Bifunctional TRPV1 Targeted Magnetothermal Switch to Attenuate Osteoarthritis Progression.

Transient receptor potential vanilloid family member 1 (TRPV1) has been revealed as a therapeutic target of osteoarthritis (OA), the most common deteriorating whole joint disease, by impeding macrophagic inflammation and chondrocytes ferroptosis. However, the clinical application for capsaicin as the TRPV1 agonist is largely limited by its chronic toxicity. To address this issue, we developed a bifunctional controllable magnetothermal switch targeting TRPV1 for the alleviation of OA progression by coupling of magnetic nanoparticles (MNPs) to TRPV1 monoclonal antibodies (MNPs-TRPV1). Under the alternating magnetic field (AMF) stimulation, MNPs-TRPV1 locally dissipated heat, which was sufficient to trigger the opening and activation of TRPV1, and effectively impeded macrophagic inflammation and chondrocyte ferroptosis. This magnetothermal modulation of TRPV1 simultaneously attenuated synovitis and cartilage degeneration in mice incurred by destabilization of medial meniscus surgery, indicating the delayed OA progression. Furthermore, MNPs-TRPV1 with AMF exposure remarkably reduced knee pain sensitivity, alleviated the crippled gait, and improved spontaneous ambulatory activity performance in the mice OA model. Overall, this work provides a potential pathogenesis-based precise OA therapy with temporally and spatially magnetothermal modulation of TRPV1 in a controllable manner.

Mettl3-mediated m6A modification plays a role in lipid metabolism disorders and progressive liver damage in mice by regulating lipid metabolism-related gene expression.

AIMS: N6-methyladenosine (m6A), the most abundant and conserved epigenetic modification of mRNA, participates in various physiological and pathological processes. However, the roles of m6A modification in liver lipid metabolism have yet to be understood entirely. We aimed to investigate the roles of the m6A "writer" protein methyltransferase-like 3 (Mettl3) in liver lipid metabolism and the underlying mechanisms. MAIN METHODS: We assessed the expression of Mettl3 in liver tissues of diabetes (db/db) mice, obese (ob/ob) mice, high saturated fat-, cholesterol-, and fructose-induced non-alcoholic fatty liver disease (NAFLD) mice, and alcohol abuse and alcoholism (NIAAA) mice by quantitative reverse-transcriptase PCR (qRT-PCR). Hepatocyte-specific Mettl3 knockout mice were used to evaluate the effects of Mettl3 deficiency in mouse liver. The molecular mechanisms underlying the roles of Mettl3 deletion in liver lipid metabolism were explored by multi-omics joint analysis of public data from the Gene Expression Omnibus database and further validated by qRT-PCR and Western blot. KEY FINDINGS: Significantly decreased Mettl3 expression was associated with NAFLD progression. Hepatocyte-specific knockout of Mettl3 resulted in significant lipid accumulation in the liver, increased serum total cholesterol levels, and progressive liver damage in mice. Mechanistically, loss of Mettl3 significantly downregulated the expression levels of multiple m6A-modified mRNAs related to lipid metabolism, including Adh7, Cpt1a, and Cyp7a1, further promoting lipid metabolism disorders and liver injury in mice. SIGNIFICANCE: In summary, our findings demonstrate that the expression alteration of genes related to lipid metabolism by Mettl3-mediated m6A modification contributes to the development of NAFLD.

Exploration of Breakdown Strength Decrease and Mitigation of Ultrathin Polypropylene.

Polypropylene film is the most important organic dielectric in capacitor technology; however, applications such as power electronic devices require more miniaturized capacitors and thinner dielectric films. The commercial biaxially oriented polypropylene film is losing the advantage of its high breakdown strength as it becomes thinner. This work carefully studies the breakdown strength of the film between 1 and 5 microns. The breakdown strength drops rapidly and hardly ensures that the capacitor reaches a volumetric energy density of 2 J/cm3. Differential scanning calorimetry, X-ray, and SEM analyses showed that this phenomenon has nothing to do with the crystallographic orientation and crystallinity of the film but is closely related to the non-uniform fibers and many voids produced by overstretching the film. Measures must be taken to avoid their premature breakdown due to high local electric fields. An improvement below 5 microns will maintain a high energy density and the important application of polypropylene films in capacitors. Without destroying the physical properties of commercial films, this work employs the ALD oxide coating scheme to augment the dielectric strength of a BOPP in the thickness range below 5 µm, especially its high temperature performance. Therefore, the problem of the reduction in dielectric strength and energy density caused by BOPP thinning can be alleviated.

