Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Supraphysiologic doses of 17ß-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism.

BACKGROUND: 17ß-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown. METHODS: In this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC-MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro. RESULTS: sE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression. CONCLUSION: These data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

PIWI-interacting RNA-23210 protects against acetaminophen-induced liver injury by targeting HNF1A and HNF4A.

Acetaminophen (APAP) overdose is one of the leading causes of acute liver failure in the US and other developed countries, the molecular mechanisms of APAP-induced hepatotoxicity remain speculative. PIWI-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, have been identified as epigenetic regulators of transposon silencing, mRNA deadenylation, and elimination. However, the functional role of piRNAs in APAP-induced liver injury remains unclear. In the current study, the piRNA profiles were constructed in HepaRG cells after APAP exposure, and the roles of piR-23210 in regulating nuclear receptors (NRs) expression, metabolizing enzymes expression, and consequently APAP-induced liver injury were systematically investigated. As a result, 57 upregulated piRNAs were identified after APAP exposure, indicating the stress-response characteristic of piRNA molecules. Subsequent in vitro and in vivo experiments proved that piR-23210 is a novel self-protective molecule that targets HNF1A and HNF4A transcripts by interacting with RNA binding protein Nucleolin (NCL), suppresses downstream CYPs (CYP2E1, CYP3A4, and CYP1A2) expression, and protects against APAP-induced liver injury. In conclusion, our findings provided new mechanistic clues revealing potential protective role of a piRNA against the hepatoxicity of APAP.

The Effect of Oxycodone on Post-operative Pain and Inflammatory Cytokine Release in Elderly Patients Undergoing Laparoscopic Gastrectomy.

Background: To evaluate the effect of oxycodone on post-operative pain and inflammation in elderly patients undergoing laparoscopic gastrectomy. Methods: Sixty patients who were of both sexes, American Society of Anesthesiologists Physical Status (ASA-PS) Class I or II, over 65 years of age and undergoing an elective laparoscopic radical gastrectomy were randomly divided into two groups: an oxycodone group (Group O) including 20 males and 10 females and a sufentanil group (Group S) including 21 males and 9 females. The post-operative analgesia regimen was as follows: 40 mg of parecoxib sodium and 0.1 mg/kg of oxycodone was intravenously injected into Group O before the abdomen closure, while 40 mg of parecoxib sodium and 0.1 µg/kg of sufentanil was injected intravenously into Group S. Both groups were infiltrated with 20 ml of 1% ropivacaine at the end of the operation. The level of serum IL-6 and IL-10 were assayed immediately at the following timepoints: at the conclusion of surgery (T1), 1 h (T2), 6 h (T3), and 24 h (T4) after the completion of the surgery. The numerical rating scale (NRS), the Ramsay sedation score, analgesic-related adverse events, post-operative pulmonary inflammation events and the post-operative stay were recorded. Results: Compared with Group S, the serum IL-6 concentrations of Group O decreased at T3 and T4, while the serum IL-10 concentrations increased (P < 0.05). In Group O, the serum IL-6 concentrations at T3 and T4 were lower than those at T1 (P < 0.05). The incidence of post-operative nausea and vomiting (PONV) and pulmonary inflammation in Group O was lower than that in Group S (P < 0.05). At each time point, the NRS of visceral pain in Group O was lower than that in Group S. At 6 and 24 h after extubation, the NRS of incision pain in Group O was lower than that in Group S (P < 0.05). Conclusion: Oxycodone can regulate the level of inflammatory cytokines and reduce post-operative inflammatory response.

A novel mechanism underlying alcohol dehydrogenase expression: hsa-miR-148a-3p promotes ADH4 expression via an AGO1-dependent manner in control and ethanol-exposed hepatic cells.

The alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) play critical roles in alcoholism development and alcohol toxicology; however, few studies have focused on the miRNA-mediated mechanisms underlying the expressions of alcohol-metabolizing enzymes. In the present study, we showed the expression changes of each alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver samples of alcoholic hepatitis (AH) patients, and predicted the miRNAs targeting the dysregulated alcohol-metabolizing genes by a systematic in silico analysis. 13 miRNAs were predicted to regulate the expressions of ADH1A, ADH4, and ALDH2, respectively, with hsa-miR-148a-3p (miR-148a) showing the most significant down-regulation in AH patients. Following experimental evidence using HepG2 cells proved that miR-148a promoted ADH4 expression by directly binding to the coding sequence of ADH4 and increasing the mRNA stability via an AGO1-dependent manner. Additional assays showed that secondary structure of ADH4 transcript affected the target accessibility and binding of miR-148a-3p. In sum, our results suggest that the expressions of key alcohol-metabolizing enzymes are repressed in AH patients, and the non-canonical positive regulation of miR-148a on ADH4 reveals a new regulationary mechanism for ADH genes.

