Local anesthetics (LAs), such as articaine (AT), exhibit limited efficacy in inflammatory environments, which constitutes a significant limitation in their clinical application within oral medicine. In our prior research, we developed AT-17, which demonstrated effective properties in chronic inflammatory conditions and appears to function as a novel oral LA that could address this challenge. In the present study, we further elucidated the beneficial effects of AT-17 in acute inflammation, particularly in oral acute inflammation, where mitochondrial-related apoptosis played a crucial role. Our findings indicated that AT-17 effectively inhibited lipopolysaccharide (LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro. This process involved the inhibition of mitochondrial reactive oxygen species (mtROS) production and the subsequent activation of the NRF2 pathway. Most notably, improvements in mitochondria-related apoptosis were key contributors to AT-17's inhibition of voltage-gated sodium channels. Additionally, AT-17 was shown to reduce mtROS production in nerve cells through the Na⁺/NCLX/ETC signaling axis. In conclusion, we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis. This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA⁺ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
Humans ; Neutrophils/metabolism* ; Single-Cell Analysis ; Lip Neoplasms/genetics* ; Hyperthermia, Induced/methods* ; Microwaves/therapeutic use* ; Transcriptome ; Carcinoma, Squamous Cell/immunology* ; Tumor Microenvironment

ObjectiveTo observe the effect of modified Erchentang on the expression of key molecules in the Jagged1/Notch1/Hes1 signaling pathway in lung tissues of rats with chronic obstructive pulmonary disease （COPD） and explore its anti-inflammatory effect and molecular mechanism on COPD through the Jagged1/Notch1/Hes1 signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， low-， medium-， and high-dose modified Erchentang groups （5， 10， 20 g·kg^-1）， and γ-secretase inhibitor DAPT group （0.02 g·kg^-1）， with 10 rats in each group. The COPD model was induced in rats by cigarette smoking combined with intratracheal instillation of lipopolysaccharide （LPS）. Rats were treated with corresponding drugs by gavage， while those in the normal group and the model group were treated with the same amount of normal saline by gavage. The serum levels of Notch1， soluble intercellular adhesion molecule-1 （sICAM-1）， activated leukocyte cell adhesion molecule （ALCAM）， and soluble vascular adhesion molecule-1 （sVCAM-1） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression of Jagged1， Notch1， and Hes1 was detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of Jagged1， Notch1， Notch1 intracellular domain （NICD1）， and Hes1 in lung tissues of rats was detected by immunohistochemistry （IHC）. ResultCompared with the normal group， the model group showed increased serum content of Notch1， sICAM-1， ALCAM， and sVCAM-1 （P<0.01）， increased mRNA expression of Jagged1， Notch1， and Hes1 in lung tissues （P<0.01）， and increased protein expression of Jagged1， Notch1， NICD1， and Hes1 （P<0.01）. Compared with the model group， the medium- and high-dose modified Erchentang groups and the DAPT group showed decreased serum content of Notch1， sICAM-1， ALCAM， and sVCAM-1 （P<0.05， P<0.05）， down-regulated mRNA expression of Jagged1， Notch1， and Hes1 （P<0.05， P<0.01）， and reduced protein expression of Jagged1， Notch1， NICD1， and Hes1（P<0.05， P<0.01）. ConclusionModified Erchentang may inhibit the inflammatory response in the lung of COPD rats， and its mechanism may be related to the resistance of inflammatory injury in the lung by decreasing the mRNA expression of Jagged1， Notch1， and Hes1 and inhibiting the release of Notch1， sICAM-1， ALCAM， and sVCAM-1.

