Objective To evaluate the efficacy of recombinant human TNK tissue-type plasminogen activator and adenosine injection through guiding in treating acute ST-segment elevation myocardial infarction(ASTEMI)in emergency primary percutaneous coronary intervention(PPCI).Methods Patients with ASTEMI who chose to receive emergency PPCI were randomly divided into control group and treatment group according to a digital random table method.The control group received conventional treatment of PPCI.If the infarct-related artery(IRA)reached TIMI flow grade 3 after PPCI,the operation was terminated.If TIMI flow was ≤2,then a guide catheter to inject sodium nitroprusside,nitroglycerin,and tirofiban into the coronary artery to improve coronary microcirculation dysfunction(CMD)was applied until the IRA reached TIMI flow grade 3.The treatment group received the conventional treatment of PPCI,and after opening of the IRA during the operation,a guide catheter to inject recombinant human TNK tissue-type plasminogen activator(8 mg)and adenosine(200 pg)into the coronary artery was applied.If the IRA reached TIMI flow grade 3,the operation was terminated.If TIMI flow was ≤2,then adenosine injection was re-applied to improve CMD until the IRA reached TIMI flow grade 3.Observation indicators were as follows:① myocardial injury indicators:cardiac troponin Ⅰ(cTnⅠ),creatine kinase isoenzyme(CK-MB),and N-Terminal pro-brain natriuretic peptide(NT-pro BNP)levels before and 12 h,24 h,36 h,and 48 h after surgery;② myocardial perfusion indicators:corrected TIMI frame count(CTFC)after surgery and ST segment regression value(STR)at 90 min after surgery;③ degree of myocardial ischemia:rest D-SPECT+adenosine stress D-SPECT examination at day 3 after surgery,observation of myocardial perfusion total score under 17 segment distribution and myocardial ischemia total segment number;@adverse drug reactions at day 30 after surgery:subcutaneous ecchymosis,gingival bleeding,gastrointestinal bleeding,urinary bleeding,hemoglobin decline,and cerebral hemorrhage;⑤ major adverse cardiovascular events(MACE)at day 30 after surgery:cardiac death,myocardial infarction,heart failure,and target vessel revascularization.Results ① Myocardial injury indicators:There was no significant difference in the levels of cTnⅠ,CK-MB,or NT-pro BNP before surgery between the two groups(all P＞0.05).The myocardial injury indicators were significantly lower in the treatment group than in the control group at 12 hours after surgery(all P＜0.05),and then showed a downward trend.There was no significant difference between the two groups at 48 hours after surgery(all P＞0.05).② Myocardial perfusion indicators:CTFC in the treatment group was significantly better than that in the control group after surgery(P＜0.05).Using the rank sum test,the STR was significantly better in the treatment group than in the control group at 90 minutes after surgery(Z=2.437,P=0.014).③ myocardial ischemia:Both groups underwent rest D-SPECT+adenosine stress D-SPECT examination at 3 days after surgery.Under the distribution of 17 myocardial segments,the total score of myocardial perfusion and the total number of myocardial ischemia segments in the treatment group were significantly better than those in the control group(all P＜0.05).④ Adverse drug reactions 30 days after surgery:There was no significant difference in subcutaneous ecchymosis,gingival bleeding,gastrointestinal bleeding,urinary system bleeding,hemoglobin decline,or cerebral hemorrhage between the two groups(P＞0.05).⑤ MACE 30 days after surgery:There was no significant difference in cardiac death,myocardial infarction,heart failure,target vessel revascularization,or total MACE between the two groups(P＞0.05).Conclusion The intra-coronary injection of recombinant human TNK tissue-type plasminogen activator and adenosine injection through a guiding catheter in emergency PPCI is safe and effective for the treatment of ASTEMI.It can improve myocardial injury,myocardial perfusion,and myocardial ischemia.

