SP1-stimulated miR-208a-5p aggravates sepsis-induced myocardial injury via targeting XIAP.

The development of sepsis can lead to many organ dysfunction and even death. Myocardial injury is one of the serious complications of sepsis leading to death. New evidence suggests that microRNAs (miRNAs) play a critical role in infection myocardial injury. However, the mechanism which miR-208a-5p regulates sepsis-induced myocardial injury remains unclear. To mimic sepsis-induced myocardial injury in vitro, rat primary cardiomyocytes were treated with LPS. Cell viability and apoptosis were tested by CCK-8 and flow cytometry, respectively. The secretion of inflammatory factors was analyzed by ELISA. mRNA and protein levels were detected by RT-qPCR and Western blotting. The interaction among SP1, XIAP and miR-208a-5p was detected using dual luciferase report assay. Ultrasonic analysis and HE staining was performed to observe the effect of miR-208a-5p in sepsis-induced rats. Our findings indicated that miR-208a-5p expression in primary rat cardiomyocytes was increased by LPS. MiR-208a-5p inhibitor reversed LPS-induced cardiomyocytes injury through inhibiting the apoptosis. Furthermore, the inflammatory injury in cardiomyocytes was induced by LPS, which was rescued by miR-208a-5p inhibitor. In addition, downregulation of miR-208a-5p improved LPS-induced sepsis myocardial injury in vivo. Mechanistically, XIAP might be a target gene of miR-208a-5p. SP1 promoted transcription of miR-208a by binding to the miR-208a promoter region. Moreover, silencing of XIAP reversed the regulatory of miR-208a-5p inhibitor on cardiomyocytes injury. To sum up, those findings revealed silencing of miR-208a-5p could alleviate sepsis-induced myocardial injury, which would grant a new process for the treatment of sepsis.

[Analysis of a Chinese pedigree affected with Spinal muscular atrophy due to compound heterozygous variants of SMN gene].

OBJECTIVE: To analyze variants of SMN gene in a Chinese pedigree affected with Spinal muscular atrophy (SMA). METHODS: A Chinese pedigree diagnosed at the Nanchang First Hospital in January 2020 was selected as the study subject. Peripheral blood samples were collected for the extraction of DNA. All exons of the SMN gene were detected by multiple ligation-dependent probe amplification (MLPA). Potential variants of the SMN gene were also detected by Whole exome sequencing (WES), and the result was verified by Sanger sequencing. cDNA extracted from fresh blood sample was used as a template to verify the location of variant on the SMN genes. RESULTS: The proband was found to harbor a heterozygous deletion of the SMN1 Exon7+Exon8, and a heterozygous c.81G>A variant. The SMN1 Exon7+Exon8 deletion was inherited from her father and grandmother, whilst the c.81G>A variant was inherited from her mother and maternal grandfather. Her aunt was also a carrier of the heterozygous deletion, while her paternal aunt, her husband, and their daughter were not. cDNA amplification and Sanger sequencing confirmed that the c.81G>A variant was located in the SMN1 gene. CONCLUSION: MLPA combined with NGS and Sanger sequencing can identify compound heterozygous variants of the SMN gene in the SMA patients.

BID- and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells.

Recovered senescent tumor cells harbor higher migration and invasion potential, owing to which they play a crucial role in tumor recurrence and drug resistance. The aim of this study was to explore the ability of BH3 mimetics in clearing senescent A549 cells and elucidate their underlying killing mechanism. Doxorubicin-induced cell senescence was determined using augmented senescence-associated beta-galactosidase (SA-ß-Gal) staining and increased P16 expression. CCK-8 and crystal violet staining demonstrated that A-1331852, BH3 mimetic, could kill senescent tumor cells without affecting the proliferating cells. A-1331852 induced caspase-dependent senescent cell death accompanied by nuclear concentration, decreased mitochondrial membrane potential, and cleavage of poly (ADP-ribose) polymerase. Most importantly, A-1331852 upregulated the expression of BID and BAX indicating their role in mediating A-1331852-induced apoptosis in senescent A549 cells. The results of fluorescence resonance energy transfer showed that A-1331852 loosened or even released the binding between BCL-xL and tBID, releasing tBID. In addition, A-1331852 also dissociated the binding between BCL-xL and BAX, eventually leading to BAX oligomerization in the mitochondria, and resulting in apoptosis via the mitochondrial pathway. In conclusion, our data demonstrate for the first time that A-1331852 promotes apoptosis of senescent A549 cells by influencing the interaction between BCL-xL and tBID and that between BCL-xL and BAX.

BAK plays a key role in A-1331852-induced apoptosis in senescent chondrocytes.

Osteoarthritis occurs when the number of senescent chondrocytes in the joints reaches an intolerable level. The purpose of our study was to explore the therapeutic effect and mechanism of action of A-1331852 in osteoarthritis. Doxorubicin and etoposide were used to induce cell senescence as determined by the cessation of cell proliferation, augmented senescence-associated beta-galactosidase (SA-ß-Gal) staining, and increased p53 expression levels. The CCK-8 cytotoxicity assay and SA-ß-Gal staining demonstrated that Bcl-xL inhibitors could selectively remove senescent chondrocytes without damaging healthy chondrocytes. A-1331852 induced caspase-dependent death of senescent chondrocytes with decreased mitochondrial membrane potential, nuclear concentration, plasma membrane rupture, and PARP cleavage. Most importantly, A-1331852 upregulated BAK expression levels, indicating that BAK plays a key role in the A-1331852-induced apoptosis of senescent chondrocytes. Live-cell fluorescence resonance energy transfer showed that A-1331852 detached the binding of Bcl-xL to BAK and promoted the oligomerization of BAK on the mitochondrial membrane. In conclusion, this study provides the first evidence that A-1331852 selectively promotes apoptosis in senescent chondrocytes by interfering with the interaction between Bcl-xL and BAK.

