[Inhibitory effect and mechanism of sodium cantharidate on human tongue squamous cell carcinoma CAL27 cells].

PURPOSE: To investigate the inhibitory effect of sodium cantharidate (SCA) on human tongue squamous cell carcinoma CAL27 cells and its mechanism. METHODS: CAL27 cells were pretreated with different concentrations of SCA. Cell viability was analyzed by CCK-8 method. The migration and invasion of CAL27 cells were measured by scratch test and Transwell chamber, and the apoptosis rate was measured by flow cytometry. p53 protein and its phosphorylation sites Ser33, Ser37, Ser46, expression of BCL-2, BAX, and cleaved caspase 3 in CAL27 cells were detected by Western blot. Statistical analysis was performed with Graphpad Prism 9.0 software package. RESULTS: Compared with the blank control group, the proliferation, migration and invasion of CAL27 cells in sodium cantharidate group were significantly decreased, and the apoptosis rate was significantly increased(P＜0.01) in a dose-dependent manner. The expression of p53 protein and its phosphorylation sites Ser33, Ser37, Ser46 protein was significantly up-regulated(P＜0.05 or P＜0.01). The expression of BCL-2 protein was down-regulated and the expression of BAX protein was significantly up-regulated(P＜0.05 or P＜0.01). The ratio of BCL-2/BAX was significantly decreased and the expression of cleaved caspase 3 protein was significantly up-regulated(P＜0.05 or P＜0.01). CONCLUSIONS: SCA can inhibit the proliferation, migration and invasion of human tongue squamous cell carcinoma CAL27 cells. It also down-regulates the ratio of BCL-2/BAX and up-regulates the expression of cleaved caspase 3 protein by regulating the phosphorylation of p53 protein, which induces apoptosis.

Clinical Outcomes of Surgical Revascularization Strategies Guided by Quantitative Flow Ratio in Primary Noncoronary Cardiac Surgery.

PURPOSE: Information regarding quantitative flow ratio (QFR) usage in coronary artery bypass grafting (CABG) is lacking. We compared the incidence of postoperative long-term adverse cardiovascular and cerebrovascular events after QFR-guided or coronary angiography-guided adult cardiac surgery with concurrent bypass surgery. MATERIALS AND METHODS: This study included 432 patients who underwent cardiopulmonary bypass (CPB) at our institution with at least 1 angiographical coronary artery lesion (diameter stenosis: 30% to 90%) between January 2015 and January 2016. The QFR of each patient was calculated. Patients who only underwent intraoperative coronary revascularization following the principles of optimal revascularization strategy were assigned to group A. Patients with coronary lesions not meeting the above criteria were placed in group B. RESULTS: The average number of distal anastomoses of patients with combined CABG in group B was similar to that in Group A (1.9±1.0 vs. 1.7±0.9; P=0.081). Group A had a shorter CPB duration (114.4±49.2 vs 135.8±55.2 minutes; P<0.001) and shorter aortic cross-clamping time (83.6±36.2 vs 101.1±40.6 minutes; P<0.001). The rates of perioperative mortality and major complications did not differ between groups. Long-term major adverse cardiovascular and cerebrovascular events (MACCEs) were less common in group A than in group B (14.7% vs 29.5%; P<0.001). CONCLUSIONS: In primary noncoronary cardiac surgery, despite the similar average numbers of distal anastomoses, the group with target vessels treated using an optimal coronary revascularization strategy presented shorter CPB time and aortic cross-clamping time than the other group. Multivariate analyses also showed a lower incidence of long-term MACCEs.

Recent advances in patient-derived tumor organoids for reconstructing TME of head and neck cancer.