Objective:To investigate the clinical effect of the modified vertical rectus abdominis myocutaneous flap in repairing the skin and soft tissue defect after abdominoperineal resection for rectal cancer.Methods:This study was a retrospective observational study. From June 2019 to July 2022, five male patients with low rectal cancer who were conformed to the inclusion criteria were admitted to the Department of Basic Surgery of Xiangya Hospital of Central South University, with ages ranging from 65 to 70 years and the sizes of the perianal skin ulcers ranging from 5 cm×4 cm to 11 cm×9 cm, and all of them underwent abdominoperineal resection. The secondary skin and soft tissue defects in the perineum with an area of 8 cm×6 cm-14 cm×12 cm (with the depth of pelvic floor dead space being 10-15 cm) were repaired intraoperatively with transplantation of modified vertical rectus abdominis myocutaneous flaps with the skin area being 9 cm×7 cm-16 cm×12 cm, the volume of the muscle being 18 cm×10 cm×5 cm-20 cm×12 cm×5 cm, and the vessel pedicle being 18-20 cm in length. During the operation, most of the anterior sheath of the rectus abdominis muscle was retained, the flap was transferred to the recipient area through the abdominal cavity, the remaining anterior sheaths of the rectus abdominis muscle on both sides of the donor area were repeatedly folded and sutured, the free edge of the transverse fascia of the abdomen was sutured with the anterior sheath of the rectus abdominis muscle, and the donor area skin was directly sutured. After the operation, the survival of the transplanted myocutaneous flap was observed. The occurrence of complications in the perineal recipient area was recorded within 2 weeks after the operation. The recovery of the perineal recipient area and the abdominal donor area was observed during follow-up, and the occurrence of complications in the donor area of the abdomen as well as the recurrence of tumors and metastasis were recorded.Results:All transplanted myocutaneous flaps in 5 patients survived after surgery. One patient had dehiscence of the incision in the perineal recipient area 2 days after surgery, which healed after 7 d with intermittent dressing changes and routine vacuum sealing drainage treatment. In the other 4 patients, no complications such as incisional rupture, incisional infection, or fat liquefaction occurred in the perineal recipient area within 2 weeks after surgery. Follow-up for 6-12 months after discharge showed that the skin of the perineal recipient area had good color, texture, and elasticity, and was not bloated in appearance; linear scars were left in the perineal recipient area and the abdominal donor area without obvious scar hyperplasia or hyperpigmentation; no complications such as incisional rupture, incisional infection, intestinal adhesion, intestinal obstruction, or weakening of the abdominal wall strength occurred in the abdominal donor area, and the abdominal appearance was good with no localized bulge or formation of abdominal hernia; there was no local recurrence of tumor or metastasis in any patient.Conclusions:The surgical approach of using the modified vertical rectus abdominis myocutaneous flap to repair the skin and soft tissue defects after abdominoperineal resection for rectal cancer is relatively simple in operation, can achieve good postoperative appearances of the donor and recipient areas with few complications, and is worthy of clinical promotion.

[Objective] To explore the safety and effectiveness of provisional stenting (PS) applied in patients with unprotected simple left main bifurcation lesions, and to observe the impact of this procedure on cardiac function, myocardial injury, and myocardial perfusion. [Methods] A retrospective analysis was made on 82 patients with unprotected simple left main bifurcation lesions who underwent elective stenting and completed a 3-month follow-up in the Department of Cardiology, Hebei Medical University First Hospital. All the patients underwent preoperative examinations, including rest dynamic single-photon emission computed tomography (D-SPECT) and regadenoson stress D-SPECT before and 3 months after surgery. The safety evaluation indicators for the surgery included immediate success rate of stent implantation, acute stent thrombosis, coronary no-reflow, branch involvement, branch acute occlusion, acute left heart failure, heart block, cardiac tamponade, major bleeding, and mortality. The effectiveness evaluation indicators included the minimum lumen area (MLA) of the left main trunk of coronary artery measured by intravenous ultrasound (IVUS) before and after surgery, as well as cardiac function indicators [brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD)] and myocardial injury indicators [creatine kinase isoenzyme-MB (CK-MB), cardiac troponin Ⅰ (cTn Ⅰ)] at day 1, day 7, 1 month, and 3 months before and after surgery. The myocardial perfusion evaluation indicators included the total myocardial perfusion score and total ischemic segment number under the 17-segment distribution of myocardial perfusion using rest D-SPECT and regadenoson stress D-SPECT before and 3 months after surgery. [Results] Safety indicators: immediate success rate of stent implantation (100%), 19 cases (23.1%) of circumflex branch involvement that underwent balloon anastomosis dilation, 1 case of acute branch occlusion, followed by double stent surgery using provisional stenting-T stenting (PS-T) technique. There were no cases of acute stent thrombosis, coronary reflow, acute left heart failure, cardiac block, cardiac tamponade, major bleeding, or death. Effectiveness indicators: the MLA of the left main trunk measured by postoperative IVUS showed significant improvement compared to the preoperative. BNP, CK-MB, and cTnⅠ showed significant improvement from day 7 after surgery compared to before. Myocardial perfusion indicators: the total score of myocardial perfusion and the total number of ischemic segments in the 17-segment distribution of the myocardium after 3 months of surgery were significantly better than before. [Conclusion] PS can improve heart function, myocardial injury, and myocardial perfusion in patients with unprotected simple left main bifurcation lesions.

