MR, including flow imaging. However, aortic flow imaging at 0.55T has limited SNR, especially in diastolic phases where there is reduced inflow-driven contrast for spoiled gradient echo (GRE) sequences. The low SNR can limit the accuracy of flow and regurgitant fraction measurements. METHODS: In this work, we developed a 2D phase contrast (PC) acquisition with balanced steady state free precession (bSSFP), termed PC-SSFP, for flow imaging and quantification at 0.55T. This PC-SSFP approach precisely nulls the 0th and 1st gradient moments at both the TE and TR, except for the flow-encoded acquisition, for which the 1st gradient moment at the TE is determined by the VENC. Our proposed sequence was tested in both phantoms and in healthy volunteers (n=11), to measure aortic flow. In volunteers, both a breath-hold and a free-breathing protocol, with averaging to increase SNR, were obtained. Total flow, peak flow, cardiac output and SNR were compared for PC-SSFP and PC-GRE. Stroke volumes were also measured and compared to planimetry method. RESULTS: In a phantom, SNR was significantly higher using PC-SSFP compared to PC-GRE (25.5±9.6 vs 8.2±2.9), and the velocity measurements agreed well (R = 1.00). In healthy subjects, for both breath-hold (bh) and free-breathing (fb) protocols, PC-SSFP measured accurate peak flow (fb: R = 0.99, bh: R = 0.96) and cardiac output (fb: R = 0.98, bh: R = 0.88), compared to PC-GRE, accurate stroke volume (fb: R = 0.94, bh: R = 0.97), compared to planimetry measurement, and offered constant high SNR (fb: 28±9 vs 18±6, bh: 24±7 vs 11±3) over the cardiac cycle in 11 subjects. CONCLUSION: PC-SSFP is a more reliable evaluation tool for aortic flow quantification, when compared to the conventional PC-GRE method at 0.55T, providing higher SNR, and thus potentially more accurate flows.

The impact of indirect structure on functional connectivity in schizophrenia using a multiplex brain network.

It is known that abnormal functional connectivity (FC) in schizophrenia (SZ) is closely related to structural connectivity (SC). We speculate that indirect SC also have an impact on FC in SZ patients. Conventional single-layer network has limitations for studying the relationship between indirect SC and FC. Thus, this study constructed a multiplex network based on structural connectivity and functional connectivity (SC-FC). The SC-FC bandwidth and SC-FC cost are used to analyze the impact of indirect SC on FC. Moreover, this paper proposed mediation ability, mediation cost, mediated strength and mediated cost to quantify the effects of mediator nodes and mediated nodes on indirect SC. The results show that SZ patients exhibit lower SC-FC bandwidth and SC-FC cost compared to healthy controls (HC), which could be caused by the limbic and subcortical network (LSN), default mode network (DMN) and visual network (VN). The mediator and mediated nodes in indirect SC of SZ patients also showed diminished effects. These findings suggest that functional communication ability and cost in SZ patients are influenced by indirect SC. This study provides new perspectives for understanding the relationship between indirect SC and FC, and provides strong evidence for interpreting the physiological mechanisms of SZ patients.

Abnormal Dynamic Reconfiguration of Multilayer Temporal Networks in Patients with Bipolar Disorder.

BACKGROUND: Multilayer networks have been used to identify abnormal dynamic reconfiguration in bipolar disorder (BD). However, these studies ignore the differences in information interactions between adjacent layers when constructing multilayer networks, and the analysis of dynamic reconfiguration is not comprehensive enough; Methods: Resting-state functional magnetic resonance imaging data were collected from 46 BD patients and 54 normal controls. A multilayer temporal network was constructed for each subject, and inter-layer coupling of different nodes was considered using network similarity. The promiscuity, recruitment, and integration coefficients were calculated to quantify the different dynamic reconfigurations between the two groups; Results: The global inter-layer coupling, recruitment, and integration coefficients were significantly lower in BD patients. These results were further observed in the attention network and the limbic/paralimbic and subcortical network, reflecting reduced temporal stability, intra- and inter-subnetwork communication abilities in BD patients. The whole-brain promiscuity was increased in BD patients. The same results were observed in the somatosensory/motor and auditory network, reflecting more functional interactions; Conclusions: This study discovered abnormal dynamic interactions of BD from the perspective of dynamic reconfiguration, which can help to understand the pathological mechanisms of BD.

