Acetyl-coenzyme A acetyltransferase 1 promotes brown adipogenesis by activating the AMPK-PGC1α signaling pathway.

Brown adipose tissue (BAT) is thermogenic, expressing high levels of uncoupling protein-1 to convert nutrient energy to heat energy, bypassing ATP synthesis. BAT is a promising therapeutic target for treatment of obesity and type 2 diabetes since it converts fatty acids into heat but mechanisms controlling brown adipogenesis remain unclear. Knockdown of acetyl-Coenzyme A acetyltransferase 1 (ACAT1) in C3H10T1/2 cells suppressed brown adipocyte maturation during the current study and ACAT1 overexpression promoted brown adipocyte maturation. The downstream target of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator-1-α (PGC1α), was involved in the action of ACAT1 on brown adipocyte maturation. ACAT1 overexpression enhanced AMPK phosphorylation and promoted PGC1α expression. It is suggested that ACAT1 promotes brown adipocyte maturation by activating the AMPK-PGC1α signaling pathway.

Amphiphilic Metallodrug Assemblies with Red-Light-Enhanced Cellular Internalization and Tumor Penetration for Anticancer Phototherapy.

Metallodrugs are widely used in cancer treatment. The modification of metallodrugs with polyethylene glycol (PEGylation) prolongs blood circulation and improves drug accumulation in tumors; it represents a general strategy for drug delivery. However, PEGylation hinders cellular internalization and tumor penetration, which reduce therapeutic efficacy. Herein, the red-light-enhanced cellular internalization and tumor penetration of a PEGylated anticancer agent, PEGylated Ru complex (Ru-PEG), are reported upon. Ru-PEG contains a red-light-cleavable PEG ligand, anticancer Ru complex moiety, and fluorescent pyrene group for imaging and self-assembly. Ru-PEG self-assembles into vesicles that circulate in the bloodstream and accumulate in the tumors. Red-light irradiation induces dePEGylation and changes the Ru-PEG vesicles to large compound micelles with smaller diameters and higher zeta potentials, which enhance tumor penetration and cellular internalization. Red-light irradiation also generates intracellular 1 O2 , which induces the death of cancer cells. This work presents a new strategy to enhance the cellular internalization and tumor penetration of anticancer agents for efficient phototherapy.

Red-Light-Responsive Metallopolymer Nanocarriers with Conjugated and Encapsulated Drugs for Phototherapy Against Multidrug-Resistant Tumors.

It is challenging to treat multidrug-resistant tumors because such tumors are resistant to a broad spectrum of structurally and functionally unrelated drugs. Herein, treatment of multidrug-resistant tumors using red-light-responsive metallopolymer nanocarriers that are conjugated with the anticancer drug chlorambucil (CHL) and encapsulated with the anticancer drug doxorubicin (DOX) is reported. An amphiphilic metallopolymer PolyRuCHL that contains a poly(ethylene glycol) (PEG) block and a red-light-responsive ruthenium (Ru)-containing block is synthesized. Chlorambucil is covalently conjugated to the Ru moieties of PolyRuCHL. Encapsulation of DOX into PolyRuCHL in an aqueous solution results in DOX@PolyRuCHL micelles. The DOX@PolyRuCHL micelles are efficiently taken up by the multidrug-resistant breast cancer cell line MCF-7R and which carries DOX into the cells. Free DOX, without the nanocarriers, is not taken up by MCF-7R or pumped out of MCF-7R via P-glycoproteins. Red light irradiation of DOX@PolyRuCHL micelles triggers the release of chlorambucil-conjugated Ru moieties and DOX. Both act synergistically to inhibit the growth of multidrug-resistant cancer cells. Furthermore, the inhibition of the growth of multidrug-resistant tumors in a mouse model using DOX@PolyRuCHL micelles is demonstrated. The design of red-light-responsive metallopolymer nanocarriers with both conjugated and encapsulated drugs opens up an avenue for photoactivated chemotherapy against multidrug-resistant tumors.

The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy.

Hepatic lipid accumulation is closely associated with nonalcoholic fatty liver disease (NAFLD). Adipose-triglyceride-lipase (ATGL) regulates triglyceride hydrolysis and maintains energy homeostasis in hepatocytes. Identifying key factors in the regulation of ATGL will help tackle hepatic lipid accumulation and related metabolic diseases. Herein, we demonstrate that syntaxin11 (STX11), a member of the SNARE family, generally expressed in immune cells, mediates lipid metabolism by binding to ATGL and inhibiting lipid droplet degradation and lipid autophagy in hepatocytes. Our data show that the C-terminal of STX11 and the patatin domain-containing segment of ATGL have direct physical interactions. Thus, STX11 overexpression prevents spatial translocation of ATGL onto LDs by recruitment of ATGL to the ER. Conversely, STX11 deficiency in hepatocytes promotes lipid hydrolysis, and the ATGL-SIRT1 signaling pathway enhances lipophagy. Overall, this study uncovered that the regulation of lipolysis and lipophagy is achieved by STX11 through the attenuation of ATGL action in hepatocytes.

