Low-energy shock waves promote the cisplatin chemosensitivity of human osteosarcoma MNNG/HOS cells via the P2X7/Akt/mTOR pathway.

Background: The current dilemma of osteosarcoma treatment is the resistance of chemotherapeutic drugs after long-term usage, which also introduces life-threatening side effects. Methods and results: To minimize chemoresistance in osteosarcoma patients, the authors applied shock waves (SWs) to human osteosarcoma MNNG/HOS cells, then evaluated the cell viability and extracellular ATP levels, and further investigated the effect of SWs on cisplatin (DDP) cytotoxicity in MNNG/HOS cells. The authors' results showed that 400 SW pulses at 0.21 mJ/mm2 exhibited little influence on the MNNG/HOS cell viability. In addition, this SW condition significantly promoted the extracellular ATP release in MNNG/HOS cells. Importantly, low-energy SWs obviously increased Akt and mammalian target of rapamycin (mTOR) phosphorylation and activation in MNNG/HOS cells, which could be partially reversed in the presence of P2X7 siRNA. The authors also found that low-energy SWs strongly increased the DDP sensitivity of MNNG/HOS cells in the absence of P2X7. Conclusions: For the first time, the authors found that SW therapy reduced the DDP resistance of MNNG/HOS osteosarcoma cells when the ATP receptor P2X7 was downregulated. SW therapy may provide a novel treatment strategy for chemoresistant human osteosarcoma.

Direct de/carboxylation of cannabidiolic acid (CBDA) and cannabidiol (CBD) from hemp plant material under supercritical CO2.

Many organic reactions rely on CO2 sources to generate important structural units and valuable chemicals. In this study, we compared the effects of cannabidiol (CBD) and cannabidiolic acid (CBDA) on the supercritical CO2 (scCO2)-induced de/carboxylation reaction. The results showed that CBD was directly carboxylated in the ortho-position to form CBDA with up to 62% conversion. Meanwhile, CBDA decarboxylation occurred on hemp plant material via varying composition. Mechanistic studies revealed that CBD carboxylation was influenced not only by the physical properties of scCO2, but also by the vegetable matrix.

Digital economy: an effective path for promoting residents' health in China.

The primary prerequisite for socioeconomic growth is good health, hence promoting residents' health is a vital objective of public policies. It is yet up for debate whether or not the digital economy (DE), which will be crucial to future economic growth, will eventually result in improvements in residents' health. Utilizing the China Family Panel Studies (CFPS) data in 2020, we explore how the DE affects residents' health. The findings reveal that residents' health is greatly enhanced by the DE. The eastern region sees a more dramatic improvement in residents' health as a result of the DE. Additionally, the DE can improve residents' health through the promotion of regional green development. The study's findings add to our knowledge of how the DE impacts residents' health while also offering recommendations for achieving universal health.

Epidemiological characteristics and temporal-spatial clustering analysis on human brucellosis in Jiangsu Province, 2006-2021.

The marked increase in the incidence rate of brucellosis is a serious public health concern in Jiangsu Province. However, its temporal and spatial distribution has not been studied in depth. The main purpose of this study is to depict the demographic, temporal and spatial distribution patterns and clustering characteristics of brucellosis cases in Jiangsu Province, China, from 2006 to 2021 to develop and implement effective scientific prevention and control strategies. Data for human brucellosis cases in Jiangsu Province from 2006 to 2021 were obtained from the Nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS). Spatial autocorrelation analysis and temporal-spatial scan statistics were used to identify potential changes in the spatial and temporal distributions of human brucellosis in Jiangsu Province. During the years 2006-2021, 1347 brucellosis cases were reported in Jiangsu Province, with an average annual incidence rate of 0.1036 per 100,000 individuals. Middle-aged and elderly individuals (aged 40-69 years) were the main infected populations, accounting for 69.72% (939/1347) of all reported cases. The incidence of brucellosis in Jiangsu showed a long-term increasing trend and displayed pronounced seasonal variations, with the peak occurring between April and June annually. The incidence gradually expanded from the northern and southern areas to the central areas between 2006 and 2021. Global spatial autocorrelation analysis demonstrated a positive correlation in the incidence of brucellosis between 2008 and 2012-2021. Temporal-spatial clustering analysis showed that the primary cluster was detected in the northern, highly endemic regions of Jiangsu, and the three secondary clusters were in areas where there had been outbreaks of brucellosis. Human brucellosis remains a serious public health issue in Jiangsu Province. Northern and southern Jiangsu regions, with high rates of brucellosis, may require special plans and measures to monitor and control the disease. Additionally, the capacity to respond to outbreaks in high-incidence areas should be improved to prevent further brucellosis outbreaks.

