Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss.With the progression of periodontitis,the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption.CD301b+macrophages are specific to the osteoimmunology microenvironment,and are emerging as vital booster for conducting bone regeneration.However,the key upstream targets of CD301b+macrophages and their potential mechanism in periodontitis remain elusive.In this study,we concentrated on the role of Tim4,a latent upstream regulator of CD301b+macrophages.We first demonstrated that the transcription level of Timd4(gene name of Tim4)in CD301b+macrophages was significantly upregulated compared to CD301b-macrophages via high-throughput RNA sequencing.Moreover,several Tim4-related functions such as apoptotic cell clearance,phagocytosis and engulfment were positively regulated by CD301b+macrophages.The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages.The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b+macrophages as periodontitis progressed.Furthermore,the deficiency of Tim4 in mice decreased CD301b+macrophages and eventually magnified alveolar bone resorption in periodontitis.Additionally,Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b+macrophages phenotype.In a word,Tim4 might regulate CD301b+macrophages through p38 MAPK signaling pathway in periodontitis,which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.

Interventions for endometriosis(EMs)include surgical excision of lesions and hormonal therapy,which usually have limited efficacy and adverse drug reactions.Traditional Chinese medicine(TCM)has the multi-component and multi-target characteristics,which can help patients achieve good clinical benefits by intervening in different parts of the disease.In this paper,we briefly discuss the modern pharmacology of Sanlang and Curcuma longa,and deeply summarize the possible mechanisms of action of TCM monomer and classical compound extracts and their active ingredients through signal pathways in inflammation,immune system,angiogenesis,hormone regulation,etc.,so as to provide theoretical bases for the clinical use of TCM monomers,drug-to-drug groups and compounds in the treatment of EMs.

Objective:To explore the mechanism of hemoperfusion combined with hemofiltration in the treatment of sepsis based on Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway.Methods:One hundred and fifty patients with sepsis treated in the Heze Municipal Hospital from February 2020 to February 2023 were retrospectively selected and they were divided into two groups according to the treatment plan, with 75 cases in each group. Both groups were treated with standard treatment for sepsis, with hemofiltration in the control group and hemoperfusion combined with hemofiltration in the observation group. The TLR4/NF-κB signal pathway-related mRNA expression (TLR4 mRNA, NF-κB mRNA), related inflammatory factors, indicators of vascular endothelial function, the levels of indicators of liver and kidney function were measured between the two groups. The 28-d morbidity and mortality rate was compared between the two groups.Results:Compared with before treatment, the levels of TLR4 mRNA, NF-κB mRNA in two groups were decreased, and the levels of above index in the observation group were lower than those in the control group: 0.34 ± 0.12 vs. 0.63 ± 0.16, 0.30 ± 0.10 vs. 0.59 ± 0.12, there were statistical differences ( P<0.05). Compared with before treatment, the levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-12 and C reactive protein (CRP) in two groups were decreased, and the levels of above index in the observation group were lower than those in the control group: (43.42 ± 7.82) ng/L vs. (56.37 ± 9.41) ng/L, (28.47 ± 6.03) ng/L vs. (39.41 ± 7.02) ng/L, (52.31 ± 5.42) ng/L vs. (70.84 ± 7.08) ng/L, (23.82 ± 7.06) mg/L vs. (38.41 ± 6.83) mg/L, there were statistical differences ( P<0.05). Compared with before treatment, the levels of advanced glycosylation end products (AGEs), soluble intercellular adhesion factor-1 (sICAM-1), homocysteine (Hcy), glutamate transaminase (ALT), glutathione transaminase(AST), blood creatinine (Scr) and blood urea nitrogen (BUN) in two groups were decreased, and the levels of above index in the observation group were lower than those in the control group: (172.37 ± 73.63) mg/L vs. (249.41 ± 80.26) mg/L, (404.26 ± 68.42) ng/L vs. (459.36 ± 70.19) ng/L, (20.27 ± 4.53) μmol/L vs. (28.96 ± 5.02) μmol/L, (62.41 ± 10.69) U/L vs. (78.52 ± 13.41) U/L, (51.47 ± 12.35) U/L vs. (64.17 ± 15.83) U/L, (3.82 ± 0.79) mmol/L vs. (5.57 ± 1.16) mmol/L, (125.16 ± 23.96) μmol/L vs. (163.24 ± 30.12) μmol/L, there were statistical differences ( P<0.05). The 28-d morbidity and mortality rate in the observation group was lower than that in the control group: 12.00%(9/75) vs. 25.33%(19/75), there was statistical difference ( χ2 = 4.39, P<0.05). Conclusions:In the treatment of sepsis, hemoperfusion combined with hemofiltration can effectively alleviate the severity of the disease, reduce the damage of hepatic and renal function, and have a certain effect on the mRNA expression of TLR4/NF-κB signaling pathway and related inflammatory factors.

