Recent studies have suggested that long-term application of anti-angiogenic drugs may impair oral mucosal wound healing. This study investigated the effect of sunitinib on oral mucosal healing impairment in mice and the therapeutic potential of Bifidobacterium breve (B. breve). A mouse hard palate mucosal defect model was used to investigate the influence of sunitinib and/or zoledronate on wound healing. The volume and density of the bone under the mucosal defect were assessed by micro-computed tomography (micro-CT). Inflammatory factors were detected by protein microarray analysis and enzyme-linked immunosorbent assay (ELISA). The senescence and biological functions were tested in oral mucosal stem cells (OMSCs) treated with sunitinib. Ligated loop experiments were used to investigate the effect of oral B. breve. Neutralizing antibody for interleukin-10 (IL-10) was used to prove the critical role of IL-10 in the pro-healing process derived from B. breve. Results showed that sunitinib caused oral mucosal wound healing impairment in mice. In vitro, sunitinib induced cellular senescence in OMSCs and affected biological functions such as proliferation, migration, and differentiation. Oral administration of B. breve reduced oral mucosal inflammation and promoted wound healing via intestinal dendritic cells (DCs)-derived IL-10. IL-10 reversed cellular senescence caused by sunitinib in OMSCs, and IL-10 neutralizing antibody blocked the ameliorative effect of B. breve on oral mucosal wound healing under sunitinib treatment conditions. In conclusion, sunitinib induces cellular senescence in OMSCs and causes oral mucosal wound healing impairment and oral administration of B. breve could improve wound healing impairment via intestinal DCs-derived IL-10.
Animals ; Mice ; Interleukin-10 ; Bifidobacterium breve ; Up-Regulation ; Angiogenesis Inhibitors ; Sunitinib ; X-Ray Microtomography ; Administration, Oral ; Wound Healing ; Antibodies, Neutralizing

Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and down-regulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.

Objective:To evaluate the efficacy and safety of oral anisodine hydrobromide tablets in the treatment of nonarteritic anterior ischemic optic neuropathy (NAION).Methods:A multicenter nonrandomized controlled trial was conducted.A total of 282 acute NAION patients (282 eyes) were recruited from 16 hospitals in China from July 2020 to May 2021.Patients were divided into two groups according to treatment methods, which were control group (124 cases, 124 eyes) receiving regular treatment including citicoline sodium plus Ginkgo biloba leaf liquid extract or Ginkgo biloba leaf extract tablets plus mecobalamin, and experimental group (158 cases, 158 eyes) receiving treatment in control group plus oral anisodine hydrobromide tablets 1 mg, twice daily for 2 to 3 months.Best corrected visual acuity (BCVA), visual field index (VFI), peripapillary retinal nerve fiber layer (pRNFL) and radial peripapillary capillary vessel density (RPC) were assessed at 1, 2, 3, and 6 months after enrollment using the standard decimal visual acuity chart, 750i Humphery visual field analyzer, Cirrus HD-OCT 4000/Cirrus HD-OCT 5000, RTVue-XR optical coherence tomography respectively.The primary outcomes were BCVA and VFI, and the secondary outcomes were pRNFL, RPC, and the side effects during the follow-up.The study adhered to the Declaration of Helsinki.All patients were fully informed about the treatment and purpose of this study and voluntarily signed the informed consent form.The study protocol was approved by Chinese PLA General Hospital (No.S2020-021-01). Results:In all, 242 patients (242 eyes) completed the follow-up of BCVA, and 98 patients (98 eyes) completed the VFI follow-up.In terms of visual function, BCVA and VFI improved significantly over time in the two groups, and BCVA and VFI were better in experimental group than in control group at various follow-up time points (all at P<0.05). In terms of structure, pRNFL gradually decreased in both groups with the extension of treatment, and pRNFL was significanthy thinner in experimental group than in control group at various follow-up time points (all at P<0.05). There was no significant difference in RPC between the two groups at the last follow-up ( P>0.05). There were two cases with side effects and one case was discontinued due to side effects 25 days after enrollment. Conclusions:Oral anisodine hydrobromide can improve visual acuity and visual field in NAION and accelerate the regression of optic disc edema, with good safety.

Objective:This study investigated the changes of cortical thickness in patients with Parkinson's cognitive dysfunction.Methods:In this cross-sectional study, general clinical data and head magnetic resonance imaging data were collected from Parkinson's disease(PD)patients and healthy controls who were hospitalized or outpatient in the Department of Geriatric Neurology of the First Affiliated Hospital of Kunming Medical University from January 2019 to December 2020.We observed the changes of cortical thickness in each group, and analyzed the correlation between cortical thickness and cognitive dysfunction in PD.Results:Compared with PD normal cognitive group, the cortical thickness of the left superiortemporal gyrus[(2.7±0.1)mm, (2.4±0.1)mm, t=-4.194], left supramarginal[(2.4±0.1)mm, (2.2±0.1)mm, t=-4.845], right insula[(3.0±0.1)mm, (2.7±0.1)mm, t=-4.170], left parahippocampal[(2.8±0.3)mm, (2.4±0.3)mm, t=-4.164]decreased in PD cognitive impairment group(all P<0.05), and cortical thickness of the right parsorbitalis[(2.5±0.2)mm, (2.4±0.2)mm, t=-4.226], left entorhinal[(3.5±0.3)mm, (3.1±0.4)mm, t=-4.583], left inferiortemporal[(2.7±0.2)mm, (2.5±0.1)mm, t=-6.229], left supramarginal[(2.4±0.1)mm, (2.1±0.1)mm, t=-3.236], right fusiform[(2.8±0.1)mm, (2.5±0.1)mm, t=-5.364], right lingual[(2.0±0.1)mm, (1.9±0.1)mm, t=-3.887], right insula[(3.0±0.1)mm, (2.7±0.2)mm, t=-5.326], right isthmuscingulate[(2.6±0.2)mm, (2.3±0.2)mm, t=-3.743]decreased in PD severe cognitive impairment group, the statistical difference was significant(all P<0.05). The cerebral cortex thickness was positively correlated with Mini-Mental State Examination and different cognitive areas, and negatively correlated with Hoehn-Yahrr grading. Conclusions:Local cortical thinning was observed in PD patients with cognitive impairment, whereas cortical involvement was more extensive in PD patients with severe cognitive impairment.

