Triple-combination therapy did not improve prognosis in anti-MDA5 positive dermatomyositis: a multicentre longitudinal cohort study.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is frequently linked with interstitial lung disease (ILD), especially the rapidly progressive ILD (RP-ILD). We conduct this research to evaluate the efficacy and safety of triple-combination (triple-combo) therapy consisting of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide in treating MDA5+ DM patients with ILD. METHODS: A multicentre longitudinal cohort study involving 115 MDA5+ DM patients from the Nanjing Medical University Myositis Associated ILD (NMMI) cohort was conducted between January 2019 and November 2022. Patients were categorised into triple-combo and non-triple therapy groups, and their outcomes were assessed. RESULTS: Contrary to expectations, triple-combo therapy did not improve the prognosis for MDA5+ DM patients but was linked to increased mortality rates, especially among those at high risk for RP-ILD. CONCLUSIONS: Our study suggests that triple-combo therapy might not be effective in improving prognosis in MDA5+ DM patients. Further research is needed to establish safer and more effective treatment modalities for this patient population.

Retrospective analysis of patients with hepatocellular carcinoma complicated with human immunodeficiency virus infection after hepatectomy.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with a 5-year relative survival rate of approximately 18%. The similarity between incidence and mortality (830000 deaths per year) underscores the bleak prognosis associated with the disease. HCC is the fourth most common malignancy and the second leading cause of cancer death in China. Most patients with HCC have a history of chronic liver disease such as chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholism or alcoholic steatohepatitis, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis. Early diagnosis and effective treatment are the keys to improving the prognosis of patients with HCC. Although the total number of human immunodeficiency virus (HIV)-infected patients is declining globally the incidence of HCC is increasing in HIV-infected patients, especially those who are coinfected with HBV or HCV. As a result, people infected with HIV still face unique challenges in terms of their risk of developing HCC. AIM: To investigate the survival prognosis and clinical efficacy of surgical resection in patients with HCC complicated with HIV infection. METHODS: The clinical data of 56 patients with HCC complicated with HIV admitted to the Third Affiliated Hospital of Nantong University from January 2013 to December 2023 were retrospectively analyzed. Among these, 27 patients underwent hepatectomy (operation group) and 29 patients received conservative treatment (nonoperation group). All patients signed informed consents in line with the provisions of medical ethics. The general data, clinicopathological features and prognoses for the patients in the two groups were analyzed and the risk factors related to the prognoses of the patients in the operation group were identified. RESULTS: The median disease-free survival (DFS) and overall survival (OS) of HIV-HCC patients in the surgical group were 13 months and 17 months, respectively, and the median OS of patients in the nonsurgical group was 12 months. The OS of the surgical group was significantly longer than that of the control group (17 months vs 12 months, respectively; P < 0.05). The risk factors associated with DFS and OS in the surgical group were initial HIV diagnosis, postoperative microvascular invasion (MVI), a CD4+ T-cell count < 200/µL, Barcelona stage C-D, and men who have sex with men (MSM; P < 0.05). CONCLUSION: Hepatectomy can effectively prolong the survival of patients with HIV-HCC but MVI identified during postoperative pathological examination, late tumor detection, late BCLC stage, CD4+ T < 200/µL and MSM are risk factors affecting the survival and prognosis of patients undergoing hepatectomy. In addition, there were significant differences between the surgical group and the nonsurgical group in terms of the initial diagnosis of HIV, Child-Pugh score, alpha-fetoprotein measurement value, and HART-efficient antiretroviral therapy after the diagnosis of HIV (P < 0.05). Therefore, these factors may also affect the survival and prognosis of patients.

Flexible and Stretchable Photoelectrochemical Sensing toward True-to-Life Monitoring of Hydrogen Peroxide Regulation in Endothelial Mechanotransduction.