Aim To evaluate the effectiveness and safety of remimazolam tosylate for administering general anesthesia in morbidly obese patients.Methods This clinical trial was conducted at a single center from De-cember 2021 to October 2023.It assessed 108 morbid-ly obese patients(body mass index,BMI≥40)who underwent laparoscopic sleeve gastrectomy.Patients were randomly assigned to either the remimazaolam group(Group R)or the propofol group(Group P)for general anesthesia induction and maintenance.The primary outcome was to compare the incidence of ad-verse events and postoperative recovery characteristics between the two groups.Results During induction pe-riod,the incidence of adverse events was higher in group P,including hypotension(P＜0.01),hypox-emia(P＜0.05),bradycardia(P＜0.01),and in-creased vasopressor requirement(P＜0.05).The time to loss of consciousness and BIS falling to 60 was shor-ter in group P than in group R(P＜0.01).There were no statistically significant differences between the two groups in terms of postoperative quality of recovery(QoR-40 score),24-hour postoperative pain visual an-alogue scale(VAS)scores and morphine consump-tion.In conclusion,remimazolam tosylate,utilized for anesthesia induction in morbidly obese patients,signif-icantly reduced hypotension and hypoxemia compared to propofol,while it could also maintain similar postop-erative recovery quality.Conclusions Remimazolam is effective in reducing the incidence of hypotension and hypoxaemia during the induction period of general anaesthesia in morbidly obese patients and it is compa-rable to propofol in terms of quality of postoperative re-covery.

ObjectiveTo evaluate the clinical curative effect of modified Shaofu Zhuyutang on pelvic pain of endometriosis （EMT） with syndrome of cold congeal and blood stasis and the influence on neural angiogenesis. MethodA total of 110 cases were divided into a control group （54 cases） and an observation group （56 cases） by the random number table method. Patients in the control group took Aifu Nuangong pills with 6 g/time and 2 times/day. Patients in the observation group took modified Shaofu Zhuyutang with 1 dose/day. Course of treatment continued for 3 menstrual cycles. Dysmenorrhea， other symptoms and signs of pelvic pain， and the EMT health profile-5 （EHP-5） for patients with syndrome of cold congeal and blood stasis and EMT were scored before and after treatment. The levels of peripheral blood nerve growth factor （NGF）， substance P （SP）， calcitonin gene-related peptide （CGRP）， brain-derived neurotrophic factor （BDNF）， soluble Fms-like tyrosine kinase（sFlt-1）， vascular endothelial growth factor （VEGF）， matrix metalloproteinase-9 （MMP-9）， and insulin growth factor-1 （IGF-1） were detected before and after treatment. The levels of prostaglandin E₂ （PGE₂）， cyclooxygenase-2 （COX-2）， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and other inflammatory factors were detected before and after treatment. The pain medication usage and recurrence were recorded. ResultThe scores of dysmenorrhea， symptoms of pelvic pain symptoms （non-menstrual pelvic pain， dyspareunia， anal falling pain， and defecation pain， etc.）， and signs of pelvic pain （pelvic tenderness and sacral ligament tender nodules） in the observation group were lower than those in the control group （P<0.01）. The disappearance rates of dysmenorrhea， pelvic tenderness， and sacral ligament tender nodules were 67.35% （33/49）， 73.33% （33/45）， and 77.27% （34/44） in the observation group， which were all higher than 45.83% （22/48）， 48.84% （21/43）， and 52.27% （23/44） in the control group. The difference was statistically significant （χ²=4.571， χ²=5.565， χ²=6.026， P<0.05）. The scores of EHP-5 and syndrome of cold congeal and blood stasis in the observation group were lower than those in the control group （P<0.01）. The levels of VEGF， MMP-9， IGF-1， NGF， SP， CGRP， and BDNF in the observation group were lower than those in the control group （P<0.01）， while the level of sFlt-1 was higher than that in the control group （P<0.01）. The levels of PGE₂， COX-2， TNF-α， and IL-6 in the observation group were lower than those in the control group （P<0.01）. The total effective rate of the observation group was 92.45% （49/53）， which was higher than 76.00% （38/50） of the control group （χ²=5.307， P<0.05）. After 6 months of follow-up， the recurrence rate in the observation group was 30.61% （15/49）， which was lower than 52.63% （20/38） in the control group （χ²=4.315， P<0.05）. The average of taking ibuprofen sustained-release capsules in the control group was higher than that in the observation group per menstrual period （P<0.01）. ConclusionModified Shaofu Zhuyutang treated pelvic pain of EMT with syndrome of cold congeal and blood stasis by regulating the mechanism of neural angiogenesis， reducing pain， and promoting the disappearance of related pains， thus improving the quality of life. Shaofu Zhuyutang has a better clinical effect than Aifu Nuangong pills and has a low recurrence rate.