ObjectiveTo study the effect of modified Erchentang on the expression of key molecules in the high mobility group Box 1 protein （HMGB1）/receptor for advanced glycation endproduct （RAGE）/nuclear factor-κB （NF-κB） signaling pathway in bronchioles of rats with chronic obstructive pulmonary disease （COPD）， to explore the mechanism of modified Erchentang against bronchiolar inflammation of COPD rats via HMGB1/RAGE/NF-κB signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， modified Erchentang low-， medium- and high-dose groups （5， 10， 20 g·kg^-1·d^-1） and ethyl pyruvate （HMGB1 inhibitor） group， with 10 in each group. The COPD rat model was prepared by cigarette smoke combined with tracheal injection of lipopolysaccharide （LPS）. After modeling， the modified Erchentang groups were given corresponding drugs （ig） and Ringer's solution （4 mL， ip）， while the EP group was treated with equal volume of normal saline （ig） and EP （0.04 g·kg^-1·d^-1， ip）. The normal group and the model group received equal volume of normal saline （ig） and Ringer's solution （ip） for 21 consecutive days. The contents of HMGB1， chemokine （C-X-C motif） ligand 1 （CXCL1）， CXCL2 and monocyte chemotactic protein-1 （MCP-1） in bronchoalveolar lavage fluid （BALF） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expressions of HMGB1， RAGE and NF-κB p65 were determined by Real-time polymerase chain reaction （Real-time PCR）， and the protein expressions of HMGB1， RAGE， p-NF-κB p65， and alpha-smooth muscle actin （α-SMA） in bronchioles tissue of rats were determined by immunohistochemistry （IHC）. ResultCompared with the conditions in the normal group， the forced vital capacity （FVC）， forced expiratory volume in the first second （FEV1） and FEV1/FVC in the model group were decreased （P<0.01） while the contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF were increased （P<0.01）. And the model group presented higher mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01） than the normal group. Compared with the model group， the modified Erchentang medium- and high-dose groups had increased FEV1/FVC （P<0.05， P<0.01）， lowered contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF （P<0.05， P<0.05）， and reduced mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.05， P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01）. ConclusionModified Erchentang can resist bronchiolar inflammation of COPD rats. The mechanism may be related to down-regulating the mRNA expressiona of HMGB1 and RAGE， inhibiting the activity of NF-κB， and reducing the release of HMGB1， CXCL1， CXCL2 and MCP-1， thus suppressing the inflammatory injury and abnormal repair of bronchioles.

Objective : To study the expression and clinical significance of Wnt signal secretory protein DKK1 in cervical cancer. Methods : Reverse transcription polymerase chain reaction (RT⁃PCR) was used to detect the expression of DKK1 mRNA in 30 pairs of cervical cancer tissues and adjacent normal tissues. The expression of DKK1 protein was detected by immunohistochemistry in 60 cases of cervical cancer and 30 cases of normal cervical tissue , and the relationship between the expression and clinicopathological characteristics of cervical cancer was analyzed. Results : The expression of DKK1 in cervical cancer tissues was lower than that in adjacent tissues and normal cervical tissues (P < 0. 05) . The expression of DKK1 was closely related to clinicopathological stage , tissue differentiation , lymph node metastasis and depth of invasion (P < 0. 05) . Conclusion The expression of DKK1 is low in cervical cancer and plays an important role in the occurrence and development of cervical cancer.

Objective:To investigate the safety and effect of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) and sorafenib on large hepatocellular carcinoma (HCC) patients treatment.Methods:From Jan 2012 to Dec 2017, 36 patients (Male: 33, Female: 3, average age: 51.8) with large HCC lesions(5-7 cm) received TACE plus with RFA and sorafenib in the Third Affiliated Hospital of Sun Yat-sen University. Efficacy was evaluated after TACE. Each patient was received follow-up after RFA procedure. The occurrence rate of complications and overall survival (OS) were recorded. Log-rank univariate analysis was used to analyze the OS data.Results:The median TACE time was 4, and the RFA time was (1.7±0.7) . Mean duration time of sorafenib administration was (37.7±28.8) months. Adverse events of sorafenib: 26(72.2%) hand-foot skin reaction, 6(16.7%) hypertension, 22(61.1%) diarrhea, 17(47.2%) alopecia, 3(8.3%) oral ulcer and 1(2.8%) gastrointestinal hemorrhage. Median OS was 63.0 months, and 1-year, 3-year and 5-year survival rate was 100%, 72.7% and 52.6%. The cumulative survival rate of patients taking whole course of sorafenib ( n=21) was better than that of patients taking remedial ( n=15); the cumulative survival rate of patients with alpha fetal protein (AFP) <200 μg/L ( n=26) before treatment was better than ≥200 μg/L ( n=10); the cumulative survival rate of patients with good TACE response ( n=19) was better than that of patients with no response ( n=17), and the differences were statistically significant (all P<0.05). Conclusions:TACE plus with RFA and sorafenib are safe and effective for large HCC patients with 5-7 cm lesions and this treatment might improve OS. The whole-course sorafenib, lower base AFP value (<200 μg/L) and good TACE response were considered as the good factors for the combination therapy in large HCC patients.