To study an automatic plan(AP) method for radiotherapy after breast-conserving surgery based on TiGRT system and and compare with manual plan (MP). The dosimetry parameters of 10 patients and the evaluation of scoring table were analyzed, it was found that the targets dose of AP were better than that of MP, but there was no statistical difference except for CI, The V5, V20 and V30 of affected lungs and whole lungs in AP were lower than all that in MP, the Dmean of hearts was slightly higher than that of MP, but the difference was not statistically significant, the MU of AP was increase by 16.1% compared with MP, the score of AP evaluation was increase by 6.1% compared with MP. So the AP could be programmed and automated while ensuring the quality of the plan, and can be used to design the plans for radiotherapy after breast-conserving surgery.
Breast Neoplasms/surgery* ; Female ; Humans ; Mastectomy, Segmental ; Organs at Risk ; Radiotherapy Dosage ; Radiotherapy Planning, Computer-Assisted ; Radiotherapy, Intensity-Modulated

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.

Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron- and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species (ROS) and inducing ferroptosis in activated hepatic stellate cells (HSCs). By using activity-based protein profiling (ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay (CETSA), we show that celastrol directly binds to peroxiredoxins (PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6, through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1 (HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2, PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.

Methods:Two thousand standard sections images werre collected from 2 000 clinical retrospective pediatric hip ultrasound videos from January 2019 to January 2021. All standard sections were annotated by the annotation team through the self-designed software based on Python 3.6 environment for image cross-media data annotation and manual review standardization process with unified standards. Among them, 1 753 were randomly selected for training the deep learning system, and the remaining 247 were used for testing the system. Further, 200 standard sections were randomly selected from the test set, and 8 clinicians independently completed the film reading annotation. The 8 independent results were then compared with the AI results.Results:The testing set consists of 247 patients. Compared with the clinician's measurements, the area under the receiver operating characteristic curve (AUC) of diagnosing hip joint maturity was 0.865, the sensitivity was 76.19%, and the specificity was 96.9%. The AUC of AI system interpretation under Graf detailed typing was 0.575, the sensitivity was 25.90%, the specificity was 89.10%. The 95% LoA of α-angle determined by Bland-Altman method, of -4.7051° to 6.5948° ( Bias -0.94, P<0.001), compared with clinicians' measurements. The 95% LoA of β-angle, of -7.7191 to 6.8777 ( Bias -0.42, P=0.077). Compared with those from 8 clinicians, the results of AI system interpretation were more stable, and the β-angle effect was more prominent. Conclusion:The AI system can quickly and accurately measure the Graf correlation index of standard DDH ultrasonic standard diagnosis plane.

Objective:To investigate the relationship between rapid eye movement sleep behavior disorder(RBD)and neurofilament light chain(NfL)levels in patients with Parkinson's disease(PD).Methods:General clinical data of 121 PD patients and 38 healthy controls(HC)who visited the Department of Geriatric Neurology of the First Affiliated Hospital of Kunming Medical University from June 2019 to January 2021 were collected in a prospective study.According to the Rapid Eye Movement Sleep Behavior Disorder Questionnaire(RBDSQ), PD patients were divided into a PD with RBD group(PD-RBD, RBDSQ≥6)and a PD without RBD group(PD-NRBD, RBDSQ<6). General clinical data and plasma NfL levels of patients in the groups were compared.In addition, symptoms during exercise, during non-exercise, and sleep quality in the groups were also compared.Results:Plasma NfL levels were higher in the PD group than in the HC group(19.39 ng/L, 12.58-31.78; 14.85 ng/L, 9.78-22.15; Z=-2.492, P<0.05); plasma NfL levels were significantly higher in the PD-RBD group than in the PD-NRBD group and in the HC group(25.29 ng/L, 19.09-34.75; 17.14 ng/L, 11.70-26.67; 14.85 ng/L, 9.78-22.15; Z=-3.434, P<0.01); there was no significant difference in plasma NfL levels between the HC group and the PD-NRBD group( P>0.05). Receiver operating characteristic(ROC)curve analysis showed that, when the plasma NfL cutoff was set at 17.86 ng/L, PD-RBD and PD-NRBD could be distinguished( AUC=0.70, 95% CI=0.60-0.80, sensitivity 82%, specificity 54%). Binary logistic regression identified NfL level as an independent predictor of PD-RBD( β=0.068, OR=1.103, P=0.003). Conclusions:PD-RBD patients have increased plasma NfL levels, which can potentially serve as a biomarker for PD with RBD.

Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18β-GA)is a natural com-pound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18β-GA inhibited the expression of α-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon reso-nance,we found that 18β-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18β-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis,highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.