This study aims to decipher the mechanism underlying the effect of Shaofu Zhuyu Decoction on endometriosis(EMT)-associated dysmenorrhea in rats with the syndrome of cold coagulation and blood stasis based on mitogen-and stress-activated protein kinase 1/2(MSK1/2).We employed a random number table to randomly assign SPF female non-pregnant rats into the sham group, and treated the rest rats with autologous transplantation+refrigerator freezing for the modeling of the syndrome of cold coagulation and blood stasis.The modeled rats were then randomly assigned into the control group and high-, medium-and low-dose Shaofu Zhuyu Decoction groups.The rats in the low-, medium-, and high-dose decoction groups were respectively administrated with 9, 4.5, and 2.3 g·kg~(-1) decoction through gavage once a day for 2 consecutive weeks, and those in the control group were administrated with 0.24 mg·kg~(-1) gestrinone through gavage once every 3 days for 2 weeks.After that, the size of ectopic focus in each rat was measured via laparotomy.Enzyme-linked immunosorbent assay(ELISA) was adopted to determine the expression of interleukin(IL)-6, IL-10, prostaglandin E2(PGE2), tumor necrosis factor-α(TNF-α).Western blot was employed to determine the protein levels of MSK1/2 and dual-specificity phosphatase 1(DUSP1) and real-time quantitative polymerase chain reaction(RT-PCR) to determine the mRNA levels of the two genes in rat eutopic endometrial tissue.Compared with the sham group, the model group showed increased levels of IL-6, PGE2, and TNF-α while decrease level of IL-10 in the serum(P<0.01).Compared with the model group, the high-and medium-dose decoction groups and the gestrinone group had declined levels of IL-6, PGE2, and TNF-α while risen level of IL-10 in the serum(P<0.01).The model group had lower protein levels and mRNA levels of MSK1/2 and DUSP1 in the eutopic endometrial tissue than the sham group(P<0.01). The high-and medium-dose decoction groups and the gestrinone group had higher protein and mRNA levels of MSK1/2 and DUSP1 in the eutopic endometrial tissue than the model group(P<0.01).The results indicated that Shaofu Zhuyu Decoction can regulate the abnormal expression of pro-inflammatory cytokines TNF-α, IL-6, and PGE2 and anti-inflammatory cytokines IL-10 and DUSP1 via MSK1/2 to alleviate EMT-associated dysmenorrhea in rats with the syndrome of cold coagulation and blood stasis.
Animals ; Female ; Rats ; Anti-Inflammatory Agents/therapeutic use* ; Cytokines ; Dinoprostone ; Drugs, Chinese Herbal/therapeutic use* ; Dual-Specificity Phosphatases ; Dysmenorrhea/genetics* ; Endometriosis/genetics* ; Gestrinone/therapeutic use* ; Interleukin-10 ; Interleukin-6 ; Mitogen-Activated Protein Kinase 8/therapeutic use* ; Mitogens/therapeutic use* ; RNA, Messenger ; Tumor Necrosis Factor-alpha/metabolism*