Multi-Frequency Entropy for Quantifying Complex Dynamics and Its Application on EEG Data.

Multivariate entropy algorithms have proven effective in the complexity dynamic analysis of electroencephalography (EEG) signals, with researchers commonly configuring the variables as multi-channel time series. However, the complex quantification of brain dynamics from a multi-frequency perspective has not been extensively explored, despite existing evidence suggesting interactions among brain rhythms at different frequencies. In this study, we proposed a novel algorithm, termed multi-frequency entropy (mFreEn), enhancing the capabilities of existing multivariate entropy algorithms and facilitating the complexity study of interactions among brain rhythms of different frequency bands. Firstly, utilizing simulated data, we evaluated the mFreEn's sensitivity to various noise signals, frequencies, and amplitudes, investigated the effects of parameters such as the embedding dimension and data length, and analyzed its anti-noise performance. The results indicated that mFreEn demonstrated enhanced sensitivity and reduced parameter dependence compared to traditional multivariate entropy algorithms. Subsequently, the mFreEn algorithm was applied to the analysis of real EEG data. We found that mFreEn exhibited a good diagnostic performance in analyzing resting-state EEG data from various brain disorders. Furthermore, mFreEn showed a good classification performance for EEG activity induced by diverse task stimuli. Consequently, mFreEn provides another important perspective to quantify complex dynamics.

One-Photon-Interference Quantum Secure Direct Communication.

Quantum secure direct communication (QSDC) is a quantum communication paradigm that transmits confidential messages directly using quantum states. Measurement-device-independent (MDI) QSDC protocols can eliminate the security loopholes associated with measurement devices. To enhance the practicality and performance of MDI-QSDC protocols, we propose a one-photon-interference MDI QSDC (OPI-QSDC) protocol which transcends the need for quantum memory, ideal single-photon sources, or entangled light sources. The security of our OPI-QSDC protocol has also been analyzed using quantum wiretap channel theory. Furthermore, our protocol could double the distance of usual prepare-and-measure protocols, since quantum states sending from adjacent nodes are connected with single-photon interference, which demonstrates its potential to extend the communication distance for point-to-point QSDC.

Efficacy and safety of various corticosteroids in the treatment of children with allergic rhinitis: A systematic review and network meta-analysis.

BACKGROUND: Intranasal corticosteroids were recommended as first-line drugs for the treatment of allergic rhinitis (AR) children. A variety of corticosteroids were available for clinical choice; however, which could relieve the clinical symptoms of patients to the greatest extent was currently unknown. Thus, we performed a network meta-analysis (NMA) to systematically evaluate the effectiveness and safety of different corticosteroids in treating children with AR, which might provide a basis for more rational clinical treatment decisions. METHODS: Seven electronic databases were searched, and the retrieval time range was the time from their inception to November 2023. The literature screening, data extraction, and assessment of the risk of bias of included studies were completed independently by two reviewers. A frequentist NMA was performed with Stata17.0 software. RESULTS: A total of 43 RCTs covering 10,897 participants were included. In the improvement of reflective total nasal symptom score (rTNSS) and instantaneous total nasal symptom score (iTNSS), fluticasone furoate nasal spray (FFNS) and beclomethasone dipropionate (BDP) nasal aerosol presented the best efficacy. Regarding the incidence of adverse reactions, mometasone furoate aqueous nasal spray (MFANS) and BDP showed a good safety profile. In terms of the influence of cortisol (urinary free cortisol, plasma cortisol) and growth, no significant difference was observed between the different groups. CONCLUSION: The results showed that BDP nasal aerosol and FFNS had best efficacy; MFANS and BDP had the best safety profile. However, this conclusion was less convincing because of the limited numbers of patients/controls and study quality.

Ce Doping Effects on the Hydrogen Sensing Properties of Graphene/SnO2-Based Sensors.