Objective:To investigate effect of Mycobacterium tuberculosis BCG-infected macrophages on damage and repair of renal tubular epithelial cells during development of renal tuberculosis.Methods:A co-culture model of BCG-infected M0 macrophages(upper chamber)and HK-2 cells(lower chamber)was established by Transwell,and THP-1 human monocyte macrophages were induced by 100 ng/ml phorbol ester(PMA)24 h to become M0 macrophages,and BCG infection cell model was established.Total cell protein was collected at 12 h and 24 h of infection,respectively.Western blot was used to detect expressions of M1 macrophage marker CD86 and M2 macrophage marker CD206 protein.M1 macrophage polarization marker cytokines IL-6 and TNF-α and M2 macrophage polarization marker cytokine TGF-β expressions in cell culture supernatant were detected by ELISA;experiment was divided into HK-2 group,BCG+HK-2 group,BCG+M0+HK-2 group and M0+HK-2 group,CCK-8 was used to detect viability of HK-2 cells in each group,and Hoechst test was used to detect HK-2 cells apoptosis in each group.Epithelial cell marker E-cadhren and fibroblast markerα-SMA expressions in HK-2 cells of each group were detected by Western blot.Results:After BCG infection of M0 macrophages,M1 macrophage viability was higher than 24 h at 12 h(P<0.05),and M2 macrophage was higher than 12 h at 24 h(P<0.05).After two cells co-culture,HK-2 cell viability was higher than 12 h at 24 h(P<0.001),apoptosis level was higher than 24 h at 12 h,epithelial cell marker protein E-cadherin protein level was higher than 12 h at 24 h(P<0.001),fibroblast level of cell marker protein α-SMA protein at 12 h was higher than that at 24 h(P<0.01).Conclusion:During development of renal tuberculosis,early BCG-infected macrophages may promote inflammatory injury of renal tubular epithelial cells through M1-type polarization;with prolongation of infec-tion time,they may repair renal tubular epithelial cells through M2-type polarization and plays an important protective role.

BACKGROUND: Data on the immunogenicity and safety of heterologous immunization schedules are inconsistent. This study aimed to evaluate the immunogenicity and safety of homologous and heterologous immunization schedules. METHODS: Multiple databases with relevant studies were searched with an end date of October 31, 2021, and a website including a series of Coronavirus disease 2019 studies was examined for studies before March 31, 2022. Randomized controlled trials (RCTs) that compared different heterologous and homologous regimens among adults that reported immunogenicity and safety outcomes were reviewed. Primary outcomes included neutralizing antibodies against the original strain and serious adverse events (SAEs). A network meta-analysis (NMA) was conducted using a random-effects model. RESULTS: In all, 11 RCTs were included in the systematic review, and nine were ultimately included in the NMA. Among participants who received two doses of CoronaVac, another dose of mRNA or a non-replicating viral vector vaccine resulted in a significantly higher level of neutralizing antibody than a third CoronaVac 600 sino unit (SU); a dose of BNT162b2 induced the highest geometric mean ratio (GMR) of 15.24, 95% confidence interval [CI]: 9.53-24.39. Following one dose of BNT162b2 vaccination, a dose of mRNA-1273 generated a significantly higher level of neutralizing antibody than BNT162b2 alone (GMR = 1.32; 95% CI: 1.06-1.64), NVX-CoV2373 (GMR = 1.60; 95% CI: 1.16-2.21), or ChAdOx1 (GMR = 1.80; 95% CI: 1.25-2.59). Following one dose of ChAdOx1, a dose of mRNA-1273 was also more effective for improving antibody levels than ChAdOx1 (GMR = 11.09; 95% CI: 8.36-14.71) or NVX-CoV2373 (GMR = 2.87; 95% CI: 1.08-3.91). No significant difference in the risk for SAEs was found in any comparisons. CONCLUSIONS: Relative to vaccination with two doses of CoronaVac, a dose of BNT162b2 as a booster substantially enhances immunogenicity reactions and has a relatively acceptable risk for SAEs relative to other vaccines. For primary vaccination, schedules including mRNA vaccines induce a greater immune response. However, the comparatively higher risk for local and systemic adverse events introduced by mRNA vaccines should be noted. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42021278149.
Adult ; Humans ; BNT162 Vaccine ; 2019-nCoV Vaccine mRNA-1273 ; Network Meta-Analysis ; Immunization Schedule ; COVID-19/prevention & control* ; COVID-19 Vaccines/adverse effects* ; Viral Vaccines ; mRNA Vaccines ; Antibodies, Neutralizing ; Antibodies, Viral