OBJECTIVE: To examine whether the combination of Naoxintong Capsule with standard care could further reduce the recurrence of ischemic stroke without increasing the risk of severe bleeding. METHODS: A total of 23 Chinese medical centers participated in this trial. Adult patients with a history of ischemic stroke were randomly assigned in a 1:1 ratio using a block design to receive either Naoxintong Capsule (1.2 g orally, twice a day) or placebo in addition to standard care. The primary endpoint was recurrence of ischemic stroke within 2 years. Secondary outcomes included myocardial infarction, death due to recurrent ischemic stroke, and all-cause mortality. The safety of drugs was monitored. Results were analyzed using the intention-to-treat principle. RESULTS: A total of 2,200 patients were enrolled from March 2015 to March 2016, of whom 143 and 158 in the Naoxintong and placebo groups were lost to follow-up, respectively. Compared with the placebo group, the recurrence rate of ischemic stroke within 2 years was significantly lower in the Naoxintong group [6.5% vs. 9.5%, hazard ratio (HR): 0.665, 95% confidence interval (CI): 0.492-0.899, P=0.008]. The two groups showed no significant differences in the secondary outcomes and safety, including rates of severe hemorrhage, cerebral hemorrhage and subarachnoid hemorrhage (P>0.05). CONCLUSION The combination of Naoxintong Capsule with standard care reduced the 2-year stroke recurrence rate in patients with ischemic stroke without increasing the risk of severe hemorrhage in high-risk patients. (Trial registration No. NCT02334969).
Adult ; Humans ; Secondary Prevention/methods* ; Ischemic Stroke ; Stroke/prevention & control* ; Cerebral Hemorrhage/complications* ; Double-Blind Method ; Platelet Aggregation Inhibitors

Objective To explore the dosimetric differences of radiotherapy plan for cervical cancer with 4 different fluence smoothing (FS) parameters using Monaco treatment planning system (Monaco TPS). Methods Fifteen patients with ⅠB2 stage cervical cancer in our hospital were enrolled in this study. And a 2 Volumetric Modulated Arc Therapy (VMAT) plan for each patient were completed by Monaco 5.11 TPS according to the X-Ray Voxel Monte Carlo (XVMC) method. For each plan was optimized by FS function, with the level of Off, Low, Medium and High. To compare the difference of plan optimization time, conformity index (CI), Homogeneity index (HI), D_mean, D_min, D_2% of PTV，dose to the organ at risk (OAR)，the number of Segments# and MU#，estimated total delivery time (ETDT), quantum Efficiency (QE) of the plans, the formation of Segments# with the same angle and verification of inserting 729 two-dimensional matrix into PTW octavius 4D module of different FS function levels, with the precondition of the Prescription isodose curve covering 95% of the target area. The data was analysed by multivariate factor analysis with the application of SPSS, and P < 0.05 was considered as statistically significant. And the Planned revenue score of different FS levels was also calculated. Results Except for the D_min of PTV (the lowest value is (32.09 ± 0.26) Gy for the Off group, and the highest value is (35.98 ± 0.42) Gy for the High group), V₄₀ of the rectum (the lowest value in the Medium group is 55.88% ± 2.02%, and the highest value in the High group was 61.90% ± 2.98%) and bladder (the lowest value was 45.01% ± 2.08% in the Medium group, and the highest value is 50.45% ± 1.98% in the High group), the V₂₀ (the lowest value High group was 49.05% ± 1.98%, the highest value Off group was 56.52% ± 1.75%) of femoral head (P < 0.05), there was no significant difference of the dose assessment results for PTV and OARs in 4 different FS function levels. In the High level, the ETDT, QE and MU# were showed better than other groups evidently, however, the number of Segments# showed no significant difference. The plan validation results was increased with the improvement of FS function level, and the level of High was considered to be the optimal. To compare the score of overall benefits of the plan, the level of Medium (−17.18 ± 0.05) got the highest score, and the Low group (−17.58 ± 0.05) and the High group (−17.42 ± 0.06) have similar scores, and Off group (−18.81 ± 0.08) has the lowest score. Conclusion Different FS levels of the Monaco 5.11 TPS can optimize the radiotherapy plan for cervical cancer, but the level of Medium is considered to be the most applicable.