ATGL promotes colorectal cancer growth by regulating autophagy process and SIRT1 expression.

CRC is a common malignant tumor in the gastrointestinal tract, and its incidence has increased significantly in recent years. Several studies revealed that lipid metabolism reprogramming contributed to tumorigenicity and malignancy by interfering with energy production, membrane formation, and signal transduction in cancers. ATGL is a kind of hydroxy fatty acid ester of fatty acid synthase, and its role in tumor remains controversial. We compared levels of adipose triglyceride lipase (ATGL) in human CRC specimens to adjacent specimens. To validate the effect of ATGL on the proliferation ability of CRC, CCK8 assay and clone formation assay were performed. To evaluate whether autophagy process takes part in the effect of ATGL on CRC proliferation, the value of LC3-II/LC3-I was detected by western blot and we blocked the SIRT1 to detect value of LC3-II/LC3-I and p62 via western blot. In the end, we detected the value of SIRT1 in CRC specimens. We found that ATGL showed high expression in CRC and positively correlated with clinical stage, indicating poor prognosis of CRC. Moreover, ATGL significantly promoted tumor cell proliferation in vitro. Mechanistically, ATGL promoted CRC cells proliferation by blocking mTOR signaling pathway and activating autophagy process. Further, ATGL regulated autophagy process through triggering SIRT1 expression. Our results reveal that ATGL promotes colorectal cancer growth by up regulating autophagy process and SIRT1 expression.

Biomechanical analysis of a novel bone cement bridging screw system combined with percutaneous vertebroplasty for treating Kummell's disease.

Kummell's Disease (KD) was originally proposed by Dr. Hermann Kummell in 1891 as a type of delayed posttraumatic vertebral collapse, which is a clinical phenomenon. The purpose of this experiment is to compare the strength of bone cement and the novel bone cement bridging screw in the treatment of thoracolumbar Kummell disease (KD) with other treatment methods. Thirty sheep spine specimens were selected. T12 to L2 segments were selected, and a KD intravertebral vacuum cleft model was made at the L1 segment. According to the ways of cement filling, the specimens were divided into percutaneous vertebroplasty (PVP), PVP combined with unilateral percutaneous pediculoplasty (PPP), PVP combined with bilateral PPP, unilateral novel bone cement bridging screw system combined with PVP, and bilateral cement bridging screw system combined with PVP groups. There were two experiments: three-dimensional biomechanical strength test and axial compression test. In the three-dimensional biomechanical strength test, we measured the strength of bone cement in specimens under six motion states, including flexion, extension, left bending, right bending, and left and right axial rotations. In the axial compression test, we detected the maximum axial pressure that the bone cement could withstand when it was under pressure until the bone cement was displaced. The unilateral or bilateral novel bone cement bridging screw with PVP groups had the best strength under flexion, extension, left bending, right bending, and had better biomechanical strength, with a significant difference from the other three groups (p < 0.05). There was no significant difference between the unilateral or bilateral novel bone cement bridging screw with PVP groups (p > 0.05). Unilateral and bilateral novel bone cement bridging screw could achieve similar bone cement strength. Compared with the other three groups, the unilateral or bilateral novel bone cement bridging screw with PVP groups are higher 136.35%, 152.43%; 41.93%, 51.58%; 34.37%, 43.50% respectively. The bilateral novel bone cement bridging screw with PVP could bear the largest pressure under vertical force. To conclude, the novel bone cement bridging screw can increase the strength of bone cement and avoid the loosening and displacement of bone cement in the treatment of KD of the thoracolumbar spine.

Screening Physical Solvents for Methyl Mercaptan Absorption Using Quantum Chemical Calculation Coupled with Experiments.