BACKGROUND: The differences between existing preclinical models and the tumor microenvironment in vivo are one of the significant challenges hindering cancer therapy development. Patient-derived tumor organoids (PDTO) can highly retain tumor heterogeneity. Thus, it provides a more reliable platform for research in tumor biology, new drug screening, and precision medicine. METHODS: We conducted a systematic review to summarise the characteristics of the existing preclinical models, the advantages of patient-derived tumor organoids in reconstructing the tumor microenvironment, and the latest research progress. Moreover, this study deciphers organoid culture technology in the clinical precision treatment of head and neck cancer to achieve better transformation. Studies were identified through a comprehensive search of Ovid MEDLINE (Wolters Kluwer), PubMed (National Library of Medicine), web of Science (Thomson Reuters) and, Scopus (Elsevier) databases, without publication date or language restrictions. RESULTS: In tumor development, the interaction between cellular and non-cellular components in the tumor microenvironment (TME) has a crucial role. Co-culture, Air-liquid interface culture, microfluidics, and decellularized matrix have depicted great potential in reconstructing the tumor microenvironment and simulating tumor genesis, development, and metastasis. CONCLUSION: An accurate determination of stromal cells, immune cells, and extracellular matrix can be achieved by reconstructing the head and neck cancer tumor microenvironment using the PDTO model. Moreover, the interaction between head and neck cancer cells can also play an essential role in implementing the individualized precision treatment of head and neck cancer.

Energy-Efficient Neuromorphic Architectures for Nuclear Radiation Detection Applications.

A comprehensive analysis and simulation of two memristor-based neuromorphic architectures for nuclear radiation detection is presented. Both scalable architectures retrofit a locally competitive algorithm to solve overcomplete sparse approximation problems by harnessing memristor crossbar execution of vector-matrix multiplications. The proposed systems demonstrate excellent accuracy and throughput while consuming minimal energy for radionuclide detection. To ensure that the simulation results of our proposed hardware are realistic, the memristor parameters are chosen from our own fabricated memristor devices. Based on these results, we conclude that memristor-based computing is the preeminent technology for a radiation detection platform.

Efficacy and Safety of Oral Propranolol or Topical Timolol for the Treatment of Superficial Infantile Hemangiomas.

Infantile hemangiomas (IHs) are the most common benign soft tissue tumors of infancy. Oral propranolol has become a first-line treatment option since the unexpected discovery of its surprising efficacy in the treatment of IHs in 2008. However, oral propranolol causes systemic complications, including hypotension, bradycardia, and hypoglycemia. To minimize systemic adverse effects of oral propranolol, timolol maleate, a nonselective ß-blocker similar to propranolol, has been used as a topical agent to treat superficial IHs. The authors evaluated the efficacy and safety of oral propranolol or topical timolol in 60 patients with IHs. Of the 60 patients recruited, 30 patients were treated using orally administrated propranolol and an additional 30 patients received topical timolol. The efficacy rate of the oral propranolol and topical timolol was 96.7% and 93.3%, respectively. There were no significant differences between the two treatment patterns for the efficacy rate. The incidence of systemic adverse effects for patients treated with oral propranolol was significantly higher than that for cases received topically timolol treatment. Topical timolol maleate is effective and well-tolerated in the treatment of IHs. It could be considered as the first-line treatment choice, especially for superficial IHs.

[Application of PAR index and cephalometrics for camouflage therapy and orthodontic-orthognathic surgery in adults with skeletal Class â ¢ malocclusion].

PURPOSE: To investigate the value of PAR index combined with cephalometry in evaluating the efficacy of mild to moderate skeletal Class Ⅲ malocclusion. METHODS: Sixty-five adult patients with skeletal Class Ⅲ malocclusion were selected and divided into group C (camouflage therapy) and group S (orthodontic-orthognathic surgery)according to different treatment methods. PAR index and cephalometric values before and after treatment in each group were compared, and then the differences of PAR index and cephalometric values before and after treatment between the two groups were compared. The clinical effect was evaluated by these indexes. SPSS 25.0 software package was used for data analysis. RESULTS: In PAR index, the tooth alignment, occlusion, overjet, overbite, midline, total score and weighted total score after treatment of both groups were all significantly lower than those before treatment(P＜0.001). The differences of left and right buccal bite and total posterior bite of group S before and after treatment was significantly larger than those of group C(P＜0.001). In cephalometric measurement, the differences of SNA, NA-PA, L1-NB, U1-L1, U1-SN and L1-MP in group C before and after treatment were significantly different(P＜0.05), while those in group S before and after treatment were SNA, SNB, ANB, NP-FH, NA-PA, L1-NB, U1-L1U1-SN and L1-MP(P＜0.001). The differences of SNB, ANB and NP-FH before and after treatment in group S were significantly greater than those in group C(P＜0.001). CONCLUSIONS: Both treatments are effective for adult patients with mild to moderate skeletal Class Ⅲ malocclusion. The effect of orthodontic-orthognathic treatment is better than camouflage therapy in occlusal relationship of posterior teeth, the position of mandible relative to cranium, the mutual position of upper jaw and lower jaw relative to cranium, and the degree of mandibular convexity. PAR index combined with cephalometric measurement can effectively judge the clinical effect of adult patients with mild to moderate skeletal Class Ⅲ malocclusion, which is a good evaluation method.