DECR1 directly activates HSL to promote lipolysis in cervical cancer cells.

Fatty acids have a high turnover rate in cancer cells to supply energy for tumor growth and proliferation. Lipolysis is particularly important for the regulation of fatty acid homeostasis and in the maintenance of cancer cells. In the current study, we explored how 2,4-Dienoyl-CoA reductase (DECR1), a short-chain dehydrogenase/reductase associated with mitochondrial and cytoplasmic compartments, promotes cancer cell growth. We report that DECR1 overexpression significantly reduced the triglyceride (TAG) content in HeLa cells; conversely, DECR1 silencing increased intracellular TAG content. Subsequently, our experiments demonstrate that DECR1 promotes lipolysis via effects on hormone sensitive lipase (HSL). The direct interaction of DECR1 with HSL increases HSL phosphorylation and activity, facilitating the translocation of HSL to lipid droplets. The ensuing enhancement of lipolysis thus increases the release of free fatty acids. Downstream effects include the promotion of cervical cancer cell migration and growth, associated with the enhanced levels of p62 protein. In summary, high levels of DECR1 serves to enhance lipolysis and the release of fatty acid energy stores to support cervical cancer cell growth.

Ru-Se Coordination: A New Dynamic Bond for Visible-Light-Responsive Materials.

Photodynamic bonds are stable in the dark and can reversibly dissociate/form under light irradiation. Photodynamic bonds are promising building blocks for responsive or healable materials, photoactivated drugs, nanocarriers, extracellular matrices, etc. However, reactive intermediates from photodynamic bonds usually lead to side reactions, which limit the use of photodynamic bonds. Here, we report that the Ru-Se coordination bond is a new photodynamic bond that reversibly dissociates under mild visible-light-irradiation conditions. We observed that Ru-Se bonds form via the coordination of a selenoether ligand with [Ru(tpy)(biq)(H2O)]Cl2 (tpy = 2,2':6',2″-terpyridine, biq = 2,2'-biquinoline) in the dark, while the Ru-Se bond reversibly dissociates under visible-light irradiation. No side reaction is detected in the formation and dissociation of Ru-Se bonds. To demonstrate that the Ru-Se bond is applicable to different operating environments, we prepared photoresponsive amphiphiles, surfaces, and polymer gels using Ru-Se bonds. The amphiphiles with Ru-Se bonds showed reversible morphological transitions between spherical micelles and bowl-shaped assemblies for dark/light irradiation cycles. The surfaces modified with Ru-Se-bond-containing compounds showed photoswitchable wettability. Polymer gels with Ru-Se cross-links underwent photoinduced reversible sol-gel transitions, which can be used for reshaping and healing. Our work demonstrates that the Ru-Se bond is a new type of dynamic bond, which can be used for constructing responsive, reprocessable, switchable, and healable materials that work in a variety of environments.

Molecular Epidemiology of mcr-1, bla KPC-2, and bla NDM-1 Harboring Clinically Isolated Escherichia coli from Pakistan.

PURPOSE: The multiple-drug resistant Escherichia coli are among the deadliest pathogens causing life-threatening infections. This study was planned to determine the molecular epidemiology of mcr-1, bla KPC-2, and bla NDM-1 harboring clinically isolated E. coli from Pakistan. METHODS: In total, 545 strains of E. coli from clinical samples were collected from June 2018 to September 2019. All the isolates were screened for colistin-resistance, extended-spectrum-ß-lactamases (ESBL), and carbapenemases through the micro-dilution method, Double-Disk-Synergy-Test (DDST), and Modified-Hodge-Test (MHT). The detection, sequence-typing, conjugal transfer, S1-PFGE, plasmid-replicon-typing, and southern-blotting for mcr, ESBL, and carbapenemase-encoding genes were performed. FINDINGS: A total of four (0.73%) colistin-resistant strains carrying alongside mcr-1 and bla CTX-M-15 genes, three of these strains also had the bla TEM-1 gene. The presence of ESBL genes was detected in 139 (25.5%) isolates harboring bla CTXM-15 (74.82%), bla TEM (34.53%), bla SHV (28.06%) and bla OXA-1 (28.78%). In 129 carbapenemase-producers, 35.83% possessed bla NDM-1, 26.67% bla KPC-2, 8.3% bla OXA-48, 25% bla VIM-1, and 20.83% bla IMP-1 genes. The sequence typing revealed that mcr-1 harboring isolates belonged to ST405, ST117, and ST156. Fifty percent of bla KPC-2 and 48.83% of bla NDM-1 were found on ST131 and ST1196, respectively. Two rare types of STs, ST7584, and ST8671 were also identified in this study. The mcr-1 gene was located on Incl2 (60-kb) plasmid. The bla KPC-2 was present on (140-kb) IncH12, (100-kb) IncN, (90-kb) Incl1, while bla NDM-1 was located on (70-kb) IncFIIK, (140-kb) IncH12, (100-kb) IncN, (60-kb) IncA/C, and (45-kb) IncFII plasmids, which were successfully trans-conjugated. Among the plasmid types, the Incl1 carrying bla KPC-2, IncH12 harboring bla KPC-2 and bla NDM-1, and IncFIIK carrying bla NDM-1 were for the first time detected in Pakistan. CONCLUSION: The mcr-1, bla KPC-2, and bla NDM-1 genes finding in various clonal and plasmids types indicate that a substantial selection of the resistance genes had occurred in our clinical strains.