Hydrogen peroxide (H2O2) levels play a vital role in redox regulation and maintaining the physiological balance of living cells, especially in cell mechanotransduction. Despite the achievements on strain-induced cellular H2O2 monitoring, the applied voltage for H2O2 electrooxidation possibly gave rise to an abnormal expression and inadequate accuracy, which was still an inescapable concern. Hence, we decorated an interlaced CuO@TiO2 nanowires (NWs) semiconductor meshwork onto a polydimethylsiloxane film-supported gold nanotubes substrate (Au NTs/PDMS) to construct a flexible photoelectrochemical (PEC) sensing platform. Under white light irradiation, CuO@TiO2 NWs synergistically exhibited great stretchability and the PEC platform enabled stable photocurrent responses from the reduction of H2O2 even during mechanical deformation. Moreover, the admirable biocompatibility and an almost negligible open circuit voltage of +0.18 V for the CuO@TiO2 NWs/Au NTs/PDMS sensor guaranteed human umbilical vein endothelial cells (HUVECs) adhesion tightly thereon even under continuous illumination for 30 min. Finally, the as-proposed stretchable PEC sensor achieved sensitive and true-to-life monitoring of transient H2O2 release during HUVECs deformation, in which H2O2 release was positively correlated to mechanical strains. This investigation opens a new shade path on in situ cellular sensing and meanwhile greatly expands the application mode of the PEC approach.

DFT Investigation on Palladium-Catalyzed [2 + 2 + 1] Spiroannulation between Aryl Halides and Alkynes: Mechanism, Base Additive Role, and Solvent and Ligand Effects.

Transition metal-catalyzed spiroannulations are practical strategies for constructing spirocyclic skeletons of pharmaceutical and biological significance, yet the microscopic mechanism still lacks in-depth explorations. Here, the palladium-catalyzed [2 + 2 + 1] spiroannulation between aryl halides and alkynes was studied by employing the density functional theory (DFT) method. Based on comprehensive explorations on a couple of possible reaction pathways, it is found that the reaction probably experiences C-I oxidative addition, alkyne migration insertion, Cs2CO3-assisted aryl C-H activation, C-Br bond oxidative addition, C-C coupling, arene dearomatization and reductive elimination in sequence and leads to the formation of the spiro[4,5]decane pentacyclic product (P) ultimately. Among these, the C-Br bond oxidative addition step acts as the rate-determining step (RDS) of the whole reaction, featuring a practical free energy barrier of 32.4 kcal·mol-1 at 130 °C. Computationally predicted kinetics such as half-life transferred from the RDS step's barrier on the optimal reaction pathway (1.2 × 101 h) coincides well with corresponding experimental results (91% yield of the spiro[4,5]decane pentacyclic product P after reacting 10 h at 130 °C). In addition, theoretical predictions regarding the solvent/ligand effects and base additive role in the reaction, rationalized by distortion-interaction/natural population/noncovalent interaction analyses, are also in good agreement with experimental data and trend. This good agreement between experiment and theory makes sense for new designations and further experimental improvements of such Pd-catalyzed transformations.

Associations of circulating total p-cresylsulfate and indoxyl sulfate concentrations with central obesity in patients with stable coronary artery disease: sex-specific insights.