Mandible-First Sequencing Increase Surgical Accuracy for Patients With Skeletal Class II Malocclusion Concomitant With Unstable Condyle-Fossa Relation.

The aim of this study was to explore whether mandible-first sequencing increases the surgical accuracy in bimaxillary orthognathic surgery for patients with skeletal class II malocclusion concomitant with the unstable condyle-fossa relation. A retrospective evaluation of 19 patients who had undergone virtually planned double-splint orthognathic surgery with different operation sequences was performed: maxilla-first (n=9) or mandible-first (n=10) surgery. The centroid position, translational, and rotational differences in the maxilla were evaluated by comparing the virtual plans with actual results. The stability was assessed by comparing the actual results with the follow-up outcomes 6 months postoperatively. The accuracy of the maxilla centroid position was improved in mandible-first sequencing surgery: mandible-first 1.87±0.94 mm versus maxilla-first 2.70±0.75 mm (P<0.05). Moreover, no significant difference was detected in the translational and orientational discrepancies between the 2 groups. Neither sequencing procedure differed in the overall stability: maxilla-first (1.48±1.13 mm) versus mandible-first (1.57±0.90 mm). This study indicated that the mandible-first surgery leads to a more accurate maxilla position than the maxilla-first surgery for patients with skeletal class II malocclusion concomitant with the unstable condyle-fossa relation.

A manual controlled theranostic nanoplatform with real-time photoacoustic quantification of drug release for chemophotothermal therapy.

The development of intelligent nanodrug delivery systems that can visually guide the on-demand quantitative control of drug release has received extensive attention. Herein, two chemotherapeutic drugs, gallic acid and 5-fluorouracil, and Fe(III) were selected to prepare nanomedicine GF-Fe via polyphenol-metal self-assembly and infinite coordination of drug-metal. GF-Fe has good biocompatibility, photothermal properties and photoacoustic (PA) signals. When deferoxamine (DFO) was artificially applied and interacted with GF-Fe, GF-Fe began to disassemble, gallic acid and 5-fluorouracil were gradually released, while the PA signal of the nanomedicine decayed synchronously. Based on this, the relationship between the intensity of the PA signal and the drug release amount was established, so as to realize the precise quantitative control of the drug release in real-time under the guidance of PA imaging. Besides, the combined effect of the two therapeutic drugs in combination with photothermal therapy (PTT) can improve the therapeutic effect, resulting in significant superadditiveness. This nanoplatform constructed by facile synthesis provided good clinical translation potential for the implementation of precise multimodal combination therapy strategies for tumors.

Transcriptomic Heterogeneity of Human Mesenchymal Stem Cells Derived from Bone Marrow, Dental Pulp, Adipose Tissue, and Umbilical Cord.