The development of a sensor capable of selectively detecting hydrogen levels in the environment holds immense importance for ensuring the safer utilization of hydrogen energy. In this study, a hydrogen sensor made of Ce-doped single-layer graphene (SLG)/SnO2 composite material was fabricated using a hydrothermal method. The study examined the impact of varying Ce doping concentrations on the hydrogen sensing capabilities of the SLG/SnO2 matrix. The results show that the SLG/SnO2 hydrogen sensor doped with 2 mol% Ce demonstrated optimal performance at a humidity of 20%. It operated most efficiently at 250 °C, with a response of 2.49, representing a 25.75% improvement over the undoped sample. The response/recovery times were 0.46/3.92 s, which are 54.9% shorter than those of the undoped sample. The enhancement in hydrogen sensitivity stems from the synergistic effect of Ce and SLG, which facilitates the coexistence of n-n and p-n heterojunctions, thereby increasing carrier mobility and refining grain structure. Analysis via X-ray photoelectron spectroscopy (XPS) reveals that Ce increases the material's oxygen vacancy concentration, enhancing its hydrogen sensitivity. Ce-doped SLG/SnO2, with its robust hydrogen sensitivity, represents one of the leading candidates for future hydrogen gas sensors.

Dietary apigenin ameliorates obesity-related hypertension through TRPV4-dependent vasorelaxation and TRPV4-independent adiponectin secretion.

BACKGROUND: Obesity-related hypertension is a major cardiovascular risk factor. Apigenin, a natural flavonoid in celery, induces vascular dilation via endothelial transient receptor potential channel vanilla 4 (TRPV4) channels. This study aimed to explore apigenin's potential to alleviate obesity-related hypertension in mice and its underlying mechanisms. METHODS: The C57BL/6 and TRPV4 knockout mice were fed a high-fat diet and subjected to dietary intervention with apigenin. Body weight and tail blood pressure of the mice were measured during the feeding. Vascular reactivity was assessed through a DMT wire myograph systems in vitro. The distribution and expression of adiponectin and pro-inflammatory markers in brown fat were detected. Injecting adeno-associated eight (AAV8) viruses into brown adipose tissue (BAT) to determine whether adiponectin is indispensable for the therapeutic effect of apigenin. Palmitic acid (PA) was used in mouse brown adipocytes to examine the detailed mechanisms regulating adiponectin secretion. RESULTS: Apigenin improved vasodilation and reduced blood pressure in obese mice, effects partly blocked in TRPV4 knockout. It also reduced weight gain independently of TRPV4. Apigenin increased adiponectin secretion from BAT; knockdown of adiponectin weakened its benefits. Apigenin downregulated Cluster of differentiation 38 (CD38), restoring Nicotinamide adenine dinucleotide+ (NAD+) levels and activating the NAD+/Sirtuin 1 (SIRT1) pathway, enhancing adiponectin expression. CONCLUSIONS: Our study indicates that dietary apigenin is suitable as a nonpharmaceutical intervention for obesity-related hypertension. In mechanism, in addition to improving vascular relaxation through the activation of endothelial TRPV4 channels, apigenin also directly alleviated adipose inflammation and increased adiponectin levels by inhibiting CD38.

Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson's and Alzheimer's disease co-pathology and behavior impairments.

Tau interacts with α-Synuclein (α-Syn) and co-localizes with it in the Lewy bodies, influencing α-Syn pathology in Parkinson's disease (PD). However, whether these biochemical events regulate α-Syn pathology spreading from the gut into the brain remains incompletely understood. Here, we show that α-Syn and Tau co-pathology is spread into the brain in gut-inducible SYN103+/- and/or TAU368+/- transgenic mouse models, eliciting behavioral defects. Gut pathology was initially observed, and α-Syn or Tau pathology was subsequently propagated into the DMV or NTS and then to other brain regions. Remarkably, more extensive spreading and widespread neuronal loss were found in double transgenic mice (Both) than in single transgenic mice. Truncal vagotomy and α-Syn deficiency significantly inhibited synucleinopathy or tauopathy spreading. The α-Syn PET tracer [18F]-F0502B detected α-Syn aggregates in the gut and brain. Thus, α-Syn and Tau co-pathology can propagate from the gut to the brain, triggering behavioral disorders.