This work presents a screening method of physical solvents for methyl mercaptan (MeSH) absorption using quantum chemical calculations. The absorption solubility and thermodynamic behaviors of dimethyl sulfoxide (DMSO), sulfolane (SUL), propylene carbonate (PC), N,N-dimethylformamide (DMF), and 1-methyl-2-pyrrolidinone (NMP) for MeSH were calculated and analyzed using the COSMO-RS model, and the absorption mechanism was probed combining the quantum theory of atoms in molecules (QTAIM) and reduced density gradient (RDG). Results show that the absorption solubility of the five solvents for MeSH by COSMO-RS model calculations follow the order of NMP > PC > DMSO > SUL > DMF, and the van der Waals forces and hydrogen bond forces determine the absorption solubility of physical solvents for MeSH. In addition, the experimental results of MeSH Henry coefficients in the above five solvents follow the same order as the calculated results. However, the calculated Henry coefficients' value largely deviates from the experimental value; therefore, we believe that this calculation method is only available for qualitative screening. This work provided a feasible approach to screening high-performance physical solvents for MeSH removal.

YAP-galectin-3 signaling mediates endothelial dysfunction in angiotensin II-induced hypertension in mice.

BACKGROUND: Vascular endothelial dysfunction is regarded as an early event of hypertension. Galectin-3 (Gal-3) is known to participate in various pathological processes. Whilst previous studies showed that inhibition of Gal-3 effectively ameliorates angiotensin II (Ang II)-induced atherosclerosis or hypertension, it remains unclear whether Ang II regulates Gal-3 expression and actions in vascular endothelium. METHODS: Using techniques of molecular biology and myograph, we investigated Ang II-mediated changes in Gal-3 expression and activity in thoracic aortas and mesenteric arteries from wild-type and Gal-3 gene deleted (Gal-3-/-) mice and cultured endothelial cells. RESULTS: The serum level of Gal-3 was significantly higher in hypertensive patients or in mice with chronic Ang II-infusion. Ang II infusion to wild-type mice enhanced Gal-3 expression in the aortic and mesenteric arteries, elevated systolic blood pressure and impaired endothelium-dependent relaxation of the thoracic aortas and mesenteric arteries, changes that were abolished in Gal-3-/- mice. In human umbilical vein endothelial cells, Ang II significantly upregulated Gal-3 expression by promoting nuclear localization of Yes-associated protein (YAP) and its interaction with transcription factor Tead1 with enhanced YAP/Tead1 binding to Gal-3 gene promoter region. Furthermore, Gal-3 deletion augmented the bioavailability of nitric oxide, suppressed oxidative stress, and alleviated inflammation in the thoracic aorta of Ang II-infused mice or endothelial cells exposed to Ang II. CONCLUSIONS: Our results demonstrate for the first time that Ang II upregulates Gal-3 expression via increment in YAP nuclear localization in vascular endothelium, and that Gal-3 mediates endothelial dysfunction contributing to the development of hypertension.

Treatment of pediatric tibial shaft nonunion using ipsilateral free non-vascularized fibular graft.

BACKGROUND: Although tibial shaft fractures are the third most common long bone fractures in children after the forearm and femur, nonunion of these fractures are rare in the pediatric population. CASE REPORT: Despite seldom seen, tibial nonunion is very complex and it is also a devastating complication of tibial fracture especially when infected. Numerous methods have been employed to treat pediatric tibial nonunion, but there is no consensus. Here, we present a case of a child with right tibial shaft fracture nonunion. We treated this patient with ipsilateral free non-vascularized fibular graft. RESULTS: Both the nonunion site and fibular donor site united well with good function in the injured extremity and no adverse events. CONCLUSION: We recommend the use of ipsilateral free non-vascularized fibular graft for the treatment of pediatric tibial shaft nonunion.

A novel peptide hydrogel of metal ion clusters for accelerating bone defect regeneration.

In the absence of adequate treatment, effective bone regeneration remains a great challenge. Exploring hydrogels with properties of excellent bioactivity, stability, non-immunogenicity, and commercialization is an important step to develop hydrogel-based bone regeneration materials. In this study, we engineered a self-assembled chelating peptide hydrogel loaded with an osteogenic metal ion cluster extracted from the processed pyritum decoction, including Fe2+, Cu2+, Zn2+, Mn2+, Mg2+, and Ca2+ ions, named processed pyritum hydrogel (PPH). We demonstrated that as a reservoir of beneficial metal ion clusters in bone regeneration, PPH has been shown to regulate a variety of genes in the process of bone regeneration. These genes are mainly involved in extracellular matrix synthesis, cell adhesion and migration, cytokine expression, antimicrobial and inflammation. Therefore, PPH accelerated the progress of various bone healing stages, and shortened the bone healing cycle by 4 weeks. Our investigation outcomes showed that the engineered metal ion cluster hydrogel is a novel, simple, and commercializable bone-regenerating hydrogel with potential clinical use.