Compared with mesenchymal stem cells (MSCs) obtained from other tissue sources, those derived from umbilical cord (UC) tissue exhibit numerous advantages and vast potential for therapeutic applications. However, MSCs from different tissue sources are heterogeneous, and therefore, the therapeutic efficacy of UC-derived MSCs as a replacement for other tissue-derived MSCs needs to be studied. To better understand the distinctions between UC-derived MSCs and MSCs derived from other tissues, we conducted a transcriptome analysis of MSCs obtained from UC and three other tissues. Correlation analysis revealed the strongest correlation between UC-MSCs (UC-MSCs) and bone marrow-MSCs (BM-MSCs). Compared with UC-MSCs, the lower differentially expressed genes of BM-MSCs, dental pulp-MSCs (DP-MSCs), and adipose tissue-MSCs (AP-MSCs) were predominantly enriched in actin-related terms, while higher differentially expressed genes were predominantly enriched in immunological processes. We also analyzed the distribution of 34 frequently or highly expressed cell characterization molecules in BM-MSCs, DP-MSCs, AP-MSCs, and UC-MSCs. CD200 (FPKM >10) was only detected in UC-MSCs, while CD106 was detected in AD-MSCs and DP-MSCs (FPKM >10). The reliability of transcriptomic data analysis was verified by quantitative real-time PCR. Finally, we recommend the use of CD200, CD106, and other similar markers with unstable expression as benchmark molecules to monitor the proliferation and differentiation potential of MSCs. This study provides comprehensive insights into the heterogeneity between UC-MSCs and MSCs derived from other tissues, which can guide the therapeutic application of UC-MSCs.

[Application of 3D printing modified tooth-supported cyst plug in decompression of mandibular cystic lesions].

PURPOSE: To evaluate the application value of 3D printing modified dental support cyst plug in fenestration of large jaw cystic lesions. METHODS: Forty patients with mandibular cystic disease in Xuzhou Central Hospital from October 2019 to April 2021 were selected. They were randomly divided into experimental group(3D printing group) and control group (traditional plug group), with 20 cases in each group. All enrolled patients underwent preoperative digital modeling of cystic lesions of the jaw, obtained the cystic cavity volume data of preoperative lesions, designed the windowing site according to the plan and performed decompression for jaw cysts. Three days after surgery, the patient's postoperative CBCT and Oral-scan data in the experimental group was obtained, and a digitally modified tooth-supported cyst plug with porous column channel was designed, and titanium alloy material for 3D printing was selected. In the control group, the plug was manually molded by experienced physicians. The visual analogue scale(VAS) score of pain, retention, mechanical properties of the plug and its effect on the adjacent teeth were compared between the two groups during the process of model preparation, and the changes of the cyst volume 1, 3 and 6 months after operation were compared between the two groups. SPSS 25.0 software package was used for data analysis. RESULTS: Compared with the control group, the patients in the experimental group who made titanium alloy as printing material by digital impression complained more comfortable, and the mechanical strength and stability of the cyst plug were better than those in the control group(P＜0.05). There was no significant difference in retention between the two groups(P＞0.05). The reduction rate of cyst volume in the experimental group was significantly higher than that in the traditional plug group 3 and 6 months after operation(P＜0.05). CONCLUSIONS: The modified tooth-supported titanium alloy cyst plug with digital 3D printing has good mechanical properties and stability. It has little damage to the abutment and no lateral force, and has the advantages of precision, individualization and comfort. The improved irrigation and injection channel can fully flush the cavity and speed up the narrowing of the cyst and reduce the waiting time before the second operation, which is worth promoting in clinical practice.

Two interacting ethylene response factors negatively regulate peach resistance to Lasiodiplodia theobromae.

Gummosis is 1 of the most common and destructive diseases threatening global peach (Prunus persica) production. Our previous studies have revealed that ethylene and methyl jasmonate enhance peach susceptibility to Lasiodiplodia theobromae, a virulent pathogen inducing gummosis; however, the underlying molecular mechanisms remain obscure. Here, 2 ethylene response factors (ERFs), PpERF98 and PpERF1, were identified as negative regulators in peach response to L. theobromae infection. Expression of 2 putative paralogs, PpERF98-1/2, was dramatically induced by ethylene and L. theobromae treatments and accumulated highly in the gummosis-sensitive cultivar. Silencing of PpERF98-1/2 increased salicylic acid (SA) content and pathogenesis-related genes PpPR1 and PpPR2 transcripts, conferring peach resistance to L. theobromae, whereas peach and tomato (Solanum lycopersicum) plants overexpressing either of PpERF98-1/2 showed opposite changes. Also, jasmonic acid markedly accumulated in PpERF98-1/2-silenced plants, but reduction in PpPR3, PpPR4, and PpCHI (Chitinase) transcripts indicated a blocked signaling pathway. PpERF98-1 and 2 were further demonstrated to directly bind the promoters of 2 putative paralogous PpERF1 genes and to activate the ERF branch of the jasmonate/ethylene signaling pathway, thus attenuating SA-dependent defenses. The lesion phenotypes of peach seedlings overexpressing PpERF1-1/2 and PpERF98-1/2 were similar. Furthermore, PpERF98-1/2 formed homodimers/heterodimers and interacted with the 2 PpERF1 proteins to amplify the jasmonate/ethylene signaling pathway, as larger lesions were observed in peach plants cooverexpressing PpERF98 with PpERF1 relative to individual PpERF98 overexpression. Overall, our work deciphers an important regulatory network of ethylene-mediated peach susceptibility to L. theobromae based on a PpERF98-PpERF1 transcriptional cascade, which could be utilized as a potential target for genetic engineering to augment protection against L. theobromae-mediated diseases in crops and trees.

