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1.
Bioact Mater ; 21: 324-339, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36185747

RESUMO

Diabetes mellitus (DM) aggravates periodontitis, resulting in accelerated periodontal bone resorption. Disordered glucose metabolism in DM causes reactive oxygen species (ROS) overproduction resulting in compromised bone healing, which makes diabetic periodontal bone regeneration a major challenge. Inspired by the natural bone healing cascade, a mesoporous silica nanoparticle (MSN)-incorporated PDLLA (poly(dl-lactide))-PEG-PDLLA (PPP) thermosensitive hydrogel with stepwise cargo release is designed to emulate the mesenchymal stem cell "recruitment-osteogenesis" cascade for diabetic periodontal bone regeneration. During therapy, SDF-1 quickly escapes from the hydrogel due to diffusion for early rat bone marrow stem cell (rBMSC) recruitment. Simultaneously, slow degradation of the hydrogel starts to gradually expose the MSNs for sustained release of metformin, which can scavenge the overproduced ROS under high glucose conditions to reverse the inhibited osteogenesis of rBMSCs by reactivating the AMPK/ß-catenin pathway, resulting in regulation of the diabetic microenvironment and facilitation of osteogenesis. In vitro experiments indicate that the hydrogel markedly restores the inhibited migration and osteogenic capacities of rBMSCs under high glucose conditions. In vivo results suggest that it can effectively recruit rBMSCs to the periodontal defect and significantly promote periodontal bone regeneration under type 2 DM. In conclusion, our work provides a novel therapeutic strategy of a bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration.

2.
Talanta ; 251: 123760, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35964515

RESUMO

The development and application of portable and user-friendly biosensing technology for rapid detection of pathogenic bacteria are essential for human and environmental care. In this work, based on the phenomenon that the filter membrane can selectively separate MnO2 nanosheets (MnO2 NSs) and Mn2+, a novel label-free sensing platform was developed to detect the Escherichia coli (E. coli) using ß-galactosidase (ß-Gal) as a marker. MnO2 NSs were utilized as a dual-mode signal molecule of smartphone-based colorimetric analysis and inductively coupled plasma mass spectrometry (ICP-MS). ß-Gal can catalyze the 4-Aminophenyl ß-D-galactopyranoside (PAPG) to produce p-aminophenol (PAP), which could reduce MnO2 NSs to Mn2+. After selective separation of MnO2 NSs and Mn2+ by the filter, colorimetric detection was achieved with a smartphone by identifying the RGB value of the MnO2 NSs coated membrane, while the Mn2+ in the filtrate was detected by ICP-MS. Under optimal conditions, the limits of detection (LODs) of E. coli by smartphone-based RGB analysis and ICP-MS were 5.6 × 103 CFU mL-1 and 35 CFU mL-1, respectively. This method was successfully used for E. coli assay in meat, vegetables, and fruit samples with the advantages of sensitivity, simplicity, and short incubation time (within 1 h).


Assuntos
Colorimetria , Escherichia coli , Colorimetria/métodos , Galactose , Humanos , Compostos de Manganês , Óxidos , Smartphone , beta-Galactosidase
3.
J Ethnopharmacol ; 301: 115815, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36220508

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum L., an herbal medicine used in India and other Asian countries, is prescribed routinely for a range of diseases, including tumor. Piperlongumine, a natural product isolated from Piper longum L., has received widespread attention due to its various pharmacological activities, such as anti-inflammatory, antimicrobial, and antitumor effects. AIM OF THE STUDY: Chronic myelogenous leukemia (CML) is a hematopoietic disease caused by Bcr-Abl fusion gene, with an incidence of 15% in adult leukemias. Targeting Bcr-Abl by imatinib provides a successful treatment approach for CML. However, imatinib resistance is an inevitable issue for CML treatment. In particular, T315I mutant is the most stubborn of the Bcr-Abl point mutants associated with imatinib resistance. Therefore, it is urgent to find an alternative approach to conquer imatinib resistance. This study investigated the role of a natural product piperlongumine in overcoming imatinib resistance in CML. MATERIALS AND METHODS: Cell viability and apoptosis were evaluated by MTS assay and Annexin V/propidium iodide counterstaining assay, respectively. Levels of intracellular signaling proteins were assessed by Western blots. Mitochondrial membrane potential was reflected by the fluorescence intensity of rhodamine-123. The function of proteasome was detected using 20S proteasomal activity assay, proteasomal deubiquitinase activity assay, and deubiquitinase active-site-directed labeling. The antitumor effects of piperlongumine were assessed with mice xenografts. RESULTS: We demonstrate that (i) Piperlongumine inhibits proteasome function by targeting 20S proteasomal peptidases and 19S proteasomal deubiquitinases (USP14 and UCHL5) in Bcr-Abl-WT and Bcr-Abl-T315I CML cells; (ii) Piperlongumine inhibits the cell viability of CML cell lines and primary CML cells; (iii) Proteasome inhibition by piperlongumine leads to cell apoptosis and downregulation of Bcr-Abl; (iv) Piperlongumine suppresses the tumor growth of CML xenografts. CONCLUSIONS: These results support that blockade of proteasome activity by piperlongumine provides a new therapeutic strategy for treating imatinib-resistant CML.