BACKGROUND/AIMS: Elevated systemic inflammation, common in obesity, increases cardiovascular disease risk. Obesity is linked to a pro-inflammatory gut microbiota that releases uremic toxins like p-cresylsulfate (PCS) and indoxyl sulfate (IS), which are implicated in coronary atherosclerosis, insulin resistance, and chronic kidney disease. This study examines the relationship between total PCS and IS levels and central obesity in patients with stable coronary artery disease (CAD). METHODS: A cross-sectional study was conducted on 373 consecutive patients with stable CAD from a single center. Serum levels of total PCS and IS were measured using an Ultra Performance LC System. Central obesity was evaluated using a body shape index (ABSI) and conicity index (CI). Six obesity-related proteins were also analyzed. Structural equation modeling (SEM) assessed direct and indirect effects of total PCS, IS, and the six obesity-related proteins on central obesity. RESULTS: Significant positive correlations were found between total PCS and IS with waist-to-hip ratio (WHR) (r = 0.174, p = 0.005 for total PCS; r = 0.144, p = 0.021 for IS), CI (r = 0.273, p < 0.0001 for total PCS; r = 0.260, p < 0.0001 for IS), and ABSI (r = 0.297, p < 0.0001 for total PCS; r = 0.285, p < 0.0001 for IS) in male patients, but not in female patients. Multivariate analysis showed higher odds ratios (ORs) for elevated CI (OR = 3.18, 95% CI: 1.54-6.75, p = 0.002) and ABSI (OR = 3.28, 95% CI: 1.54-7.24, p = 0.002) in patients with high PCS levels, and elevated CI (OR = 2.30, 95% CI: 1.15-4.66, p = 0.018) and ABSI (OR = 2.22, 95% CI: 1.07-4.72, p = 0.033) in those with high IS levels, compared to those with low toxin levels. SEM analysis indicated that total PCS and IS directly impacted central obesity indices and indirectly influenced central adiposity measures like WHR through high sensitivity C-reactive protein (hs-CRP) (ß = 0.252, p < 0.001). CONCLUSIONS: Circulating total PCS and IS contribute to central obesity in male patients with stable CAD, partially mediated by hs-CRP.

Three-dimensional atomic insights into the metal-oxide interface in Zr-ZrO2 nanoparticles.

Metal-oxide interfaces with poor coherency have specific properties comparing to bulk materials and offer broad applications in heterogeneous catalysis, battery, and electronics. However, current understanding of the three-dimensional (3D) atomic metal-oxide interfaces remains limited because of their inherent structural complexity and the limitations of conventional two-dimensional imaging techniques. Here, we determine the 3D atomic structure of metal-oxide interfaces in zirconium-zirconia nanoparticles using atomic-resolution electron tomography. We quantitatively analyze the atomic concentration and the degree of oxidation, and find the coherency and translational symmetry of the interfaces are broken. Atoms at the interface have low structural ordering, low coordination, and elongated bond length. Moreover, we observe porous structures such as Zr vacancies and nano-pores, and investigate their distribution. Our findings provide a clear 3D atomic picture of metal-oxide interface with direct experimental evidence. We anticipate this work could encourage future studies on fundamental problems of oxides, such as interfacial structures in semiconductor and atomic motion during oxidation process.

ResNet diagnosis of rotor faults in oil transfer pumps.

To address rotor imbalance and misalignment in oil transfer pumps, an innovative diagnostic framework using Residual Network (ResNet) is proposed. The model incorporates advanced signal processing algorithms and strategic sensor placement to enhance diagnostic efficacy. A fault simulation test rig captured vibration signals from eight key measurement points on the pump. One-dimensional and multi-dimensional signal processing techniques generated comprehensive datasets for training and validating the model. Sensor placement optimization, focusing on the bearing seat's axial direction, inlet flange's vertical direction, and outlet flange's axial direction, increased rotor fault sensitivity. Time-frequency data processed via Short-Time Fourier Transform (STFT) achieved the highest diagnostic accuracy, surpassing 98 %. This study highlights the importance of optimal signal processing and precise sensor placement in improving the accuracy of diagnosing rotor faults in oil transfer pumps, thus enhancing the operational reliability and efficiency of energy transportation systems.

Integrated analysis of facial microbiome and skin physio-optical properties unveils cutotype-dependent aging effects.

BACKGROUND: Our facial skin hosts millions of microorganisms, primarily bacteria, crucial for skin health by maintaining the physical barrier, modulating immune response, and metabolizing bioactive materials. Aging significantly influences the composition and function of the facial microbiome, impacting skin immunity, hydration, and inflammation, highlighting potential avenues for interventions targeting aging-related facial microbes amidst changes in skin physiological properties. RESULTS: We conducted a multi-center and deep sequencing survey to investigate the intricate interplay of aging, skin physio-optical conditions, and facial microbiome. Leveraging a newly-generated dataset of 2737 species-level metagenome-assembled genomes (MAGs), our integrative analysis highlighted aging as the primary driver, influencing both facial microbiome composition and key skin characteristics, including moisture, sebum production, gloss, pH, elasticity, and sensitivity. Further mediation analysis revealed that skin characteristics significantly impacted the microbiome, mostly as a mediator of aging. Utilizing this dataset, we uncovered two consistent cutotypes across sampling cities and identified aging-related microbial MAGs. Additionally, a Facial Aging Index (FAI) was formulated based on the microbiome, uncovering the cutotype-dependent effects of unhealthy lifestyles on skin aging. Finally, we distinguished aging related microbial pathways influenced by lifestyles with cutotype-dependent effect. CONCLUSIONS: Together, our findings emphasize aging's central role in facial microbiome dynamics, and support personalized skin microbiome interventions by targeting lifestyle, skin properties, and aging-related microbial factors. Video Abstract.