The Service Capability of Primary Health Institutions under the Hierarchical Medical System.

BACKGROUND: Primary health institutions (PHIs) are the foundation of the whole health system and the basic link to achieve the goal of all people enjoying primary health care. However, the service capability of primary health institutions is not under the hierarchical medical system. METHOD: Data were collected from the China Health Statistics Yearbook between 2014 and 2020. PHIs included community health centres, community health stations, and township hospitals in our study. The service capability of primary health institutions was analysed from the perspective of structure, process, and results. Structure capability was evaluated using the number of beds, number of personnel, number of health technicians, and proportion of the number of personnel in PHIs accounting for the total number of health personnel. Process capability was evaluated using the number of general practitioners. The number of outpatients and inpatients, medical income, the proportion of drug income, and the average number of patients and beds served by physicians in PHIs per day were employed to evaluate the resulting capability. RESULTS: From 2014 to 2020, the number of community health service centres/stations increased, while the number of township health centres decreased. In the aspect of structure capability, the total number of personnel and health technicians in community health centres/stations and township hospitals both increased during 2014 and 2020. However, the increasing rate in PHIs was a little bit less than that of general medical institutions. The proportion of male health technicians in community health centres and township hospitals both decreased, while the proportion of female technicians in both increased. From 2014 to 2020, the number of beds in PHIs also increased from 138.12 × 104 to 164.94 × 104. However, the proportion of beds in PHIs accounting for the total number of beds in medical institutions decreased. For the resulting capability, from 2014 to 2019, the proportion of diagnosis and treatment times in PHIs decreased from 57.41% to 51.96%, although it increased in 2020. The proportion of inpatients in PHIs decreased from 20.03% to 16.11%. From 2014 to 2020, the utilisation rate of hospital beds in PHIs decreased (from 55.6% to 34% for community health centres and 60.5% to 53.6% for township hospitals). The average daily bed days of doctors in township hospitals was higher than that of doctors in community health service centres. However, the average medical cost of outpatients and the per capita medical cost of inpatients in community health service centres were higher than in township hospitals. CONCLUSION: In recent years, although the service capability showed an increasing trend in PHIs, the growth rate was lower than the general health institutions. The utilisation rates of PHIs, including beds and physicians, were decreased. Among PHIs, the utilisation in township hospitals was higher than in community health centres with a relatively low price. Under the hierarchical medical system and normalisation period of the COVID-19 epidemic, it is important to improve the service capability to achieve its goal of increasing PHI utilisation and decreasing secondary and tertiary hospital utilisation.

Addition of chemoradiotherapy to palliative chemotherapy in de novo metastatic nasopharyngeal carcinoma: a real-world study.