Abnormal Dynamic Reconstruction of Overlapping Communities in Schizophrenia Patients.

OBJECTIVE: This study aims to explore the changes in dynamic overlapping communities in the brains of schizophrenia (SZ) patients and further investigate the dynamic restructuring patterns of overlapping communities in SZ patients. MATERIALS AND METHODS: A total of 43 SZ patients and 49 normal controls (NC) were selected for resting-state functional MRI (rs-fMRI) scans. Dynamic functional connectivity analysis was conducted separately on SZ patients and NC using rs-fMRI and Jackknife Correlation techniques to construct dynamic brain network models. Based on these models, a dynamic overlapping community detection method was utilized to explore the abnormal overlapping community structure in SZ patients using evaluation metrics such as the structural stability of overlapping communities, nodes' functional diversity, and activity level of overlapping communities. RESULTS: The stability of communities in SZ patients showed a decreasing trend. The changes in the overlapping community structure of SZ patients may be related to a decrease in the diversity of overlapping node functions. Additionally, compared to the NC group, the activity level of overlapping communities of SZ patients was significantly reduced. CONCLUSION: The structure or organization of the brain functional network in SZ patients is abnormal or disrupted, and the activity of the brain network in information processing and transmission is weakened in SZ patients.

Continuous Dictionary of Nodes Model and Bilinear-Diffusion Representation Learning for Brain Disease Analysis.

Brain networks based on functional magnetic resonance imaging (fMRI) provide a crucial perspective for diagnosing brain diseases. Representation learning has recently attracted tremendous attention due to its strong representation capability, which can be naturally applied to brain disease analysis. However, traditional representation learning only considers direct and local node interactions in original brain networks, posing challenges in constructing higher-order brain networks to represent indirect and extensive node interactions. To address this problem, we propose the Continuous Dictionary of Nodes model and Bilinear-Diffusion (CDON-BD) network for brain disease analysis. The CDON model is innovatively used to learn the original brain network, with its encoder weights directly regarded as latent features. To fully integrate latent features, we further utilize Bilinear Pooling to construct higher-order brain networks. The Diffusion Module is designed to capture extensive node interactions in higher-order brain networks. Compared to state-of-the-art methods, CDON-BD demonstrates competitive classification performance on two real datasets. Moreover, the higher-order representations learned by our method reveal brain regions relevant to the diseases, contributing to a better understanding of the pathology of brain diseases.

Trajectory on postpartum depression of Chinese women and the risk prediction models: A machine-learning based three-wave follow-up research.

BACKGROUND: Our study delves into postpartum depression (PPD) extending observation up to six months postpartum, addressing the gap in long-term follow-ups and uncover critical intervention points. METHOD: Through a continuous three-wave cohort study involving 3174 of 10,730 invited postpartum women, we utilized machine learning to predict PPD risk, incorporating self-reported surveys and health records from October 2021 to Jan 2023. RESULTS: PPD prevalence slightly decreased from 30.9 % to 29.1 % over six months. The Random Forest model emerged as the most effective, identifying key predictors of PPD at different stages. The top three factors at first month were newborn's birth weight, maternal weight before delivery and before pregnancy. The EPDS scores of last time, newborn's birth weight and maternal weight before pregnancy and before delivery were main predictors for EPDS scores at third and sixth months postpartum. LIMITATION: The study faces limitations such as potential selection bias due to the convenience sampling method and the reliance on self-reported measures, which may introduce reporting bias. Furthermore, the high attrition rate could affect the representativeness of the sample and the generalizability of the findings. CONCLUSION: There is a slight decrease in PPD rates over six months, yet the prevalence remains high. This underscores the need for early and ongoing mental health support for new mothers. Our study highlights the efficacy of machine learning in enhancing PPD risk assessment and tailoring intervention strategies, paving the way for more personalized healthcare approaches in postpartum care.