Assuntos
Antineoplásicos , Produtos Biológicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Camundongos , Animais , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proliferação de Células , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética , Apoptose , Enzimas Desubiquitinantes/uso terapêutico , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Ubiquitina Tiolesterase/uso terapêutico
4.
J Environ Sci (China) ; 124: 360-370, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182145

RESUMO

Efficient and robust photocatalysts for environmental pollutants removal with outstanding stability have great significance. Herein, we report a kind of three dimensional (3D) photocatalyst presented as Z-scheme heterojunction, which combining TiO2 and ZnxCd1-xS with graphene aerogel to contrast TiO2-ZnxCd1-xS graphene aerogel (TSGA, x=0.5) through a moderate hydrothermal process. The as-prepared Z-scheme TSGA was used to remove aqueous Cr(VI) via a synergistic effect of adsorption and visible light photocatalysis. The adsorption equilibrium can be reached about 40 min, then after about 30 min irradiation under visible light (wavelength (λ) > 420 nm) the removal rate of Cr(VI) almost reached 100%, which is much better than the performance of pristine TiO2 and Zn0.5Cd0.5S, as well as TiO2 graphene aerogel (TGA) and Zn0.5Cd0.5S graphene aerogel (SGA). The virulent Cr(VI) was reduced to Cr(III) with hypotoxicity after photocatalysis on TSGA, meanwhile the as-synthesized TSGA presented a good stability and reusability. The reduced graphene oxide (rGO) sheets between TiO2 and Zn0.5Cd0.5S played a role as charge transfer mediator, promoting the photoinduced electrons transfer and photocatalysis ability of TSGA was enhanced significantly. Hence, such photocatalyst exhibits a potential application on removing heavy metals with high efficiency and stability from polluted aqueous environment.

5.
J Environ Manage ; 325(Pt A): 116505, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36270131

RESUMO

As the most biodiversity-rich part of the protected areas system, habitats within the pilot national parks have long been threatened by drastic human-induced land use and land cover changes. The growing concern about habitat loss has spurred China's national park project to shift from pilot to construction phase with the official establishment of China's first group of national parks (CFGNPs) in October 2021. But far too little attention has been paid to the synergistic work concerning the habitat quality (HQ) dynamics of all five national parks. Here, the InVEST model, combined with a satellite-derived land use and land cover product and a hot spot analysis (HSA) method, was used to investigate the HQ dynamics at the park- and pixel-scale within the CFGNPs. Our results demonstrate that the past ecological conservation practices within national parks have been unpromising, especially in Giant Panda National Park, Northeast China Tiger and Leopard National Park (NCTL), and Wuyi Mountain National Park (WYM), where HQ as a whole showed a significant decline. Furthermore, more than half of Hainan Tropical Rainforest National Park (87.2%), WYM (77.4%), and NCTL (52.9%) showed significant HQ degradation from 1980 to 2019. Besides, increasing trends in the area shares of HQ degraded pixels were observed in all five national parks from 1980-1999 to 2000-2019. The HSA implied that the hot spots of high HQ degradation rates tend to occur in areas closer to urban settlements or on the edge of national parks, where human activities are intensive. Despite these disappointing findings, we highlighted from the observed local successes and the HQ plateau that the construction of CFGNPs is expected to reverse the deteriorating HQ trends. Thus, we concluded our paper by proposing an HSA-based regulatory zoning scheme that includes five subzones to guide the future construction of China's national park system.