Influence of Internet Use on Commercial Health Insurance of Chinese Residents.

As a necessary supplement to social medical insurance, commercial health insurance is an important part of the Healthy China strategy. This study, based on the Chinese General Social Survey (CGSS) data in 2017, uses the probit model to analyze and study the internal relationship between Internet use and commercial health insurance purchase of urban and rural residents. The research results show that the use of the Internet significantly promoted commercial health insurance purchases of residents, and the promotion effect for rural residents is apparently better than that among urban residents. In addition, the social level of residents is improved through the use of Internet, which can promote commercial health insurance purchases. It provides a significant reference value for the effective integration of Internet use and commercial health insurance, and the high-quality development of the modern insurance industry.

Dual pH and Temperature-Sensitive Nanogels Loaded with Eugenol for Regulating Central Nervous System.

Fragrances have many biological activities such as anti-anxiety, anti-depression, and improving cognitive memory. However, most fragrances are so volatile that the useful lifespan of the fragrances is very short and excessive fragrance concentration makes us uncomfortable. In this study, dual pH and temperature-sensitive nanogels named EG@CPMONGs were prepared to encapsulate eugenol. This nano-fragrance was then applied to silk. In the following, the effects of EG@CPMO-NGs on the regulation of central nervous systems were evaluated. Open-field tests showed that EG@CPMONGs had an obvious effect on stress relief. Elevated plus-maze tests proved the significant effect of EG@CPMO-NGs on anti-anxiety. Morris water maze tests demonstrated the positive impact of nano-fragrance on spatial learning and memory. Therefore, these dual pH and temperature-sensitive nanogels loaded with eugenol had significant and positive effects on the central nervous system.

Sulfur recycle in biogas production: Novel Higee desulfurization process using natural amino acid salts.

In this work, a desulfurization method using natural amino acid salts (AAS), which can be green prepared by biological fermentation, is proposed to remove H2S from raw biogas. Biogas purification and fertilizer production can be simultaneously achieved to close sulfur recycle. The reaction kinetic characteristics of H2S absorption with three kinds of AAS, including potassium ß-alaninate (PA), potassium sarcosinate (PS) and potassium l-prolinate (PP) are first studied. Kinetic parameters including orders of reaction, rate constants, pre-exponential factors and activation energies are given. AAS absorbent exhibits good potential for biogas desulfurization. Higee (high gravity) technology is utilized to intensify H2S removal. The effects of operating conditions on H2S removal efficiency are investigated and PP shows the best desulfurization performance. The phytotoxicity of AAS and amino acid salt sulfide (AASS) is assessed by the germination index of mungbean seeds. PP and its salt sulfide (PPS) show relatively low phytotoxicity and their allowable agricultural feeding concentrations are below 0.08 M and 0.04 M, respectively. The desulfurization method demonstrates a green route for biogas purification to achieve sulfur recycle.

Association between serum arsenic and oral cancer risk: A case-control study in southeast China.

OBJECTIVES: Evidence on serum arsenic and oral cancer risk was limited. We aimed to evaluate the association between serum arsenic and the risk of oral cancer in a southeast China population. METHODS: Serum arsenic was determined for 325 oral cancer patients and 648 controls using inductively coupled plasma-mass spectrometry (ICP-MS). Logistic regression and restricted cubic spline were analysed the association between serum arsenic level and oral cancer risk, and crude and adjusted odds ratios (aOR) with 95% confidence interval (95% CI) were calculated. Factors adjusted for included age, gender, BMI, smoking, drinking, education, residence, marital status and dietary factors. Stratification analysis was further performed according to drinking, smoking and dietary characteristics. RESULTS: Serum arsenic level was lower in the case group (P50  = 19.2µg/L, IQR = 11.6 ~ 26.4µg/L) than in the control group (P50  = 30.2 µg/L, IQR = 25.0 ~ 36.4 µg/L). An inverse but nonlinear association was observed between arsenic level and oral cancer risk by restricted cubic spline. These with moderate serum arsenic levels had a lower risk of oral cancer than those with low levels (OR = 0.11; 95%CI: 0.07-0.18), after adjusting for demographic and dietary intake factors. We also kept serum arsenic as a continuous variable in a regression model, where a similar inverse association between arsenic and oral cancer was observed, with OR = 0.86 (95%CI: 0.84-0.88). Stratification analysis revealed no significant multiplicative interactions between serum arsenic and smoking, drinking or dietary intake. CONCLUSION: Serum arsenic is inversely related to oral cancer risk. Relative to those with low levels of arsenic, people with moderate serum arsenic levels had a lower risk of oral cancer. If confirmed, serum arsenic level may be a useful predictive marker for oral cancer risk.