YTHDF3 Regulates the Degradation and Stability of m6A-Enriched Transcripts to Facilitate the Progression of Castration-Resistant Prostate Cancer.

RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of SPOP and NXK3.1 but stabilized RNA expressions of TWIST1 and SNAI2 dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading SPOP in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity.

Robotic-assisted versus video-assisted lobectomy for resectable non-small-cell lung cancer: the RVlob randomized controlled trial.

Background: The long-term survival and perioperative outcomes of robotic-assisted lobectomy (RAL) and video-assisted lobectomy (VAL) in resectable non-small-cell lung cancer (NSCLC) were found to be comparable in retrospective studies, but they have not been investigated in a randomized trial setting. We conducted the RVlob trial to investigate if RAL was non-inferior to VAL in patients with resectable NSCLC. Methods: In this single-center, open-label, and parallel-arm randomized controlled trial conducted in Ruijin Hospital (Shanghai, China) between May 2017 and May 2020, we randomly assigned patients with resectable NSCLC in a 1:1 ratio to receive either RAL or VAL. One of the primary endpoints was 3-year overall survival. Secondary endpoints included 3-year disease-free survival. The Kaplan-Meier approach was used to calculate overall survival and disease-free survival at 3 years. This study was registered with ClinicalTrials.gov, NCT03134534. Findings: A total of 320 patients were randomized to receive RAL (n = 157) or VAL (n = 163). The baseline characteristics of patients were well balanced between the two groups. After a median follow-up of 58.0 months, the 3-year overall survival was 94.6% (95% confidence interval [CI], 91.0-98.3) in the RAL group and 91.5% (95% CI, 87.2-96.0) in the VAL group (hazard ratio [HR] for death, 0.65; 95% CI, 0.33-1.28; P = 0.21); noninferiority of RAL was confirmed according to the predefined margin of -5% (absolute difference, 2.96%; a one-sided 90% CI, -1.39% to ∞; P = 0.0029 for noninferiority). The 3-year disease-free survival was 88.7% (95% CI, 83.6-94.1) in the RAL group and 85.4% (95% CI, 80.0-91.2) in the VAL group (HR for disease recurrence or death, 0.87; 95% CI, 0.50-1.52; P = 0.62). Interpretation: This study is the first randomized trial to show that RAL resulted in non-inferior overall survival compared with VAL in patients with resectable NSCLC. Based on our results, RAL is an equally oncologically effective treatment and can be considered as an alternative to VAL for resectable NSCLC. Funding: National Natural Science Foundation of China (82072557), National Key Research and Development Program of China (2021YFC2500900), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20172005, the 2nd round of disbursement), program of Shanghai Academic Research Leader from Science and Technology Commission of Shanghai Municipality (20XD1402300), Novel Interdisciplinary Research Project from Shanghai Municipal Health Commission (2022JC023), and Interdisciplinary Program of Shanghai Jiao Tong University (YG2023ZD04).

Salvianolic acid B improves diabetic skin wound repair through Pink1/Parkin-mediated mitophagy.

Diabetic skin wound is a disturbing and rapidly evolving clinical issue. Here, we investigated how salvianolic acid B (Sal B) affected the diabetic wound healing process. Following Sal B administration, histopathological damage was investigated by H&E and Masson staining, and CD34, apoptosis and mitophagy markers were measured by immunofluorescence, immunohistochemistry, and western blotting. Migration, proliferation, and mitochondrial function of high glucose (HG) -induced HMEC-1 cells were measured. The effects of si-Parkin on endothelial cell migration, apoptosis and mitochondrial autophagy were examined. Sal B alleviated inflammatory cell infiltration and promoted angiogenesis in skin wound tissue. Apoptosis and mitophagy were ameliorated by Sal B in diabetic skin wound tissues and HG-induced HMEC-1 cells. Parkin inhibition impaired the migratorypromoted cell apoptosis and inhibited mitophagy of HMEC-1 cells. This finding demonstrated that Sal B promoted diabetic skin wound repair via Pink1/Parkin-mediated mitophagy, improved our understanding of the diabetic wound healing process.

Multidimensional role of adapalene in regulating cell death in multiple myeloma.