Assuntos
Conservação dos Recursos Naturais , Parques Recreativos , Humanos , Conservação dos Recursos Naturais/métodos , Ecossistema , Biodiversidade , China
6.
J Colloid Interface Sci ; 630(Pt B): 215-223, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36327724

RESUMO

Electrocatalytic nitrogen reduction reaction (eNRR) is a promising method for the sustainable production of ammonia as an alternative to the traditional energy-intensive Haber-Bosch process. In this work, an efficient strategy by atomic spin regulation to promote NRR through Fe-transition metal (TM) hybrid heteronuclear dual-atom catalysts has been studied. By means of DFT computations, the stability, activity, and selectivity of 30 kinds of Fe-based dual-atoms anchored on N-doped porous graphene are systematically investigated to evaluate their catalytic performance. Fe/MoNC is screened as an excellent NRR catalyst with the limiting potentials of 0.63 V, and also suppresses HER. In the Fe/MoNC, the neighboring Fe atom regulates the spin state of the Mo center in MoN4 from high-spin state (2.63 µB) to medium-spin state (0.74 µB), which can effectively relieve the strong overlapping between Mo 4d orbital with the NxHy intermediates, promote the desorption of reaction product, and eventually achieve a lower limiting potential. Interestingly, the archetype of the active center of nitrogenase is also a FeMo-cofactor, which is consistent with our screening results. The work may provide new insight into the mechanism of nitrogenase, and promote the rational design of efficient NRR catalysts by atomic spin regulation.


Assuntos
Diatomáceas , Catálise , Nitrogênio , Amônia , Nitrogenase
7.
Cancer Cell Int ; 22(1): 332, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316734

RESUMO

OBJECTIVE: To evaluate the efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with favorable-risk acute myeloid leukemia in first remission. METHOD: Twenty patients who received auto-HSCT at our center between January 2014 and January 2021 were retrospectively reviewed. RESULTS: Until last follow-up, three patients in the cohort were dead due to relapse. The estimated 1-year and 5-year overall survival were 95.00% ± 4.87% and 83.82% ± 8.58%, respectively. The estimated 5-year RFS and CIR (cumulative incidence of relapse) were 85.00% ± 7.98% and 15.00% ±7.98%, respectively. CONCLUSION: The outcome of auto-HSCT in patients with favorable-risk acute myeloid leukemia in first remission was excellent and auto-HSCT could be an effective treatment for these patients.

8.
J Immunother Cancer ; 10(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36319063

RESUMO

BACKGROUND: Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+ regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy. METHODS: MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8+ cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs. RESULTS: In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγ+CD8+ T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated. CONCLUSIONS: Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers.


Assuntos
Adenocarcinoma , Neoplasias do Colo , MicroRNAs , Humanos , Camundongos , Animais , Receptores Tipo II do Fator de Necrose Tumoral/genética , Linfócitos T Reguladores , Microambiente Tumoral , Linfócitos T CD8-Positivos , Adenocarcinoma/genética , Epigênese Genética , MicroRNAs/metabolismo
9.
Chem Sci ; 13(40): 11738-11745, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36320912

RESUMO

Selective elimination of senescent cells (senolysis) has become a promising therapeutic strategy for the management of chronic renal failure (CRF), but the senolytic molecular pathways towards CRF therapy are limited. Here, we present for the first time a senescence-associated ß-galactosidase (SA-ß-gal) activatable theragnostic prodrug strategy to pertinently and effectively treat CRF in mice with the aid of fluorescence-guided senolysis. The signs of premature senescence, including the overexpression of ß-gal, have been found in kidneys of mice with CRF, making this enzyme particularly suitable as a trigger of prodrugs for CRF therapy. With this unique design, our pioneering prodrug TSPD achieved the activation of a fluorophore for tracking and the specific release of the parent drug, gemcitabine, in ß-gal-enriched cells after activation with SA-ß-gal. In mice with CRF, abdominal administration of TSPD was effective for improvement of the kidney functions, supporting the feasibility of the SA-ß-gal-dependent senolysis therapy towards CRF.