A Study on Overcoming Post-TACE Drug Resistance in HCC Based on Controllable Oxygen Release-Magnetic Hyperthermia Therapy.

Drug-eluting bead transcatheter arterial chemoembolization (D-TACE) is one of the first-line treatment for intermediate hepatocellular carcinoma (HCC). However, the dual hypoxia microenvironment, due to inherent tumor hypoxia and TACE-induced hypoxia, triggers drug resistance in HCC. To address this challenge, the study develops multicavitary microspheres capable of encapsulating oxygen and harnessing magnetic hyperthermia to enhance oxygen permeability. The novel multicavitary oxygen-encapsulated magnetothermal drug-eluting microspheres (OTD-Ms) effectively reduce hypoxia-related proteins (HIF-1α, VEGF-A) and drug resistance (P-gp) both in vitro and in vivo. Moreover, these microspheres demonstrate improved TACE efficacy and enhance survival rates in a rabbit VX-2 tumor model, suggesting their potential for HCC treatment.

Study on the cost-control effect of diagnosis-related groups based on meta-analysis.

OBJECTIVE: To evaluate the effect of diagnosis-related group (DRG) payment method systematically before and after implementation in terms of average hospitalization day, cost and care quality. METHOD: Restricted the period from 2019 to May 31, 2023, we use 6 databases from CNKI, Wipu, Wanfang, PubMed, ScienceDirect, and web of science. With the related study, we extract the data about DRG, then we conducted meta-analysis of the data about length of stay (LOS) and cost by RevMan 5.4 and Stata 12.0 software. Care quality is in conjunction with literature reports. RESULT: About 24 articles were included, covering 2 indicators: average hospitalization expenses and days. Meta-analysis shows that implementing DRG payment method has an advantage in terms of average hospital stay (pooled effect: -1.13%, 95% CI: -1.42 to -0.84, P = .00), and the difference is statistically significant. There is also an advantage in average hospitalization expenses (pooled effect: -2.58, 95% CI: -3.38 to -1.79, P = .00), and the difference is statistically significant. CONCLUSION: The use of DRG payment method can effectively reduce LOS and average hospitalization expenses. However, quality of care may decline with DRG adoption.

[Pollution Assessment and Source Apportionment of Heavy Metals in the Surrounding Soil of Typical Mining Areas in Tongling, Anhui Province].

To study the level of heavy metal pollution and ecological risks in the soil around typical mining areas in Tongling, a total of 150 soil samples were collected from the study area. The content characteristics of 10 elements, namely, As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Fe, and Zn, in the soils were analyzed. Methods including enrichment factor, the geo-accumulation index, single-factor pollution index, Nemero comprehensive pollution index, and potential ecological risk index were used to evaluate the pollution status of heavy metals in the soil of the study area. The pollution sources of heavy metals in the soil were also analyzed using correlation analysis, cluster analysis, and principal component analysis. The results showed that except for Cr and Fe, the average contents of the other eight heavy metal elements were higher than the soil background values in the study area. Pb, Zn, As, Cu, and Cd had a high degree of variation and were significantly affected by external interference. The spatial distribution showed that both Cr and Ni showed a decreasing trend from the edge to the central region, whereas the other eight heavy metals showed a decreasing trend from the central region to the surrounding areas. The pollution level of Cd and Cu in the soil of the research area was relatively severe. The overall ecological risk was at a medium to low level. Cd and Hg were the main contributing factors. As, Cd, Cu, Fe, Mn, Pb, and Zn mainly came from agricultural, industrial, and transportation sources, whereas Cr and Ni were mainly from natural sources. However, the sources of Hg were relatively complex. The research results can provide a scientific basis for the prevention and control of soil heavy metal pollution in metal mining areas, as well as the remediation of mine pollution.