Neurocognitive deficits and sequelae following severe hand, foot, and mouth disease from 2009 to 2017, in JiangSu Province, China: a long-term follow-up study.

BACKGROUND: The aim of this study was to evaluate the long-term sequelae and cognitive profiles resulting from severe hand, foot, and mouth disease (HFMD) with central nervous system (CNS) involvement. METHODS: 294 HFMD cases were included in a retrospective follow-up study. Physical examinations were conducted. The Chinese Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was used to assess intelligence. RESULTS: 58 mild HFMD cases and 99 severe HFMD cases with mild CNS involvement did not present any neurological sequelae. In comparison, the sequelae incidence for severe HFMD with more severe CNS complications was 50.0%. The proportion of full-scale intelligence quotient (FSIQ) impairment was 45.0%. In the 2:6-3:11 age group, severe HFMD with more severe CNS complications and lower maternal education level were risk factors for verbal comprehension disorder. Urban-rural residence and lower paternal education level were risk factors for FSIQ disorder. Furthermore, in the 4:0-6:11 age group, severe HFMD with more severe CNS complication was a risk factor for visual spatial disorder and fluid reasoning disorder. Lower paternal education level was a risk factor for FSIQ disorder. CONCLUSION: Early assessment and intervention among severe HFMD patients with more severe CNS involvement at a very young age will prove beneficial for their future performance.

Influence of Commercial Insurance Purchase on the Health Status of Chinese Residents.

Under the context of rapid economic and social development, and growing demands for a better life, Chinese residents have been increasingly concerned with their health status and issues. In this study, the internal relations between the purchase of commercial insurance by residents and their health status are analyzed and studied with a polytomous logit model based on the data of Chinese General Social Survey (CGSS) in 2015. According to the research result, purchase of commercial insurance significantly improved the health status of residents, with an improving effect for rural residents apparently better than that among urban residents. In addition, purchase of commercial insurance can promote the health status of residents by increasing their household income. This research will provide an effective reference for the innovative development and medical reform of the commercial insurance of China in the future, which is theoretically and practically significant to the implementation of the Healthy China Strategy.

Functional outcomes and adverse effects following three interventions for displaced midshaft clavicular fractures: A Bayesian network meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of the most commonly used interventions for clavicle fractures remains controversial. These interventions are: open reduction and plate fixation (ORPF), non-surgical intervention (NSI), and use of an intramedullary nail (IMN). In adult patients with clavicle fractures, choosing which intervention might be best is challenging. MATERIALS AND METHODS: PubMed, Journals@Ovid Full Text, Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and Embase were performed to search English-language studies from the inception to February 2020. Randomized controlled trials (RCTs) comparing any of these three interventions were included. Patient and baseline characteristics, nonunion, major complications, Constant-Murley score (CMS), and Disabilities of the Arm, Shoulder and Hand score (DASH) were extracted. Then, we evaluated the functional outcomes and adverse effects after use of these three interventions for the management of displaced midshaft clavicle fractures in a Bayesian network meta-analysis. RESULTS: A Bayesian random-effects model was conducted, and nonunion and major complications were evaluated with: risk ratio (RR) and 95% confidential interval (CI); while CMS and DASH were evaluated with mean differences (MD) and the corresponding 95% confidential interval CI. The rank probability of each endpoint was assessed on the basis of the surface area under the cumulative ranking curve (SUCRA). DISCUSSION: ORPF is most likely to be successful in achieving objective functional outcomes as captured by the CMS, and IMN demonstrates significant efficacy for subjective functional outcomes, as captured by DASH scores. Compared with the other interventions examined, IMN was associated with decreased risk for adverse effects. LEVELS OF EVIDENCE: I; meta-analysis.

CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death.

Hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. In this study, the effects of CASK in HCC were investigated using gain- or loss-of-function strategies by performing cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy, tumor xenograft experiment and immunohistochemistry staining. The current results suggested that CASK expression was positively associated with sorafenib resistance and poor prognosis of HCC. Moreover, inhibition of CASK increased the role of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite effects. Besides, when treatment with sorafenib, inhibition of apoptosis using the pan-caspase inhibitor Z-VAD-FMK and inhibition of autophagy using autophagy inhibitor 3-Methyladenine (3-MA) or small interfering RNA (siRNA) of LC3B all significantly reversed CASK knockout-induced effects, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with siRNA targeting JNK significantly attenuated CASK knockout-mediated autophagic cell death. Collectively, all these results together indicated that CASK might be a promising biomarker and a potential therapeutic target for HCC patients.