Objective To investigate the efficacy and safety of percutanous transhepatic intrahepatic portosystemic shunt(PTIPS)for chronic portal vein occlusion and cavernous transformation with symptomatic portal hypertension.Methods The clinical and imaging data of 38 patients with chronic portal vein occlusion and cavernous transformation with symptomatic portal hypertension, who received PTIPS in our hospital from November 2009 to June 2016,were analyzed retrospectively.The differences of the portosystemic pressure gradient(PPG)measured before and after PTIPS procedure was analyzed by a paired samples t-test. All the patients were followed up and the curative effect and operation-correlated complications were observed.Results The PTIPS procedure was technically successful in 36 patients.The other two patients with unsuccessful PTIPS underwent medical treatment,and one of them died of recurrent variceal bleeding 25 months later. Effective portal decompression and free antegrade shunt flow were achieved in 36 patients with successful PTIPS.And the mean PPG was decreased from(25.2±2.9)to(13.2± 1.3) mmHg (1 mmHg=0.133 kPa) before and after PTIPS respectively and the difference was statistically significant(P<0.05).During the procedure,arterial hemorrhage occurred in two patients who subsequently underwent embolization. Biliary injury occurred in one case and percutanous transhepatic biliary drainage (PTBD)was then performed.The mean follow-up period of the 36 patients was(26.7±10.4)months(range from 3.0 to 74.0 months).Hepatic encephalopathy appeared in 4 cases,among which,3 patients recovered after receiving medical treatment, while 1 patient experienced Grade 3 hepatic encephalopathy and recovered after implanting a smaller cover-stent.Shunt dysfunction occurred in 10 cases,of which 8 cases recovered after shunt revision with stent implantation or ballon angioplasty, while 2 cases underwent anticoagulation by warfarin only. During follow-up period, 7 patients died of liver failure(n=4), hepatic cellular carcinoma(n=1), recurrent varicose vein bleeding(n=1), and renal failure(n=1). The other patients remained asymptomatic and shunt patency. Conclusions PTIPS is both safe and effective for the treatment of symptomatic portal hypertension caused by chronic portal vein occlusion and cavernous transformation.The technical success rate is high,and the short-term curative effect is satisfied.

Objective To investigate the technique,efficacy,and safety of percutaneous interventional treatments for biliary complications (BC) after liver transplantation (LT).Methods The clinical and imaging data of 127 patients with BC after LT,who received percutaneous interventional treatments in the Third Affiliated Hospital of Sun Yat-sen University from January 2006 to December 2015,were analyzed retrospectively.On the basis of the cholangiographic appearance,patients were classified into 5 groups:biliary leakage group (n =11),anastomotic biliary strictures group (n=28),hilar biliary strictures group (n =30),multifocal biliary strictures group (n =51),and bilomas group (n =7).The modality of interventional treatments was percutanous transhepatic biliary drainage (PTBD),PTBD combined with balloon dilation,PTBD combined with balloon dilation and stent implantation.The methods of biliary drainage included external drainage and external-internal drainage.All the patients were followed up after treatment.The curative effect and operation-correlated complications were observed.Results The first successful rate of PTBD was 97.6％ (124/ 127).The total curative rate,improvement rate and inefficacy rate of interventional treatments were 37.8％ (48/127),44.9％ (57/127) and 17.3％ (22/127) respectively.In biliary leakage group,all the patients were cured by percutaneous interventional treatments with the curative rate being 100％.In anastomotic biliary strictures group,the cure and improvement rates were 64.3％ (18/28) and 35.7％ (10/28) respectively.The efficacy rate was 100％ (28/28).In hilar biliary strictures group,the cure,improvement and inefficacy rates were 40％ (12/30),53.3％ (16/30) and 6.7％ (2/30) respectively.The efficacy rate was 93.3％ (28/30).In multifocal biliary strictures group,the cure,improvement and inefficacy rates were 13.7％ (7/51),54.9％ (28/51) and 31.4％ (16/51) respectively.The efficacy rate was 68.6％ (35/51).In bilomas group,3 cases (3/7) obtained improvement and treatment of 4 cases was inefficative.The efficacy was the best for the patients with bilary leakage,and it was the worst for the patient with bilomas (P＜0.001).The main operation-correlated complication was bile tract infection during drainage.The rates of bile tract infection were 32.4％ (34/105) and 81.8％ (18/22) in patients with external drainage and external-internal drainage,respectively.There was statistically significant difference between these two items (P＜ 0.001).Conclusion PTBD combined with balloon dilation and biliary stent implantation is a safe and effective therapeutic modality for BC after LT,which can improve patients' clinical symptoms,improve patients' quality of life.The patients with bilomas should be treated by retransplantation as soon as possible.The biliary external drainage can decrease the rate of biliary tract infection significantly.