10.
Front Pharmacol ; 13: 969611, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324685

RESUMO

The successful treatment of breast cancer is hampered by toxicity to normal cells, impaired drug accumulation at the tumor site, and multidrug resistance. We designed a novel multifunctional liposome, CUR-DTX-L, to co-deliver curcumin (CUR) and the chemotherapeutic drug docetaxel (DTX) for the treatment of breast cancer in order to address multidrug resistance (MDR) and the low efficacy of chemotherapy. The mean particle size, polydispersity index, zeta potential, and encapsulation efficiency of CUR-DTX-L were 208.53 ± 6.82 nm, 0.055 ± 0.001, -23.1 ± 2.1 mV, and 98.32 ± 2.37%, respectively. An in vitro release study and CCK-8 assays showed that CUR-DTX-L has better sustained release effects and antitumor efficacy than free drugs, the antitumor efficacy was verified by MCF-7 tumor-bearing mice, the CUR-DTX-L showed better antitumor efficacy than other groups, and the in vivo pharmacokinetic study indicated that the plasma concentration-time curve, mean residence time, and biological half-life time of CUR-DTX-L were significantly increased compared with free drugs, suggesting that it is a promising drug delivery system for the synergistic treatment of breast cancer.

11.
Circ J ; 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36328564

RESUMO

BACKGROUND: The relationship between venous congestion and acute kidney injury (AKI) in cardiac surgery after cardiopulmonary bypass has not thoroughly investigated. Vacuum-assisted venous drainage (VAVD) reduces venous congestion, so we hypothesized that it would reduce the incidence of AKI in cardiovascular surgery.Methods and Results: We used a retrospective propensity score-matched analysis to evaluate the effect of VAVD on AKI in adult patients undergoing cardiac surgery. The primary outcomes were AKI and renal replacement therapy (RRT). Multivariable logistic regression was used to explore the association between VAVD exposure and adverse kidney outcomes. Of 15,387 eligible subjects, 13,480 and 1,907 had gravity drainage (GD) or VAVD, respectively, during cardiopulmonary bypass. On the basis of propensity scores, there were 1,468 matched patient pairs for GD and VAVD. The average central venous pressure (CVP) in the GD group was higher than in the VAVD group (4.43±1.23 mmHg vs. 2.30±0.98 mmHg, P<0.001). The occurrence of AKI and RRT was statistically significantly different in the 2 groups [(600/1,468, 40.87%) vs. (445/1,468, 30.31%), P<0.001; (36/1,468, 2.45% vs. 8/1,468; 0.54%), P<0.001, respectively)]. Multivariate logistic regression analysis revealed that VAVD was effective in protecting kidney function. CONCLUSIONS: VAVD was associated with a lower CVP and lower incidence of AKI, suggesting it protects adult cardiac patients from adverse renal outcomes.

12.
Int J Biometeorol ; 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36331668

RESUMO

It has been observed that high temperature exposure is associated with a reduction in lung function and some possible biological mechanisms have been suggested. However, it is unclear if thermal perception plays a role in the association. From September 3rd to 15th, 2018, in Guangzhou, China, we repeatedly measured daily thermal perception and lung function among 126 participants with outdoor military training. We performed a linear mixed model and stratified analyses by the origin of students, gender, and the training period to evaluate the effects of thermal perception on lung function. A total of 399 measurements were collected. Per vote increase in thermal sensation vote towards the "hot" direction was associated with a - 0.04 L (95% CI: - 0.08 to - 0.01) decrease in forced vital capacity (FVC), and - 0.04 L (95% CI: - 0.08 to - 0.01) decrease in forced expiratory volume in 1 s (FEV1). Per grade increase towards the "very uncomfortable" direction for thermal comfort vote was associated with an increased percentage of forced expiratory volume in 1 s (FEV1%) by 1.52% (95% CI: 0.18 to 2.86). For thermal preference, with preferred cooler vote increased by one level, FVC and FEV1 decreased by - 0.05 L/s (95% CI: - 0.08 to - 0.02) and - 0.05L/s (95% CI: - 0.08 to - 0.02), respectively. The effects of thermal perception on lung function were stronger among non-local and in the first week of training. Our study suggests that in the same high-temperature environment, thermal perception is associated with lung function, even in healthy adults.