Novosphingobium silvae sp. nov., isolated from subtropical forest soil.

A novel bacterial strain, designated FGD1T, was isolated from subtropical forest soil of the Nanling National Forest Park located in Guangdong Province, P.R. China. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain FGD1T was most closely related to Novosphingobium lindaniclasticum DSM 25049T (98.8 %), followed by N. barchaimii DSM 25411T (98.7 %), N. guangzhouense DSM 32207T (98.2 %), N. panipatense DSM 22890T (98.1 %) and other species of Novosphingobium (<98 %). The draft genome sequence was 4.58 Mb in length with a G+C content of 65.1 mol%. The calculated average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain FGD1T and closely related type strains were 77.7‒79.6 % and 21.7-22.9 %, respectively. Major fatty acids were summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c), summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), C14 : 0 2-OH and C16 : 0. The predominant respiratory quinone was ubiquinone 10 and the major polyamine was spermidine. Polar lipids were composed of sphingoglycolipid, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, diphosphatidylglycerol, an unidentified phospholipid and lipid. The polyphasic taxonomic results indicated that strain FGD1T represents a novel species of the genus Novosphingobium, for which the name Novosphingobium silvae sp. nov. is proposed. The type strain is FGD1T (=GDMCC 1.1761T=KACC 21283T).

Methylobacterium nonmethylotrophicum sp. nov., isolated from tungsten mine tailing.

A novel pink-pigmented strain, designated 6HR-1T, was isolated from tungsten mine tailings in Jiangxi Province, PR China. Cells were Gram-stain-negative, aerobic, non-spore-forming, rod-shaped and motile with a polar flagellum (monotrichous). It could not utilize methanol, methylamine, formaldehyde or formate as a sole carbon source. The methanol dehydrogenase mxaF gene was absent but the xoxF gene was present. Phylogenomic and 16S rRNA gene phylogenetic analyses clearly showed that strain 6HR-1T was affiliated to the genus Methylobacterium and closely related to 'Methylobacterium terrae' 17Sr1-28T (98.6 %), Methylobacterium platani JCM 14648T (97.7 %), Methylobacterium variabile DSM 16961T (97.7 %) and Methylobacterium currus KACC 19662T (97.4 %). The average nucleotide identity and digital DNA-DNA hybridization values between strain 6HR-1T and its closely related type species were 87.4-88.7 and 33.2-36.3 %, respectively. It had summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c) as the major fatty acid and ubiquinone 10 as the predominant respiratory quinone. Polyphasic characterization supported that strain 6HR-1T represents a novel species of the genus Methylobacterium, for which the name Methylobacterium nonmethylotrophicum sp. nov. is proposed with the type strain 6HR-1T (=GDMCC 1.662T=KCTC 42760T).

Sphingomonas lenta sp. nov., a slowly growing bacterium isolated from an abandoned lead-zinc mine.

A novel slowly growing member of the genus Sphingomonas, designated 1PNM-20T, was isolated from an abandoned lead-zinc mine in Meizhou, Guangdong Province, PR China. A polyphasic taxonomic study was performed to characterize the novel strain. Growth occurred on Reasoner's 2A (R2A) agar and peptone-yeast extract (PYE) agar, but not in liquid R2A or PYE media. Cells were Gram-stain-negative, aerobic, non-spore-forming, rod-shaped and motile with a polar flagellum (monotrichous). 16S rRNA gene sequence comparison showed that it shared the highest similarity with Sphingomonas carriPR0302T (97.2 %), followed by Sphingomonas spermidinifaciens 9NM-10T (97.0 %), Sphingomonas floccifaciens FQM01T (97.0 %) and other species of Sphingomonas (<97 %). Phylogenetic analyses clearly showed that strain 1PNM-20T fell into the cluster of Sphingomonas, and was most closely related to S. carri. The draft genome sequence was 3.76 Mb in length with a DNA G+C content of 69.8 mol%. Major fatty acids were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 0 and 11-methyl C18 : 1ω7c, with C14 : 0 2-OH as the main hydroxy fatty acid. Ubiquinone 10 (Q-10) was the predominant respiratory quinone, and sym-homospermidine was displayed as the major polyamine. The polar lipids were composed of sphingoglycolipid, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unidentified phospholipid and an unidentified glycolipid. The phenotypic, phylogenetic and chemotaxonomic results supported the hypothesis that strain 1PNM-20T represents a novel species of the genus Sphingomonas, for which the name Sphingomonas lenta sp. nov. is proposed. The type strain is 1PNM-20T (=GDMCC 1.660T=DSM 27572T).