This study explored the in vivo effects and mechanisms of the modern classical prescription Supplemented Gegen Qinlian Decoction Formula(SGDF) against diabetic kidney disease(DKD). Sixty rats were randomly divided into the normal group, model group, SGDF group, and rosiglitazone(ROS) group. The modified DKD rat model was established by employing the following three methods: exposure to high-fat diet, unilateral nephrectomy, and intraperitoneal injection of streptozotocin(STZ). After modeling, rats in the four groups were treated with double distilled water, SGDF suspension, and ROS suspension, respectively, by gavage every day. At the end of the 6 th week of drug administration, all the rats were sacrificed for collecting urine, blood, and kidney tissue, followed by the examination of rat general conditions, urine and blood biochemical indicators, glomerulosclerosis-related indicators, podocyte pyroptosis markers, insulin resistance(IR)-related indicators, and key molecules in the insulin receptor substrate(IRS) 1/phosphatidylinositol-3-kinase(PI3 K)/serine threonine kinase(Akt) signaling pathway. The results showed that SGDF and ROS improved the general conditions, some renal function indicators and glomerulosclerosis of DKD model rats without affecting the blood glucose(BG). Besides, they ameliorated the expression characteristics and levels of podocyte pyroptosis markers, alleviated IR, and up-regulated the protein expression levels of the key molecules in IRS1/PI3 K/Akt pathway to varying degrees. In conclusion, similar to ROS, SGDF relieves DKD by targeting multiple targets in vivo. Specifically, it exerts the therapeutic effects by alleviating podocyte pyroptosis and IR. This study has preliminarily provided the pharmacological evidence for the research and development of new drugs for the treatment of DKD based on SGDF.
Animals ; Diabetes Mellitus ; Diabetic Nephropathies/drug therapy* ; Drugs, Chinese Herbal ; Insulin Resistance ; Podocytes ; Pyroptosis ; Rats

Cyclophosphamide (CPA) is one of the most commonly used alkylating agents in the treatment of malignant cancer. CPA is metabolized by cytochrome P450 enzymes into 4-hydroxycyclophosphamide in vivo which can exhibit anti-tumor activity. Metabolic activation of CPA can cause adverse reactions such as myelosuppression, cystitis, and liver injury. The aim of this study was to evaluate the dynamic changes of hepatic injury induced by CPA in mice. Male BALB/c mice were injected CPA (200 mg·kg^-1) intraperitoneally. Both serum and liver samples were collected at 0, 2, 6, 12 and 24 hours after dosing. The animal experiment protocol was approved by the Institutional Animal Care and Use Committee at Sun Yat-sen University. The results showed that hepatotoxicity was observed at 2 hours after CPA dosing, and the most serious liver injury was measured at 12 hours. The level of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malondialdehyde (MDA) was significantly increased, glutathione (GSH) level was significantly decreased, hepatocyte edema and vacuolar degeneration were widely observed in liver tissue, and began to recover 24 hours after dosing. In addition, due to oxidative stress damage caused by CPA, nuclear factor-erythroid 2-related factor 2 (NRF2) signaling pathway was activated and the mRNA and protein expression of its downstream targets such as quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate cysteine modifier subunit (GCLM) were up-regulated, which alleviated oxidative stress injury. In a summary, this study demonstrate the dynamic change of CPA-induced liver injury and the NRF2-mediated protective mechanisms, providing new insights into the CPA-induced liver injury.