13.
Asia Pac J Public Health ; : 10105395221134651, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36321513

RESUMO

China is a multi-ethnic country, and the prevalence of Helicobacter pylori (H pylori) infection may be diverse among ethnics. This meta-analysis was conducted to compare the prevalence of H pylori infection between Tibetans and Han ethnics. Ten studies that reported the prevalence of H pylori infection between Tibetans and Hans in China were eligible. The pooled prevalence of H pylori infection was 62.2% versus 55.3% among Tibetans and Hans, respectively. Tibetans had a higher risk of H pylori infection than Hans (odds ratio [OR] = 1.38, 95% confidence interval [CI] [1.05, 1.80]). In subgroup analysis, Tibetans with upper gastrointestinal symptoms (OR = 1.51, 95% CI [1.06-2.16]), inhabiting in Tibet (OR = 1.51, 95% CI [1.22, 1.87]), or inhabiting in Northwestern region (OR = 1.15, 95% CI [1.00, 1.31]) had significantly higher risks of H pylori infection. In addition, in the recent 10 years, Hans showed a decreased risk of H pylori infection (OR = 1.81, 95% CI [1.42, 2.30]). Heterogeneity was common, while sensitivity analyses showed partially inconsistent results against main findings. This study demonstrated higher prevalence of H pylori infection in Tibetans compared with Hans, especially in recent years, or in Tibet and northwest China, as well as symptomatic Tibetans. The results suggest tailored strategy and robustness need to be further considered for H pylori screening and eradication among Tibetans.

14.
Oral Dis ; 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36321868

RESUMO

OBJECTIVE: To analysis the relationship between periodontitis (PD) and oral squamous cell carcinoma (OSCC) by bioinformatic analysis. MATERIALS AND METHODS: We analyzed the gene expression profiles of PD (GSE16134) from the Gene Expression Omnibus (GEO) database and OSCC samples from TCGA-HNSC (head and neck squamous cell carcinoma) and identified common differentially expressed genes (DEGs) in PD and OSCC. Then, functional annotation and signaling pathway enrichment, protein interaction network construction, and hub gene identification were performed. Subsequently, the function and signaling pathway enrichment of hub genes, miRNA interaction, and transcription factor interaction analyses were carried out. We analyzed GSE10334 and GSE30784 as validation datasets, and performed RT-qPCR experiments simultaneously for validation, and obtained 4 hub genes. Finally, immune infiltration analysis and clinical correlation analysis of 4 hub genes and related miRNAs were performed. RESULTS: We identified 31 DEGs (16 up-regulated and 15 down-regulated). 4 hub genes were obtained by RT-qPCR and validation dataset analysis, including IL-1ß, CXCL8, MMP12 and MMP13. The expression levels of them were all significantly upregulated in both diseases. The functions of these genes focus on three areas: neutrophil chemotaxis, migration, and CXCR chemokine receptor binding. Key pathways include IL-17 signaling pathway, chemokine signaling pathway, and cytokine-cytokine receptor interactions pathway. Immune infiltration analysis showed that the expressions of 4 hub genes were closely related to a variety of immune cells. ROC curve analysis indicated that AUCs of 4 hub genes are all greater than 0.7, among which MMP12 and MMP13 were greater than 0.9. Kaplan-Meier survival analysis indicated that worse OS was strongly correlated with CXCL8 and MMP13 high expression groups. MMP12 low expression group was strongly associated with worse OS. The results of multivariate Cox regression analysis showed that age, N stage, CXCL8, MMP12, and MMP13 were independent prognostic factors for OS. We also identified 3 miRNAs, including hsa-miR-19b-3p, hsa-miR-181b-2-3p, and hsa-miR-495-3p, that were closely related to 4 hub genes. Hsa-miR-495-3p is closely related to the diagnosis and prognosis of OSCC. CONCLUSIONS: We identified 4 hub genes between PD and OSCC, including IL-1ß, CXCL8, MMP12, and MMP13. These genes may mediate the co-morbid process of PD and OSCC through inflammation-related pathways such as the IL-17 signaling pathway. It is worth noting that CXCL8, MMP12 and MMP13 have great significance in the diagnosis and prognosis of OSCC.