Objective To study the feasibility and efficacy of percutaneous transhepatic intrahepatic portosystemic shunt (PTIPS) in patients with portal hypertension due to chronic portal vein occlusion after splenectomy.Methods 27 patients who had portal hypertension due to chronic portal vein occlusion after splenectomy underwent PTIPS between December 2010 and March 2015.These patients were enrolled in this retrospective study.The success rates,efficacy,and complications were evaluated.Significance in the differences in the portosystemic pressure gradient (PPG) as measured before and after PTIPS procedure was assessed.Results PTIPS was successfully carried out in 25 patients but failed in 2.No fatal procedural complications were observed.The mean PPG dropped from (22.3 ± 5.7) mmHg to (12.4 ± 3.1) mmHg after successful PTIPS (1 mmHg =0.133 kPa,P ＜0.05).The median follow-up in the 25 patients with successful PTIPS were 22 months and there were 3 (12.0％) deaths from liver failure due to severe cirrhosis,and 1 death (4.0％) from stroke during the follow-up period.Shunt dysfunction happened in 4 (16.0％) patients.The original symptoms reoccurred in 2 patients (8.0％) and the remaining patients were diagnosed by routine CT or US examination.Three patients recovered after shunt revision with stent implantation or balloon angioplasty,while one patient refused any further therapy except oral medication.This patient suffered from the first episode of rebleeding 36 months after PTIPS.Hepatic encephalopathy developed in 2 (8.0％) patients,1 patient recovered after medical treatment,while the other who developed Grade 3 hepatic encephalopathy recovered after implanting a smaller cover stent.The remaining patients were asymptomatic with patent shunts.Conclusion PTIPS was a feasible,safe,and efficacious treatment for portal hypertension due to chronic portal vein occlusion after splenectomy.

Objective To investigate the clinical effect of percutaneous transluminal angiography in diabetic infrapopliteal arterial disease patients and the influence of post-procedural intraluminal small dose urokinase infusion on infrapopliteal arterial blood flow.Methods From January 2011 to September 2013,37 limbs (16 left and 21 right) in 28 diabetic patients inflicted with infrapopliteal critical limb ischemia underwent endovascular recannalization at our institution and were retrospectively analyzed.Stenotic or occlusive lesions were demonstrated in 74 infrapopliteal vessels,including 30 anterior tibial arteries (ATA),22 posterior tibial arteries (PTA),and 22 peroneal arteries (PA).In 30 limbs,tandem lesions in iliac-femoral arteries were also diagnosed.Antegrade ipsilateral femoral access,retrograde contralateral femoral or brachial arterial access had all been adopted as well as both angioplasty and stenting.Case specific decisions were made based on pre-procedural computed tomographic angiogram (CTA).Ankle-brachial index (ABI) was recorded before and after each procedure.Urokinase was continuously infused through arterial sheath catheter into vessels of target limb from a microinfusion pump at 200 000 to 300 000 units per 24 hour for 48 hours after procedure.Angiogram was performed before and after thrombolysis therapy aiming to ascertain the number of frames of images obtained during the period of time it took blood flow to carry contrast medium from the level of tibial plateau to ankle,which was recorded as index frame count (IFC).Patients were followed up for at least 3 months.ABI and ultrasound or CTA were performed on each follow-up visit to validate patency.Quantitative data such as ABI value and IFC were analyzed using paired samples t-test.Results Thirty two limbs were radiographically recanalized by angioplasty or stenting.Technical success rate was 86.4％ (32/37).Average ABI of all limbs increased significantly from 0.70±0.31 to 0.90± 0.21 (t=10.734,P＜0.05).Of the 32 limbs recanalized,IFC decreased significantly from 6.3 ± 1.6 before thrombolysis to 4.7± 1.4 after thrombolysis (t=12.136,P＜0.05).Six rest pain patients reported significantly alleviated symptoms.Fourteen limbs presented with feet ulcers or gangrene.Of these patients after endovascular treatment,1 underwent ankle level amputation,3 underwent toe amputation and 3 patients who did not seek further treatment reported spontaneous autoamputation and wound healing.The remaining 9 patients reported wound healing within 1 to 3 months.Secondary angioplasty was needed for symptom recurrence in 3 limbs of 3 patients 3 to 24 months after first procedure.Conclusions Endovascular treatment of diabetic infrapopliteal arterial diseases exhibited significant short term effect and was safe to perform.Small dose urokinase infusion after recanalization procedure was safe and effective in helping to improve infragenicular blood flow.