Cellular senescence is a fundamental biological process that has profound implications in cancer development and therapeutics, but the underlying mechanisms remain elusive. Here we show that carnitine palmitoyltransferase 1C (CPT1C), an enzyme that catalyzes carnitinylation of fatty acids for transport into mitochondria for β-oxidation, plays a major role in the regulation of cancer cell senescence through mitochondria-associated metabolic reprograming. Metabolomics analysis suggested alterations in mitochondria activity, as revealed by the marked decrease in acylcarnitines in senescent human pancreatic carcinoma PANC-1 cells, indicating low CPT1C activity. Direct analyses of mRNA and protein show that CPT1C is significantly reduced in senescent cells. Furthermore, abnormal mitochondrial function was observed in senescent PANC-1 cells, leading to lower cell survival under metabolic stress and suppressed tumorigenesis in a mouse xenograft model. Knock-down of CPT1C in PANC-1 cells induced mitochondrial dysfunction, caused senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and inhibited tumorigenesis in vivo. Further, CPT1C knock-down suppressed xenograft tumor growth in situ. Silencing of CPT1C in five other tumor cell lines also caused cellular senescence. On the contrary, gain-of-function of CPT1C reversed PANC-1 cell senescence and enhanced mitochondrial function. This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence.

The archetypal membrane skeleton is that of the erythrocyte, consisting predominantly of spectrin, actin, ankyrin R and protein 4.1R. The presence in the Golgi of a membrane skeleton with a similar structure has been inferred, based on the identification of Golgi-associated spectrin and ankyrin. It has long been assumed that a Golgi-specific protein 4.1 must also exist, but it has not previously been found. We demonstrate here that a hitherto unknown form of protein 4.1, a 200 kDa 4.1B, is associated with the Golgi of Madin-Darby canine kidney (MDCK) and human bronchial epithelial (HBE) cells. This 4.1B variant behaves like a Golgi marker after treatment with Brefeldin A and during mitosis. Depletion of the protein in HBE cells by siRNA resulted in disruption of the Golgi structure and failure of Na+/K+-ATPase, ZO-1 and ZO-2 to migrate to the membrane. Thus, this newly identified Golgi-specific protein 4.1 appears to have an essential role in maintaining the structure of the Golgi and in assembly of a subset of membrane proteins.

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.

With the rapid rise in the prevalence of non-tuberculous mycobacteria (NTM) diseases across the world, the microbiological diagnosis of NTM isolates is becoming increasingly important for the diagnosis and treatment of NTM disease. In this study, the clinical presentation, species distribution and drug susceptibility of patients with NTM disease visiting the Chongqing Public Health Medical Centre during March 2016–April 2019 were retrospectively analysed. Among the 146 patients with NTM disease, eight NTM species (complex) were identified. The predominant NTM species in these patients were identified to be Mycobacterium abscessus complex (53, 36.3%), M. intracellulare (38, 26%) and M. fortuitum (17, 11.7%). In addition, two or more species were isolated from 7.5% of the patients. Pulmonary NTM disease (142, 97.3%) showed the highest prevalence among the patients. It was observed that 40.1% of the patients with pulmonary NTM disease had chronic pulmonary obstructive disease and bronchiectasis, while 22.5% had prior tuberculosis. Male patients showed more association with the conditions of cough and haemoptysis than the female patients. In an in vitro antimicrobial susceptibility testing, most of the species showed susceptibility to linezolid, amikacin and clarithromycin, while M. fortuitum exhibited low susceptibility to tobramycin. In conclusion, the prevalence of NTM disease, especially that of the pulmonary NTM disease, is common in Southwest China. Species identification and drug susceptibility testing are thus extremely important to ensure appropriate treatment regimens for patient care and management.

Enantiopure A4L4 tetrahedral cages were obtained through chirality transfer in the anion-coordination-driven assembly (ACDA) of chiral C3-symmetric tris-bis(urea) ligands with phosphate.

A biphenyl-bridged bis-tris(urea) ligand L was rationally designed with a favorable angle to construct a hexagon-shaped A 6 L 6 (A = anion) complex upon assembly with phosphate anions (PO 4 3− ) via anioncoordination-driven assembly (ACDA). Due to the moderate flexibility of L, another well-defined discrete architecture, a square-like A 4 L 4 complex, has also been obtained from ligand L and PO 4 3− . Interconversion between these two self-assemblies can be readily realized by solvent regulation. In addition, the two anionic architectures display different binding abilities for selected cationic guest molecules, enabling the uptake of a desired guest from a mixture of guests.

Purpose The aim of this study is to investigate para-aminosalicylic acid (PAS) resistance-related gene mutations in clinical Mycobacterium tuberculosis (MTB) isolates and analyze the associated risk factors in southwestern China. Patients and methods Total 122 PAS-resistant and 55 PAS-susceptible clinical isolates were obtained from Chongqing Public Health Medical Center between April 2014 and January 2018. Drug susceptibility test was performed, and the PAS resistance-related genes were sequenced. Results PAS-resistant strains were more likely to resist streptomycin (OR: 9.5, 95% CI: 3.87-23.3; P <0.01), isoniazid (OR: 5.98, 95% CI: 2.14–16.76; P <0.01), rifampin (OR: 5.01, 95% CI: 2.11–11.88; P <0.01), ethambutol (OR: 2.79, 95% CI: 1.44–5.4; P <0.01), levofloxacin (OR: 2.56, 95% CI: 1.33–4.93; P <0.01), and amikacin (OR: 4.29, 95% CI: 1.70–10.83; P <0.01). The sequencing results showed that 112 (91.8%) PAS-resistant strains harbored 30 different mutations in folC, thyA , and ribD . Mutations in folC were the most commonly observed in PAS-resistant isolates (54.5%, 61/112), followed by mutations in thyA and ribD . Residues I43 in folC , R235 in thyA , and −11 G in upstream of ribD were hotspots for mutation sites. Conclusion PAS drug resistance in MTB in southwestern China is mainly caused by mutations in folC, thyA , and ribD , among which folC was the most frequent mutation. Some mutation hotspots exist in the three genes, which accounts for about 80% of total mutations. These results highlight the possibility of developing molecular diagnostic methods for PAS-resistant tuberculosis in the future.

Kanamycin B as the secondary metabolite of wild‐type Streptomyces kanamyceticus ( S. kanamyceticus ) ATCC12853 is often used for the synthesis of dibekacin and arbekacin. To construct the strain has the ability for kanamycin B production; the pSET152 derivatives from Escherichia coli ET12567 were introduced to S. kanamyceticus by intergeneric conjugal transfer. In this study, we established a reliable genetic manipulation system for S. kanamyceticus . The key factors of conjugal transfer were evaluated, including donor‐to‐recipient ratio, heat‐shock, and the overlaying time of antibiotics. When spores were used as recipient, the optimal conjugation frequency was up to 6.7 × 10 −6 . And mycelia were used as an alternative recipient for conjugation instead of spores; the most suitable donor‐to‐recipient ratio is 1:1 (10 7 :10 7 ). After incubated for only 10–12 hr and overlaid with antibiotics subsequently, the conjugation frequency can reach to 6.2 × 10 −5 which is sufficient for gene knockout and other genetic operation. Based on the optimized conjugal transfer condition, kanJ was knocked out successfully. The kanamycin B yield of kanJ ‐disruption strain can reach to 543.18 ± 42 mg/L while the kanamycin B yield of wild‐type strain was only 46.57 ± 12 mg/L. The current work helps improve the content of kanamycin B in the fermentation broth of S. kanamyceticus effectively to ensure the supply for the synthesis of several critical semisynthetic antibiotics.