15.
Diabetes Metab Syndr Obes ; 15: 3319-3327, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36329806

RESUMO

With the development of economy and improvement of people's living standards, the incidence of obesity and type 2 diabetes mellitus (T2DM) has increased significantly and obesity has also become one of the most important risk factors of T2DM. In light of these trends, there have been many ways to take effect in losing weight. However, they also have corresponding deficiencies including inapparent curative effect, complex and incomplete reversible procedures and severe complications. Duodenal-Jejunal Bypass Liner (DJBL), which mimics Roux-en-Y gastric bypass (RYGB), is proved to play a key role in weight loss and control of T2DM. DJBL is reversible, less invasive and is more suitable for the treatment of obesity and T2DM, which is associated with multiple mechanisms, including incretin effect, gastric emptying mechanism, bile acid regulation, intestinal microbiota, inflammatory reaction mechanism and neural mechanism. In our review, we aimed to elaborate DJBL's clinical efficacy, safety and mechanisms in detail.

16.
Neuron ; 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36323321

RESUMO

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2+ tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of ß-catenin. Piezo2 knockout reverses WNT/ß-catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer.

17.
Arch Sex Behav ; 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376745

RESUMO

Although young people want to know more about sexuality, they do not feel they have received what they need to learn. In Chinese societies, scant research has solicited direct input from the youth to obtain their views on sexuality education (SE) deliverables. We found research gaps in the lack of Chinese preteens' input regarding SE timing, knowledge perception, learning readiness, and preteens' reasons for obtaining information about sexual health. In Hong Kong, a not-for-profit agency collected data from Chinese preadolescents who expressed opinions through a general survey. This agency surveyed students from 24 primary schools and provided anonymous secondary data for this team to analyze further. Among 4569 fifth- and sixth-grade students (average 11 years old), girls were more likely than boys to seek sex-related information from teachers, library books, and mothers. In contrast, boys were more likely than girls to obtain information from friends, pornographic comics, and the internet. Logistic regression analysis indicated that gender, age, instructional sources, openness to sexual health knowledge, and perceived and actual levels of knowledge predicted preteens' desire to receive SE earlier in grade school. Girls and older students were significantly more likely to report their preference to receive SE in an earlier grade. We recommend that preteens and their parents be encouraged to collaborate with teachers to participate in school-based SE programming.

18.
J Chem Inf Model ; 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36377848

RESUMO

GPCRs regulate multiple intracellular signaling cascades. Biasedly activating one signaling pathway over the others provides additional clinical utility to optimize GPCR-based therapies. GPCR heterodimers possess different functions from their monomeric states, including their selectivity to different transducers. However, the biased signaling mechanism induced by the heterodimerization remains unclear. Motivated by the issue, we select an important GPCR heterodimer (µOR/δOR heterodimer) as a case and use microsecond Gaussian accelerated molecular dynamics simulation coupled with potential of mean force and protein structure network (PSN) to probe mechanisms regarding the heterodimerization-induced constitutive ß-arrestin activity and efficacy change of the agonist DAMGO. The results show that only the lowest energy state of the µOR/δOR heterodimer, which adopts a slightly outward shift of TM6 and an ICL2 conformation close to the receptor core, can selectively accommodate ß-arrestins. PSN further reveals important roles of H8, ICL1, and ICL2 in regulating the constitutive ß-arrestin-biased activity for the apo µOR/δOR heterodimer. In addition, the heterodimerization can allosterically alter the binding mode of DAMGO mainly by means of W7.35. Consequently, DAMGO transmits the structural signal mainly through TM6 and TM7 in the dimer, rather than TM3 similar to the µOR monomer, thus changing the efficacy of DAMGO from a balanced agonist to the ß-arrestin-biased one. On the other side, the binding of DAMGO to the heterodimer can stabilize µOR/δOR heterodimers through a stronger interaction of TM1/TM1 and H8/H8, accordingly enhancing the interaction of µOR with δOR and the binding affinity of the dimer to the ß-arrestin. The agonist DAMGO does not change main compositions of the regulation network from the dimer interface to the transducer binding pocket of the µOR protomer, but induces an increase in the structural communication of the network, which should contribute to the enhanced ß-arrestin coupling. Our observations, for the first time, reveal the molecular mechanism of the biased signaling induced by the heterodimerization for GPCRs, which should be beneficial to more comprehensively understand the GPCR bias signaling.

19.
Small ; : e2205694, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36366925

RESUMO

Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.

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