Fighting against Drug-Resistant Tumors using a Dual-Responsive Pt(IV)/Ru(II) Bimetallic Polymer.

Drug resistance is a major problem in cancer treatment. Herein, the design of a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin-resistant tumors in a patient-derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA-type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction-responsive Pt(IV) and red-light-responsive Ru(II) moieties. PolyPt/Ru self-assembles into nanoparticles that are efficiently taken up by cisplatin-resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1 O2 , induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1 O2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drug-resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli-responsive multi-metallic polymers provides a new strategy to overcome drug resistance.

Alcohol-Soluble Isoindigo Derivative IIDTh-NSB as a Novel Modifier of ZnO in Inverted Polymer Solar Cells.

Alcohol-soluble isoindigo derivative with thiophene groups and sulfobetaine zwitterions, IIDTh-NSB was applied as a novel modifier of ZnO in inverted polymer solar cells (i-PSCs). When IIDTh-NSB (0.2 mg/mL) was spin-coated on ZnO as an electron transport layer (ETL), power conversion efficiency (PCE) of the PTB7:PC71BM based i-PSCs reached 8.88%, which is a 20% improvement of that of 7.40% for the device with the ZnO-only ETL. If ZnO was doped by IIDTh-NSB of 1.0 wt %, the PCE of 8.50% could be achieved in the i-PSCs. Combined measurements of capacitance-voltage characteristics, carrier mobility, and photocurrent density-effective voltage characteristics revealed that incorporating IIDTh-NSB as the modifier of ZnO by coating or doping enhanced the built-in potential, charge carrier density and mobility, exciton dissociation, and charge carrier extraction in the i-PSCs because of the improved interfacial contact between the photoactive layer and ZnO as shown in water contact angle measurements and atomic force microscopy images. Finally, impedance spectroscopy investigation provided strong lines of evidence that incorporating IIDTh-NSB as the modifier of ZnO led to the great enhancement in short-circuit current density and fill factor. Furthermore, all the devices with IIDTh-NSB as a modifier of ZnO presented better stability than the device with ZnO-only. These findings suggest that IIDTh-NSB is an effective and competitive material for modification of ZnO in the i-PSCs.

High Performance Small-Molecule Cathode Interlayer Materials with D-A-D Conjugated Central Skeletons and Side Flexible Alcohol/Water-Soluble Groups for Polymer Solar Cells.

A new class of organic cathode interfacial layer (CIL) materials based on isoindigo derivatives (IID) substituted with pyridinium or sulfonate zwitterion groups were designed, synthesized, and applied in polymer solar cells (PSCs) with PTB7:PC71BM (PTB7: polythieno[3,4-b]-thiophene-co-benzodithiophene and PC71BM: [6,6]-phenyl C71-butyric acidmethyl ester) as an active layer. Compared with the control device, PSCs with an IID-based CIL show simultaneous enhancement of open-circuit voltage (Voc), short-circuit current (Jsc), and fill factor (FF). Systematic optimizations of the central conjugated core and side flexible alcohol-soluble groups demonstrated that isoindigo-based CIL material with thiophene and sulfonate zwitterion substituent groups can efficiently enhance the PSC performance. The highest power conversion efficiency (PCE) of 9.12%, which is 1.75 times that of the control device without CIL, was achieved for the PSC having an isoindigo-based CIL. For the PSCs with an isoindigo-based CIL, the molecule-dependent performance property studies revealed that the central conjugated core with D-A-D characteristics and the side chains with sulfonate zwitterions groups represents an efficient strategy for constructing high performance CILs. Our study results may open a new avenue toward high performance PSCs.

All-trans-retinoic acid ameliorated high fat diet-induced atherosclerosis in rabbits by inhibiting platelet activation and inflammation.

BACKGROUND: All-trans-retinoic acid (atRA) is effective for many proliferative diseases. We investigated the protective effects of atRA against atherosclerosis. METHODS: Rabbits were randomly allocated to receive basal diet or an HFD for 4 weeks. HFD group then received rosuvastatin (3 mg/day), atRA (5 mg/kg/day), or the same volume of vehicle, respectively, for next 8 weeks. RESULTS: HFD group showed increases in plasma lipids and aortic plaque formation. P-selectin expression and fibrinogen binding on platelets or deposition on the intima of the aorta also increased significantly as did the levels of TNF-α, IL-6, and fibrinogen in plasma. After 8 weeks of treatment with atRA, there was a significant decrease in plasma lipids and improvement in aortic lesions. AtRA also inhibited the expression of P-selectin and fibrinogen binding on platelets and deposition on the intima of the aorta. CONCLUSION: AtRA can ameliorate HFD-induced AS in rabbits by inhibiting platelet activation and inflammation.