BACKGROUND: To determine whether concurrent chemotherapy is necessary during locoregional radiotherapy (RT) after palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (mNPC). METHODS: A total of 746 patients with mNPC from 2000 to 2017 at our hospital were retrospectively reviewed. Among them, 355 patients received PCT followed by RT. Overall survival (OS) and progression-free survival (PFS), including locoregional progression-free survival (LRPFS) and distant progression-free survival (DPFS) were estimated with the Kaplan-Meier method and log-rank test. Cox proportional-hazards models, landmark analyses, propensity score matching, and subgroup analyses were used to address confounding. RESULTS: Of the patients included in our study, 192 received radiotherapy alone after PCT (PCT + RT), and 163 received concurrent chemoradiotherapy after PCT (PCT + CCRT). The prognosis of PCT + CCRT was significantly better than that of PCT + RT (5 year OS, 53.0 vs 36.2%; P = 0.004). After matching, the 5 year OS rates of the two groups were 55.7 and 39.0%, respectively (P = 0.034) and the median DPFS were 29.4 and 18.7 months, respectively (P = 0.052). Multivariate Cox regression analysis indicated that PCT + CCRT was an independent favorable prognostic factor (P = 0.009). In addition, conducting concurrent chemoradiotherapy after 4-6 cycles of PCT or conducting concurrent chemotherapy with single-agent platinum was associated with significant survival benefit in the matched cohort (5 year OS rate, 60.4 or 57.4%, respectively). The survival difference between groups remained significant when evaluating patients who survived for ≥ 1 year (P = 0.028). CONCLUSIONS: The optimal treatment strategy of mNPC is the combination of PCT followed by concurrent chemoradiotherapy. More specifically, concurrent chemoradiotherapy with single-agent platinum after 4-6 cycles of PCT is suggested.

Effect of cardiac rehabilitation training on patients with coronary heart disease: a systematic review and meta-analysis.

BACKGROUND: In recent years, the incidence of heart disease has increased and patients are younger. Cardiac rehabilitation training has been proposed to improve the prognosis of patients with heart disease. Cardiac rehabilitation includes moderate-intensity continuous training (MCT) and high-intensity interval training (HIIT). These two training methods have different effects in improving the prognosis of patients. The aim of the present study was to improve reference for patients with cardiac rehabilitation. METHODS: English databases, including PubMed, Cochrane Library, and Embase, were searched from the establishment of the database to April 2021 for randomized controlled trials (RCTs) of rehabilitation training at different intensities. RevMan 5.3 was used for the meta-analysis. RESULTS: A total of 8 articles (with a total of 465 patients) were included, including 236 patients in the experimental group and 229 patients in the control group. Different intensities of training had statistically significant differences in peak oxygen uptake [mean difference (MD): 1.21, 95% confidence interval (CI): -0.66 to 3.07, P=0.20] and the left ventricular ejection fraction difference (MD: 2.53, 95% CI: -2.10 to 7.17, P=0.28). DISCUSSION: Cardiac rehabilitation training can effectively improve the patient's cardiac function indicators and self-care ability, and reduce the incidence of cardiovascular disease (CVD). However, large-sample, multicenter, and long-term RCTs are needed to strengthen the findings of the study.

GSK-3ß in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer.

Glycogen synthase kinase-3ß (GSK-3ß) is an evolutionarily conserved serine/threonine kinase, functioning in numerous cellular processes including cell proliferation, DNA repair, cell cycle, signaling and metabolic pathways. GSK-3ß is implicated in different diseases including inflammation, neurodegenerative disease, diabetes and cancers. GSK-3ß is involved in biological processes of tumorigenesis, therefore, it is rational that GSK-3ß inhibitors were employed to target malignant tumors. The effects of GSK-3ß inhibitors in combination of radiation and chemotherapeutic drugs have been reported in various types of cancers, suggesting GSK-3ß would play important roles in cancer treatments. GSK-3ß is involved in multiple signal pathway including Wnt/ß-catenin, PI3K/PTEN/AKT and Notch. GSK-3ß also functions in DNA repair through phosphorylation of DNA repair factors and affecting their binding to chromatin. This review focuses on the molecular mechanism of GSK-3ß in DNA repair, special in base excision repair and double-strands break repair, the roles of GSK-3ß in inhibition of apoptosis through activation of NF-κB, and the effects of GSK-3ß inhibitors on radio- and chemosensitization of various types of cancers. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.

Berberine activates caspase-9/cytochrome c-mediated apoptosis to suppress triple-negative breast cancer cells in vitro and in vivo.