Shikonin inhibits migration and invasion of triple-negative breast cancer cells by suppressing epithelial-mesenchymal transition via miR-17-5p/PTEN/Akt pathway.

Background: Triple-negative breast cancer (TNBC) is a great threat to global women's health due to its high metastatic potential. Epithelial-to-mesenchymal transition (EMT) is considered as a key event in the process of metastasis. So the pharmacological targeting of EMT might be a promising strategy in improving the therapeutic efficacy of TNBC. Here, we investigated the effect of shikonin exerting on EMT and consequently the metastasis of TNBC cells and its underlying mechanism. Methods: The invasive and migratory capacities of MDA-MB-231 and BT549 cells were tested using transwell invasion and wound healing assay. MiR-17-5p expression was examined by qRT-PCR. MiR-17-5p targeted genes were predicted with different bioinformatic algorithms from four databases (TargetScan, miRanda, PITA and picTar) and further screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The differential expressions of predicted genes and their correlations with miR-17-5p were identified in breast cancer patients based on The Cancer Genome Atlas (TCGA) database. The interaction between phosphatase and tensin homolog deleted on chromosome ten (PTEN) and miR-17-5p was analyzed by luciferase reporter assay. The overexpression vector and small interfering RNA were constructed to investigate the role PTEN played in metastasis and EMT regulation. The expressions of EMT markers, protein kinase B (Akt) and phospho-Akt (p-Akt) were evaluated by western blot. Results: Shikonin suppressed the migration and invasion of MDA-MB-231 and BT549 cells and meanwhile the corresponding alterations of EMT biomarkers were observed in shikonin treated MDA-MB-231 cells. Shikonin inhibited the expression of miR-17-5p, which was upregulated in breast cancer. The 3'-untranslated region (3'-UTR) of PTEN was found to be direct binding target of miR-17-5p by luciferase reporter assays. PTEN functioned as a suppressor both in the metastasis and EMT of TNBC cells. Moreover, Akt and p-Akt (Ser473) were involved in the process of inhibition in cancer cell migration, invasion and EMT by shikonin. Conclusions: Shikonin inhibits migration and invasion of TNBC cells by suppressing EMT via miR-17-5p/PTEN/Akt pathway. This suggests shikonin as a promising therapeutic agent to counteract metastasis in the TNBC patients.

AMPK upregulates KCa2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice.

The opening of endothelial small-conductance calcium-activated potassium channels (KCa2.3) is essential for endothelium-dependent hyperpolarization (EDH), which predominantly occurs in small resistance arteries. Adenosine monophosphate-activated protein kinase (AMPK), an important metabolic regulator, has been implicated in regulating endothelial nitric oxide synthase activity. However, it was unclear whether AMPK regulated endothelial KCa2.3-mediated EDH-type vasodilation. Using bioinformatics analysis and myograph system, we investigated the regulation by AMPK of KCa2.3 in human umbilical vein endothelial cells (HUVECs) or mouse second-order mesenteric resistance arteries. In HUVECs, AMPK activation either by activators (AICAR, A769662 and MK-8722) or expression of the constitutively active form of AMPK significantly upregulated KCa2.3 expression. Such effects were abolished by AMPK inhibitor (compound C) or AMPK α1-/α2-siRNA, extracellular-signal-regulated-kinase 5 (ERK5) inhibitor (ERK5-IN-1), and specific siRNA to myocyte-enhancer factor 2 (MEF2) or krüppel-like factor 2/4 (KLF2/4). KCa2.3 expression was significantly reduced in mesenteric resistance arteries in AMPKα2 knockout mice when compared with littermate control mice. Furthermore, in high-fat diet fed mice, 2-week treatment with AICAR restored endothelial KCa2.3 expression in mesenteric resistance arteries with improved endothelial dysfunction. Our results demonstrate that activation of AMPK upregulates KCa2.3 channel expression through the ERK5-MEF2-KLF2/4 signaling pathway in vascular endothelium, which contributes to benefits through KCa2.3-mediated EDH-type vasodilation in mesenteric resistance arteries.