A retrospective comparative cohort study of ultra-pulse CO2 lattice laser and glucocorticoids in the treatment of vulvar epithelial nonneoplastic lesions.

Background: A comparison of topical glucocorticoids with CO2 fractional laser treatment was conducted to investigate the differences in the efficacy of non-neoplastic vulvar epithelial lesion treatments in different pathological types and to provide a scientific basis for the management of these disorders. This paper was to study the difference of curative effect of different pathological types of non-tumor vulvar epithelial lesions and provide scientific basis for the treatment of these diseases. Methods: From November 2016 to July 2018, 178 cases of vulvar lichen simplex chronicus (LSC) or lichen sclerosus were confirmed with vulvar biopsy at our institute. Finally, 160 patients were enrolled in this trial. The patients were divided into 2 groups: a group treated with topical hormone and a group treated with CO2 lattice laser therapies. There were 80 cases in each group, including 40 with LSC and 40 with lichen sclerosus. Patients applied 1 gram of progesterone cream and betamethasone cream to the affected area in the morning and evening, respectively, once a day for 3 months. The efficacy was evaluated with the Patient Global Impression of Change (PGI-C) subjective symptom improvement scale and clinical efficacy evaluation scale. The formula was applied to calculate the curative effect index. Results: The PGI-C scores at 1, 3, and 6 months of treatment showed that the laser treatment group had remarkably superior outcomes to the glucocorticoid treatment group. The clinical efficacy score scale at 3- and 6-month treatments indicated a significantly greater curative effect in the laser than in the glucocorticoid treatment (P=0.006 and P=0.002 respectively). In the glucocorticoid group, the clinical effects of different pathological subtypes were significantly different following the 1- and 3-month treatments. The efficacy of treatment for LSC was better than that for lichen sclerosus. Following the 3- and 6-month treatments, the clinical effect for LSC was better than that of lichen sclerosus (3 months: 95% vs. 75%; 6 months: and 95% vs. 70%). Conclusions: Ultrapulse CO2 lattice laser was more effective than was glucocorticoid therapy in the treatment of vulvar epithelial non-tumor-like lesions.

Comprehensive physio-biochemical and transcriptomic characterization to decipher the network of key genes under waterlogging stress and its recuperation in Prunus persica.