Aims: Multiple myeloma (MM) remains a challenging condition to cure, with persistent drug resistance negating the benefits of treatment advancements. The unraveling complexities in programmed cell death (PCD), inclusive of apoptosis, autophagy, and ferroptosis, have highlighted novel therapeutic avenues. Our study focuses on deciphering how adapalene (ADA), a small molecule compound, accelerates the demise of MM cells via targeting their compensatory survival mechanisms. Methods: To assess the impact of ADA on MM, we employed flow cytometry and trypan blue exclusion assays to determine cell viabilities across MM cell lines and primary patient samples post-treatment. To delineate ADA's therapeutic targets and mechanisms, we conducted RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations. We further designed pre-clinical trials emphasizing MM, exploring the efficacy of ADA as a standalone and in combination with bortezomib (BTZ). Results: ADA elicited a dose-responsive induction of MM cell death. Building upon ADA's anti-MM capabilities as a single agent, we proposed that ADA-BTZ co-treatment might amplify this lethality. Indeed, ADA and BTZ together greatly potentiated MM cell death. ADA proved beneficial in restoring BTZ susceptibility in BTZ-resistant relapsed or refractory MM (RRMM) patient cells. Molecular simulations highlighted ADA's high affinity (-9.17 kcal/mol) for CD138, with MM-GBSA revealing a binding free energy of -27.39 kcal/mol. Detailed interaction analyses indicated hydrogen-bonding of ADA with CD138 at the Asp35 and Gln34 residues. Additionally, ADA emerged as a versatile instigator of both ferroptosis and apoptosis in MM cells. Furthermore, ADA disrupted activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway triggered by BTZ, fostering cell death in BTZ-resistant MM subsets. Conclusion: ADA demonstrates a comprehensive capability to orchestrate MM cell death, exerting pronounced anti-MM activity while disrupting NF-κB-related drug resistance. ADA sensitization of MM cells to BTZ unravels its potential as a novel therapeutic drug for MM management.

[Changes in Serum HOXA9 , PCâ ¢, SE-CAD Levels in AML Patients after Chemotherapy with DCAG Regimen and Their Relationship with Prognosis].

OBJECTIVE: To investigate the changes in serum homeobox A9 (HOXA9 ), soluble E-cadherin (SE-CAD) and type Ⅲ procollagen (PCⅢ) levels in acute myeloid leukemia (AML) patients after chemotherapy with DCAG regimen and their relationship with prognosis. METHODS: The clinical data of 80 patients with relapsed/refractory AML diagnosed and treated in our hospital from March 2018 to December 2021 were retrospectively analyzed. According to different treatment regimen, the patients were divided into DCAG group (n=40) and CAG group (n=40). The clinical efficacy and changes of HOXA9 , SE-CAD and PCⅢ levels before and after treatment were compared. In addition, all patients were divided into remission group (n=58) and non-remission group (n=22) according to the clinical efficacy. Univariate and multivariate analyses were performed to analyze the risk factors affecting the prognosis of AML patients. The predictive efficacy of the three single indicators, HOXA9 , SE-CAD, and PC III, and their combination on prognosis was analyzed. RESULTS: Compared with before treatment, the levels of HOXA9 , SE-CAD and PCⅢ in both the DCAG and CAG groups were decreased after treatment, and the improvement of each indicator and the clinical efficacy in the DCAG group were significantly better than those in the CAG group (all P < 0.05). Multivariate analysis showed that increased bone marrow blast count, HOXA9 mRNA, SE-CAD and PCⅢ levels were independent risk factors affecting the efficacy of chemotherapy in AML patients (all P < 0.05). ROC curves showed that the combination of HOXA9 mRNA, SE-CAD and PCIII could effectively predict the prognosis of AML patients, with a sensitivity of 84.80% and a specificity of 88.20%. CONCLUSION: DCAG regimen can significantly improve the levels of HOXA9 mRNA, SE-CAD and PCⅢ in AML patients, these three indicators are all independent risk factors affecting the prognosis of AML patients, and the combination of the three indicators can effectively predict the prognosis of the patients.