Discovery of lignans and curcuminoids as the effective inhibitors of pancreatic lipase: structure-activity relationship and inhibitory mechanism.

Pancreatic lipase (PL) is the main enzyme in the digestive system that breaks down triglyceride and promotes its absorption. In this paper, we found that lignans 2, 3 and 21, curcuminoids 24-26 exhibited significant inhibitory potential against PL. The structure-activity relationship (SAR) indicated that benzo-1, 3-dioxole group in the construction of lignans is essential to inhibitory effects against PL, while double bonds at C-7/C-2 position and 4-hydroxyphenyl moiety in the structure of curcuminoids are beneficial for PL inhibition. The kinetic studies and molecular docking were also conducted, the results showed that the three curcuminoids with the strongest inhibition effect above were all mixed inhibitors of PL. Furthermore, curcuminoids 24-26 displayed a preferential selectivity towards, in contrast to other serine hydrolases. The above results indicate that lignans and curcuminoids are natural functional components for PL inhibition, providing new ideas for finding and developing novel lead compounds for the treatment of obesity.

Caramel doped with aromatic compounds as halogen- and phosphorus-free flame-retardant strategy for wool fabric.

The development of halogen- and phosphorus-free flame-retardant strategies is urgently needed in textile industry. In this study, a caramel product doped with aromatic compounds was developed via caramelization and aldol reactions using glucose and p-phthaldialdehyde. The modified caramel (Car@PDA) was subsequently used as a sustainable approach to improve flame retardancy of wool fabric. The flame retardancy, washing durability, heat generation, and flame-retardant mode of action of Car@PDA on wool fabric were investigated. The modified wool fabrics showed excellent flame retardancy, with the limiting oxygen index increasing to 32.5 % and the damaged length decreasing to 10.1 cm, with good self-extinguishing capacity. Car@PDA could combine with wool fibers through Schiff base reaction and electrostatic attraction, so the modified wool fabrics still self-extinguished and met the B1 flame-retardant requirements after 10 washing cycles. The modified wool showed significantly decreased heat release capacity and fire growth rate, suggesting high fire safety. Car@PDA promoted the decomposition of the fabric to form char barrier, thereby achieving an effective flame-retardant effect. In addition, the Car@PDA modification had a minimal effect on the tensile strength and handle of wool fabric. This study provides an innovative way to create bio-based, halogen- and phosphorus-free flame-retardants for protein wool fabrics.

Oleanolic acid promotes porcine oocyte maturation by activating the Nrf2/HO-1 signalling pathway.

This study investigated the potential role and underlying mechanisms of oleanolic acid (OA), a pentacyclic triterpene with antioxidant and anti-inflammatory properties, in porcine oocytes during in vitro maturation (IVM). The results showed that supplementation with 5 µM OA during IVM resulted in a greater percentage of mature oocytes, parthenogenetically activated embryos and somatic cell nuclear-transferred embryos. This was evidenced by significant increases in the rate of first polar body expulsion, the expansion of cumulus granulosa cells and the total cell number in blastocysts. Further analysis revealed that OA promoted fatty acid accumulation and upregulated the mRNA expression of genes involved in fatty acid ß-oxidation. OA significantly increased the intracellular mitochondrial membrane potential and ATP levels and effectively inhibited BAX/BCL2 and Cleaved Caspase3 protein expression. Notably, OA increased the protein levels of intracellular Nrf2 and HO-1, and the GSH levels and the activities of the antioxidant enzymes SOD and catalase (CAT), while reducing ROS levels. Mechanistically, OA activated the Nrf2/HO-1 signalling pathway, which is crucial for regulating the expression of antioxidant-related targets in IVM porcine oocytes. Our findings indicated that OA improved antioxidant capacity by activating the Nrf2/HO-1 signalling pathway, thereby promoting porcine oocyte maturation.