Waterlogging is a major abiotic stress that plants encounter as a result of climate change impacts. Peach is very sensitive to hypoxia during waterlogging, which causes poor tree vigor and huge economic losses. The molecular mechanism underlying the peach response to waterlogging and reoxygenation remains unclear. Here, the physiological and molecular responses of 3-week-old peach seedlings under waterlogged and recovery conditions were comprehensively analyzed. As a result, waterlogging significantly reduced plant height and biomass with inhibition of root growth when compared with control and reoxygenation. Similar results were observed for photosynthetic activities and gaseous exchange parameters. Waterlogging increased lipid peroxidation, hydrogen peroxide, proline, glutamic acid and glutathione contents, while superoxide dismutase, peroxidases and catalase activities were decreased. The glucose and fructose contents were accumulated, contrary to sucrose which was reduced remarkably throughout the stress periods. The level of endogenous indole acetic acid (IAA) was increased in waterlogging but decreased after reoxygenation. However, the change trends of jasmonic acid (JA), cytokinins and abscisic acid (ABA) levels were opposite to IAA. In transcriptomic analysis, there were 13,343 differentially expressed genes (DEGs) with higher and 16,112 genes with lower expression. These DEGs were greatly enriched in carbohydrate metabolism, anaerobic fermentation, glutathione metabolism and IAA hormone biosynthesis under waterlogging, while they were significantly enriched in photosynthesis, reactive oxygen species scavenging, ABA and JA hormones biosynthesis in reoxygenation. Moreover, several genes related to stress response, carbohydrate metabolism and hormones biosynthesis were significantly changed in waterlogging and reoxygenation, which indicated unbalanced amino acid, carbon and fatty acid pools in peach roots. Taken together, these results suggest that glutathione, primary sugars and hormone biosynthesis and signaling might play key roles in plant response to waterlogging. Our work provides a comprehensive understanding of gene regulatory networks and metabolites in waterlogging stress and its recuperation, which will facilitate peach waterlogging control.

Comparison of electrophysiology therapy and glucocorticoid therapy in the treatment of 2 subtypes of vulvar epithelial non-neoplastic lesions: a prospective cohort study.

Background: Lichen-like lesions with degeneration and pigmentation alterations can be divided into the following 2 types: (I) chronic simple lichen; and (II) sclerosing lichen. The etiology of the disease is unknown. This study sought to examine the therapeutic effects of electrophysiological smooth-muscle electrical stimulation in the treatment of lichen-like lesions of the vulva. Methods: A total of 80 outpatients, who had been confirmed to have vulvar lichen-like lesions by vulvar biopsy at our hospital from November 2016 to March 2018, were prospectively included in this study. The patients received electrophysiology or glucocorticoid therapy. After completing a treatment cycle according to the clinical treatment routine, the outpatients were monitored at 1-, 3- and 6-month intervals. Patients used an improvement scale (i.e., the patient global impression of change scale) to score their subjective perceptions and subjective symptoms. The clinical curative effect scale was used to calculate the curative effect index and grade the curative effect. Results: After 1 month of treatment, the active enhancement of simple lichen in the electrophysiological treatment group and glucocorticoid treatment group improved, while the active enhancement of simple lichen in the electrophysiological treatment group improved after 3 months of treatment. After 6 months of treatment, the subjective improvement score of the electrophysiological treatment group was better than that of lichen sclerosus. After 3 months of treatment, the effective rate of the electrophysiological therapy group was better than that of the glucocorticoid therapy group. After 6 months of treatment in the electrophysiological treatment group, the efficacy of simple lichen is also better than that of sclerotic lichen. Conclusions: Conventional hormone therapy is easier for patients to accept because of its convenience and low costs.

Surgical treatment of cardiac lipoma: 20 years' experience in a single center.

BACKGROUND: Primary cardiac lipoma is very rare, and no consensus has been developed regarding its ideal treatment strategy. This study reviewed the surgical treatment of cardiac lipomas in 20 patients over 20 years. METHODS: Twenty patients with cardiac lipomas were treated at Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College from January 1, 2002, to January 1, 2022. The patients' clinical data and pathological reports were retrospectively analyzed, and the follow-up with a range of 1 year to 20 years was conducted. RESULTS: The cardiac lipomas were located in the right atrium (RA) or superior vena cava (SVC) in seven patients (35%) (RA in six patients and SVC in one patient), left ventricle in eight patients (40%) (left ventricular chamber in four patients and left ventricular subepicardium and myocardium in four patients), right ventricle in three patients (15%) (right ventricular chamber in one patient and right ventricular subepicardial layer and myocardium in two patients), subepicardial interventricular groove in one patient (5%), and pericardium in one patient (5%). Complete resection was achieved in 14 patients (70%), including seven patients with lipomas in the RA or SVC. Incomplete resection occurred in six patients (30%) with lipomas in the ventricles. No perioperative deaths occurred. Long-term follow-up was conducted for 19 patients (95%), including two (10%) who died. Both patients who died had lipomas incompletely resected due to ventricles involvement, and preoperative malignant arrhythmias persisted post-operatively. CONCLUSIONS: The complete resection rate was high, and the long-term prognosis was satisfactory in patients with cardiac lipomas that did not involve the ventricle. The complete resection rate was low in patients with cardiac lipomas in ventricles; and complications, including malignant arrhythmia, were common. Failure of complete resection and post-operative ventricular arrhythmia are correlated with post-operative mortality.

Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation.

BACKGROUND/AIMS: The activation of the complement system and subsequent inflammatory responses are important features of myocardial ischemia/reperfusion (I/R) injury. Exosomes are nanoscale extracellular vesicles that play a significant role in remote ischemic preconditioning (RIPC) cardioprotection. The present study aimed to test whether RIPC-induced plasma exosomes (RIPC-Exo) exert protective effects on myocardial I/R injury by inhibiting complement activation and inflammation and whether exosomal heat shock protein 90 (HSP90) mediates these effects. METHODS: Rat hearts underwent 30 min of coronary ligation followed by 2 h of reperfusion. Plasma exosomes were isolated from RIPC rats and injected into the infarcted myocardium immediately after ligation. Sixty rats were randomly divided into Sham, I/R, I/R + RIPC-Exo (50 µg/µl), and RIPC-Exo + GA (geldanamycin, 1 mg/kg, administration 30 min before ligation) groups. Cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB), infarct size, the expression of HSP90, complement component (C)3, C5a, c-Jun N-terminal kinase (JNK), interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha and intercellular adhesion molecule -1 (ICAM-1) were assessed. RESULTS: RIPC-Exo treatment significantly reduced I/R-induced cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB) and infarct size. These beneficial effects were accompanied by decreased C3 and C5a expression, decreased inflammatory factor levels (IL-1ß, TNF-α, and ICAM-1), decreased JNK and Bax, and increased Bcl-2 expression. Meanwhile, the expression of HSP90 in the exosomes from rat plasma increased significantly after RIPC. However, treatment with HSP90 inhibitor GA significantly reversed the cardioprotection of RIPC-Exo, as well as activated complement component, JNK signalling and inflammation, indicating that HSP90 in exosomes isolated from the RIPC was important in mediating the cardioprotective effects during I/R. CONCLUSION: Exosomal HSP90 induced by RIPC played a significant role in cardioprotection against I/R injury, and its function was in part linked to the inhibition of the complement system, JNK signalling and local and systemic inflammation, ultimately alleviating I/R-induced myocardial injury and apoptosis by the upregulation of Bcl-2 expression and the downregulation of proapoptotic Bax.

Construction of Artificial Controllable Aggregation Trojan Horse-Like Nanoplatform for Enhanced NIR-II Photothermal Therapy.

Promoting the aggregation of nanoprobes at tumor sites and realizing precise imaging and treatment of tumors is still one of the important problems to be solved in the field of nanomedicine. Poly-2-phenylbenzobisthiazole (PB) is a novel conjugated polymer with good biocompatibility, excellent photothermal properties in the second near-infrared region (NIR-II), but poor water dispersibility. Herein, a novel self-assembly/polymerization two-in-one strategy was proposed to prepare a new family of poly-2-phenyl-benzobisthiazole-based nanoparticles. Because the hydrophobic polymer PB was well "camouflaged" in the hydrophilic polyphenol-metal networks, the prepared "Trojan horse-like" nanoparticle TF-PB exhibited good water dispersibility. Besides, TF-PB can play a role as a contrast agent for photoacoustic and magnetic resonance dual-modality imaging. When deferoxamine was artificially applied and interacted with TF-PB, the polyphenol-metal networks disintegrated and the hydrophobic material PB was exposed and started hydrophobic aggregation. Thus, it can be applied for precise enhanced photothermal therapy (PTT) in the NIR-II. Meanwhile, the aggregation process enabled non-invasive, fast, and accurate real-time monitoring by self-enhancing photoacoustic imaging. This work has realized the artificially controllable aggregation of photothermal materials in the tumor site, solved the limitations of traditional PTT, and also has good application prospects in clinical therapy.

A simple liposome-based bionic bacterium for tumor treatment by re-education of tumor-associated microphages in combination with chemotherapy.