Berberine (BBR) is an isoquinoline alkaloid isolated from Cotridis rhizoma and exhibits multiple biological roles including anti-microbe, anti-inflammation and anti-tumor activities. In this study, two triple-negative breast cancer cell (TNBC) lines, MDA-MB-231 and BT549, were used to investigate the effect of BBR on growth of TNBC in vitro and in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the viability of cells treated with BBR. After 48h treatments, a 50% inhibitory concentration (IC50) of BBR to BT549 and MDA-MB-231 cells are at 16.575±1.219µg/ml and 18.525±6.139µg/ml respectively. BBR reduced colony formation of BT549 and MDA-MB-231 cells. The wound-healing assay showed BBR decreased breast cancer cell migrations (P<0.01). AnnexinV-PI staining assay confirmed BBR induced cellular apoptosis. The expressions of caspase-3, caspase-9, Bcl-2 and Bax were detected by western blot, which showed BBR activated caspase-3, 9 and Bax, but down-regulated Bcl-2 expression. BBR promoted the release of cytochrome c through the immunofluorescent analysis (P<0.01). We also found BBR increased the level of cellular γH2AX and increased the expression of Ligase4, which suggests BBR induces the double-strand breaks (DSB). These results thus demonstrated that BBR induced DSB, subsequently increased the release of cytochrome c and eventually triggered the caspase9-dependent apoptosis. In addition, we used a MDA-MB-231 mouse-xenograftmodel to evaluate the effect of BBR on tumor growth. BBR suppressed tumor growth and increased caspase-9 levels in xenograft tumors through immunohistochemistry analysis (P<0.01). Taken together, these results demonstrate that BBR activates caspase-9/cytochrome c-mediated apoptosis to inhibit the growth of TNBC breast cancer cells in vitro and in vivo.

Scorpion venom heat-resistant peptide (SVHRP) enhances neurogenesis and neurite outgrowth of immature neurons in adult mice by up-regulating brain-derived neurotrophic factor (BDNF).

Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2'-dexoxyuridine (BrdU)-positive cells, BrdU-positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP.

Lipid production by Lipomyces starkeyi cells in glucose solution without auxiliary nutrients.

Two-stage fermentation process was used for lipid production by Lipomyces starkeyi AS 2.1560 in glucose solution without auxiliary nutrients. In the first stage, cells were cultivated in a nutrient-rich medium for propagation. In the second stage, cells were resuspended in glucose solution to achieve high cellular lipid contents. The effects of the inocula age, cell density and initial glucose concentration on lipid production were briefly studied. When high cell density fermentation was performed in a 7-L stirred-tank bioreactor for 40h using non-sterile glucose solution as carbon source, the biomass, lipid and lipid content reached 104.6g/L, 67.9g/L and 64.9%, respectively. More significantly, lipid productivity reached 2.0g/Lh during the initial 16h-period and 1.6g/Lh for the entire culture. Our results demonstrated that cell propagation and lipid accumulation processes can be spatially separated, allowing further optimization to improve both processes. The two-stage fermentation method should have a great potential to develop more efficient processes to convert renewable materials into biofuel and related products.

[Microbial lipid production by Rhodosporidium toruloides in a two-stage culture mode].

To shorten the cultivation time and reduce the consumption of raw materials for microbial lipid production, oleaginous yeast Rhodosporidium toruloides AS 2.1389 was cultivated using a two-stage culture mode, in which the cell propagation and lipid accumulation were separated. The yeast cells recovered from the propagation culture were re-suspended in glucose solution for lipid accumulation, through which lipid content over 55% of the dry cell weight was achieved, the longer the propagation stage was, the higher the lipid content. Analysis of the lipid indicated that the long-chain fatty acids with 16 and 18 carbon atoms were major components, suggesting that the lipid can be an alternative feedstock for biodiesel production.

[Mechanism of DNA transformation based on mineral nanofibers and method improvement].

Sepiolite--an inexpensive, resourceful, fibrous yet inoffensive mineral--made DNA transformation rapid, simple and efficient but the mechanism for DNA transformation was still unclear. Through RNA competition test, we proposed the different transforming mechanisms from the previous report. Meanwhile, we optimized the transforming method and could transfer a colony stored at 4 degrees C for a month with plasmid through sepiolite fibers. The cells could be transformed well without competent cells preparation or incubation process. In sum, this was a novel potential transforming method, which could be explored further if the chemical method and electroporation could not be used.