Distribution and diversity of ticks determined by environmental factors in Ningxia, China.

Ticks are important vectors of zoonotic pathogens, and represent an increasing threat for human and animal health. Considering the complex natural environments of Ningxia Hui Autonomous Region, China, we expect the diverse tick species in this region. Here, we conduct a field survey on parasitic and host-seeking ticks. A total of 10,419 ticks were collected, which belonged to nine species of four genera. There were significant differences in terms of vegetation index, altitude, and seven climatic factors among the four tick genera -Hyalomma, Dermacentor, Haemaphysalis, and Ixodes, except between Haemaphysalis and Ixodes, where no significant differences were observed in these factors. The ecological niche modelling revealed that the suitable habitats for Hyalomma asiaticum was in the northwest Ningxia, with annual ground surface temperature as the most important factor. The suitable area for Dermacentor nuttalli was in the southwest and eastern regions of Ningxia with elevation as the highest contribution. D. silvarum was best suited to the southern Ningxia also with elevation as the most important factor. The four tick species including Haemaphysalis longicornis, Hae. qinghaiensis, Hae. japonica, and Ixodes persulcatus were best suited to the southernmost Ningxia with annual precipitation as the main factors for Hae. longicornis and elevation for the other three ticks. The results of predicted potential distribution of different tick species provide a scientific basis for the prevention and control of ticks and tick-borne diseases in the region. Furthermore, the subsequent impacts of the Greening Program to regain forests and grasslands from former agricultural lands in Ningxia on tick population dynamics deserve further investigation.

Potential adaptive habitats for the narrowly distributed and rare bamboo species Chimonobambusa tumidissinoda J. R. Xue & T. P. Yi ex Ohrnb. under future climate change in China.

The global climate change has resulted in substantial modifications to the distribution patterns of narrowly distributed species across different time periods, leading to an imminent threat to the survival of some vulnerable species. Chimonobambusa tumidissinoda J. R. Xue & T. P. Yi ex Ohrnb., a bamboo species endemic to the transition zone from the Yunnan-Guizhou Plateau to the Sichuan Basin with high economic and ecological value, exhibits a limited range and rarity. Utilizing eight environmental variables and 56 occurrence records, we employed the MaxEnt model to predict the potential distribution range of C. tumidissinoda under current and future climate scenarios. The findings revealed that precipitation of the driest month (Bio14), elevation and isothermality (Bio3) were the crucial factors determining the species' distribution, accounting for 31.24%, 28.27% and 17.24% of data variability, respectively. The distribution centroid of C. tumidissinoda is anticipated to shift towards higher latitudes in response to future climate change, and the projected habitat suitability is expected to expand under ssp245 and ssp585 scenarios while remaining unchanged or contracting under the ssp126 scenario. Despite these expansions, the suitable habitats remain limited, with the largest being approximately 2.08 × 104 km2, indicating a significant threat to its survival. Our study provides insights into the adaptive responses of C. tumidissinoda to climate change, enriching scientific knowledge for developing effective conservation measurements as well as sustainable utilization.

[Mechanism of berberine in improving adipocytic IR by mediating BMAL1:CLOCK complex and regulating glucose and lipid metabolism].