Through consulting the ancient materia medica and medical books， combined with modern literature， this paper made a textual research on the name， origin， producing area， harvesting time and processing method of Piperis Kadsurae Caulis， in order to provide basis for the development of the famous classical formulas containing this herb. According to textual research， it is shown that the earliest name for Piperis Kadsurae Caulis as medicine was Nanteng in Bencao Shiyi， and there were other names such as Dinggongteng and Shinanteng in the ancient materia medica. The name of Haifengteng should appear in the Ming dynasty. Before the Song dynasty， the origin of Piperis Kadsurae Caulis was probably derived from caulis of Piper wallichii. After the Song dynasty， the main origins should be some species in Piper， such as P. kadsura and P. hancei， and its origin in the successive editions of Chinese Pharmacopoeia was only P. kadsura. Combining the original plant research， market survey and distribution of wild resources， it is suggested that the Haifengteng used in the famous classical formulas apart form the P. kadsura， the P. hancei should be add as original plant. Due to climate change and the heat-loving habit of Piper， the producing area of Haifengteng gradually moved from the Qinling Mountains to the southern areas rich in Piper， and Quanzhou area of Fujian province has been recommended since the Ming dynasty. The harvesting period of Piperis Kadsurae Caulis is from July to August in the lunar calendar， the above-ground parts are dried by removing fibrous roots， thin stems and leaves. In the past dynasties， there are few records on the processing of this herb， so it is suggested that Piperis Kadsurae Caulis in famous classical formulas without special processing requirements should be used as raw products.

COVID-19 epidemic continues to spread around the world till these days, and it is urgent to develop more safe and effective new drugs. Due to the limited P3 biosafety laboratories for directly screening inhibitors of virulent viruses with high infectivity, it is necessary to develop rapid and efficient screening methods for viral proteases and other related targets. The main protease (M^pro), which plays a key role in the replication cycle of SARS-CoV-2, is highly conserved and has no homologous proteases in humans, making it an ideal target for drug development. From two different levels, namely, molecular level and cellular level, this paper summarizes the reported screening methods of SARS-CoV-2 M^pro inhibitors through a variety of representative examples, expecting to provide references for further development of SARS-CoV-2 M^pro inhibitors.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

As a common protease with high similarity among coronavirus species, the main protease (M^pro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.

In this study, the mechanism of Xiaoyan Lidan formula (XYLDF) against 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC)-induced chronic intrahepatic cholestasis (CIHC) in mice was investigated based on metabolomics, molecular docking and pharmacological methods. In the pharmacodynamics study, a dosage of 5 g·kg^-1 (clinical equivalent) XYLDF was administered in DDC-induced mice, then the effect of XYLDF against CIHC was evaluated by measuring the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP) as well as total bilirubin (TBIL) in serum and observing liver histopathological changes. All experiments were approved by the Ethical Committee Experimental Animal Center of Guangzhou University of Chinese Medicine (ZYD-2021-001). The serum metabolites of mice in each group were detected and identified based on ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry, and the relevant biological pathways and molecular key targets were further enriched. Molecular docking technology was used to further evaluate the binding activity of the main active ingredients of XYLDF with potential targets. Subsequently, the in vitro experiment was conducted for the validation of the vital target. The results showed that compared with the model group, XYLDF significantly decreased the levels of ALT, AST, AKP and TBIL in the serum of CIHC mice, as well as alleviated inflammatory infiltration and hepatocyte necrosis in liver tissue. According to the metabonomic study, a total of 35 differential metabolites was identified as biomarkers associated with cholestasis, 12 of which were significantly recovered by XYLDF treatment. These biomarkers were involved in the pathways of primary bile acid biosynthesis and linoleic metabolism, which are closely related to the mechanism of XYLDF against CIHC. Protein-protein interaction network indicated that cytochrome P450 3A4 (CYP3A4) and cytochrome P450 1A1 (CYP1A1) are significant potential targets with good binding properties with six major active ingredients of XYLDF. Furthermore, it was found that 4-methoxy-5-hydroxycanthin-6-one, dehydroandrographolide and isodocarpin, three of the main active components in XYLDF, markedly induced the expression of CYP3A4 mRNA in vitro. This study revealed that XYLDF mainly mediates the biosynthesis of bile acids in CIHC mice to improve liver tissue lesions and bile efflux disorders, among which, CYP3A4 is the key target in the protection of XYLDF against CIHC. This research provides a reference for further elucidation of the pharmacological mechanism of XYLDF.