Re-education of tumor-associated macrophages (TAMs) into M1-like macrophages (Mφ1) has become one of the aims of tumor immunotherapy. Injection of live bacteria has been applied for this purpose; however, an acute innate immune response might be caused in this progress, and therefore a bacteria-based strategy with great security is needed. In this study, the bacterial walls of Staphylococcus aureus were inserted into the bilayer of liposome to construct liposome-based bionic bacteria (Bio-Bac), and doxorubicin (DOX) was encapsulated to form DOX@Bio-Bac. DOX@Bio-Bac re-educated the THP-1-derived TAMs into Mφ1 in vitro, and subsequently inhibited the migration and invasion of CAL27 cells. In a mouse model of hepatocellular carcinoma with lymphatic metastasis, the re-education of TAMs was proved, and an effective inhibition of tumor growth and metastasis in mice was observed. The liposome-based bionic bacteria constructed in this study provide a new strategy for re-education of TAMs, replacing the bacterial therapy reported previously, and a more effective anti-tumor effect can be obtained by combining the chemotherapy drugs with this bionic bacterium.

[Corilagin-induced apoptosis of oral squamous carcinoma CAL-27 cells in vitro and in vivo and its mechanism].

PURPOSE: To investigate the effect of corilagin on proliferation and apoptosis of human oral squamous cell carcinoma CAL-27 cells, and to explore the molecular mechanism of inducing cell apoptosis. METHODS: In vitro experiments, Cal-27 cells were treated with different concentrations of corilagin, cell-counting kit-8(CCK-8) assay and colony formation assay were performed to evaluate cell proliferation; flow cytometric analysis was used to evaluate cell apoptosis; qRT-PCR and Western blot assays were performed to evaluate the effect of corilagin on the expression levels of Bax, Bcl-2, Caspase-3, Cleaved Caspase-3 in CAL-27 cells. In vivo experiments, tumor-bearing nude mice was constructed with CAL-27 cells to evaluate the antitumor effect of corilagin. GraphPad Prism 8.0 software package was used for statistical analysis of the data. RESULTS: In vitro experiments showed that corilagin in a dose-dependent manner inhibited proliferation, induced apoptosis, up-regulated Bax, caspase-3, cleaved caspase-3 and down-regulated Bcl-2 at the mRNA and protein levels of CAL-27 cells, and the differences were statistically significant(P＜0.05). In vivo experiments showed that compared with the control group, corilagin could significantly reduce the volume of tumor in nude mice(P＜0.05). CONCLUSIONS: Corilagin can significantly inhibit CAL-27 cell growth and promote its apoptosis both in vitro and in vivo, which may be related to the mediation of Bax/Bcl-2/Caspase-3 signaling pathway.

Gene therapy using human FMRP isoforms driven by the human FMR1 promoter rescues fragile X syndrome mouse deficits.

Fragile X syndrome (FXS) is caused by the loss of the fragile X messenger ribonucleoprotein 1 (FMRP) encoded by the FMR1 gene. Gene therapy using adeno-associated virus (AAV) to restore FMRP expression is a promising therapeutic strategy. However, so far AAV gene therapy tests for FXS only utilized rodent FMRPs driven by promoters other than the human FMR1 promoter. Restoration of human FMRP in appropriate cell types and at physiological levels, preferably driven by the human FMR1 promoter, would be more suitable for its clinical use. Herein, we generated two human FMR1 promoter subdomains that effectively drive gene expression. When AAVs expressing two different human FMRP isoforms under the control of a human FMR1 promoter subdomain were administered into bilateral ventricles of neonatal Fmr1 -/y and wild-type (WT) mice, both human FMRP isoforms were expressed throughout the brain in a pattern reminiscent to that of mouse FMRP. Importantly, human FMRP expression attenuated social behavior deficits and stereotyped and repetitive behavior, and reversed dysmorphological dendritic spines in Fmr1 -/y mice, without affecting WT mouse behaviors. Our results demonstrate that human FMR1 promoter can effectively drive human FMRP expression in the brain to attenuate Fmr1 -/y mouse deficits, strengthening the notion of using AAV gene therapy for FXS treatment.