To explore the action mechanism of berberine in improving adipocytic insulin resistance(IR) by mediating brain and muscle arnt-like 1(BMAL1): circadian locomotor output cycles kaput(CLOCK) complex and regulating glucose and lipid metabolism. After the IR-3T3-L1 adipocyte model was established by dexamethasone induction for 96 h, 0.5, 1, 5, 10, and 20 µmol·L~(-1) berberine was administered for 24 h. The glucose oxidase method and cell counting kit-8(CCK-8) were used to detect extracellular glucose content and cell viability, respectively. The triglyceride(TG) and glycerol contents were detected by enzyme colorimetry. Oil red O staining was used to detect lipid droplets, and fluorescence staining was used to detect Ca~(2+), mitochondrial structure, and reactive oxygen species(ROS). Adiponectin(ADPN), BMAL1, CLOCK, hormone-sensitive triglyceride lipase(HSL), carbohydrate-response element-binding protein(ChREBP), sterol regulatory element-binding protein 1C(SREBP-1C), peroxisome proliferator-activated receptor γ coactivator 1α(PGC1α), carnitine palmitoyl transferase 1α(CPT1α), and peroxisome proliferator-activated receptor α(PPARα) were detected by Western blot(WB). Moreover, the nuclear localization of BMAL1 was detected by immunofluorescence. In addition, 20 µmol·L~(-1) CLK8 inhibitor was added to detect glucose consumption and BMAL1/ChREBP/PPARα protein. The results showed that berberine increased glucose consumption in IR-3T3-L1 adipocytes without affecting cell viability and reduced TG content. In addition, 5 µmol·L~(-1) berberine increased glycerol content and reduced lipid droplet accumulation due to enhanced lipolysis, while 10 µmol·L~(-1) berberine did not affect glycerol content, and fewer lipid droplets were observed due to enhanced lipolysis and glycerol utilization. Berberine improved mitochondrial function by reducing intracellular Ca~(2+) and ROS in IR-3T3-L1 adipocytes and upregulated PGC1α to improve the mitochondrial structure. The results also showed that berberine elevated ADPN to increase the insulin sensitivity of IR-3T3-L1 adipocytes, upregulated peripheral rhythm-related proteins BMAL1 and CLOCK, and strengthened the nuclear localization of BMAL1. In addition, berberine increased key lipolysis protein and lipid oxidation rate-limiting enzyme CPT1α and downregulated the key protein of TG synthesis, SREBP-1C. Moreover, ChREBP and PPARα in IR-3T3-L1 adipocytes were upregula-ted. All the above results suggested that berberine may transform glucose into lipids to enhance the hypoglycemic effect. By considering that CLK8 specifically inhibited the CLOCK acylation to modify BMAL1 and form complex, the results showed that the addition of CLK8 to the berberine group reduced glucose consumption, which suggested that berberine upregulated the formation of BMAL1:CLOCK complex to improve glucose metabolism. The addition of CLK8 to the berberine group upregulated BMAL1 but downregulated ChREBP and PPARα, which suggested that berberine mediated BMAL1:CLOCK complex for the regulation of glucose and lipid metabo-lism to improve adipocytic IR.

Dual inhibition of topoisomerase II and microtubule of podophyllotoxin derivative 5p overcomes cancer multidrug resistance.

Compound 5p is a 4ß-N-substituted podophyllotoxin derivative, which exhibited potent activity toward drug-resistant K562/A02 cells and decreased MDR-1 mRNA expression. Here, we further investigated its detail mechanism and tested its antitumor activity. 5p exerted catalytic inhibition of topoisomerase IIα, and didn't show the inhibitor of topoisomerase I. 5p exhibited the inhibitory effect on microtubule polymerization. 5p showed potent anti-proliferation against breast cancer, oral squamous carcinoma, and their drug-resistant cell lines, with resistance index of 0.61 and 0.86, respectively. 5p downregulated the expression levels of P-gp in KBV200 cells and BCRP in MCF7/ADR cells in dose-dependent manner. Moreover, 5p induced KB and KBV200 cells arrest at G2/M phase by up-regulating the expression of γ-H2AX, p-Histone H3 and cyclin B1. 5p induced apoptosis and pyroptosis by increased the expression levels of cleaved-PARP, cleaved-caspase3, N-GSDME as well as LDH release in KB and KBV200 cells. In addition, 5p efficiently impaired tumor growth in KB and KBV200 xenograft mice. Conclusively, this work elucidated the dual inhibitor of topoisomerase II and microtubule of 5p and its mechanism of overcoming the multidrug resistance, indicating that 5p exerts the antitumor potentiality.