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides.

A family of novel chloramphenicol base-amide organocatalysts possessing a NH functionality at C-1 position as monodentate hydrogen bond donor were developed and evaluated for enantioselective organocatalytic alcoholysis of meso-cyclic anhydrides. These structural diversified organocatalysts were found to induce high enantioselectivity in alcoholysis of anhydrides and was successfully applied to the asymmetric synthesis of (S)-GABOB.

Diastereoselective synthesis of pitavastatin calcium via bismuth-catalyzed two-component hemiacetal/oxa-Michael addition reaction.

An efficient and concise asymmetric synthesis of pitavastatin calcium (1) starting from commercially available (S)-epichlorohydrin is described. A convergent C1 + C6 route allowed for the assembly of the pitavastatin C7 side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C6-formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of (S)-α,ß-unsaturated ketone 4 with acetaldehyde.

Mercury transformation and distribution across a polyvinyl chloride (PVC) production line in China.

The production of polyvinyl chloride (PVC) via the calcium carbide process utilizes a catalyst containing large amounts of mercury (Hg) and is therefore one of the most important sources of anthropogenic Hg in China. To measure the emission of Hg from PVC production, we established a flowchart for the calcium carbide process, for which we quantified the Hg content of the material/product at each step. Results indicated that 71.5% of the total Hg (Hg(T)) was lost from the catalyst, most of which was recovered by the Hg remover, accounting for 46.0% of the total Hg (Hg(T)). We determined that 3.7% of the Hg(T) was released into the environment, mostly in solid wastes and byproducts such as hydrochloric acid. Furthermore, no Hg has been detected in the PVC end product. However, we were only able to account for 78.1% of the Hg across the whole system, leaving 21.7% unaccounted for in the mass balance. A rough estimation indicates that most of the "missing" Hg had accumulated in deposits on the inner surface of converters and downstream pipelines; however, the emission to the atmosphere was ≤ 1% of the Hg(T). For a PVC production line equipped with a Hg remover, emissions of Hg to the atmosphere have been estimated to be 4.9 g per tonne PVC. Currently, almost all calcium carbide facilities have been equipped with a Hg remover, which may reduce the release of Hg in China by ∼ 500 t/year.

Surface roughness influence on extracellular electron microbiologically influenced corrosion of C1018 carbon steel by Desulfovibrio ferrophilus IS5 biofilm.

Carbon steel microbiologically influenced corrosion (MIC) by sulfate reducing bacteria (SRB) is known to occur via extracellular electron transfer (EET). A higher biofilm sessile cell count leads to more electrons being harvested for sulfate reduction by SRB in energy production. Metal surface roughness can impact the severity of MIC by SRB because of varied biofilm attachment. C1018 carbon steel coupons (1.2 cm2 top working surface) polished to 36 grit (4.06 µm roughness which is relatively rough) and 600 grit (0.13 µm) were incubated in enriched artificial seawater inoculated with highly corrosive Desulfovibrio ferrophilus IS5 at 28 â„ƒ for 7 d and 30 d. It was found that after 7 d of SRB incubation, 36 grit coupons had a 11% higher sessile cell count at (2.0 ± 0.17) × 108 cells/cm2, 52% higher weight loss at 22.4 ± 5.9 mg/cm2 (1.48 ± 0.39 mm/a uniform corrosion rate), and 18% higher maximum pit depth at 53 µm compared with 600 grit coupons. However, after 30 d, the differences diminished. Electrochemical tests with transient information supported the weight loss data trends. This work suggests that a rougher surface facilitates initial biofilm establishment but provides no long-term advantage for increased biofilm growth.

Conductive magnetic nanowires accelerated electron transfer between C1020 carbon steel and Desulfovibrio vulgaris biofilm.

Microbial biofilms are behind microbiologically influenced corrosion (MIC). Sessile cells in biofilms are many times more concentrated volumetrically than planktonic cells in the bulk fluids, thus providing locally high concentrations of chemicals. More importantly, "electroactive" sessile cells in biofilms are capable of utilizing extracellularly supplied electrons (e.g., from elemental Fe) for intracellular reduction of an oxidant such as sulfate in energy metabolism. MIC directly caused by anaerobic biofilms is classified into two main types based on their mechanisms: extracellular electron transfer MIC (EET-MIC) and metabolite MIC (M-MIC). Sulfate-reducing bacteria (SRB) are notorious for their corrosivity. They can cause EET-MIC in carbon steel, but they can also secrete biogenic H2S to corrode other metals such as Cu directly via M-MIC. This study investigated the use of conductive magnetic nanowires as electron mediators to accelerate and thus identify EET-MIC of C1020 by Desulfovibrio vulgaris. The presence of 40 ppm (w/w) nanowires in ATCC 1249 culture medium at 37 °C resulted in 45 % higher weight loss and 57 % deeper corrosion pits after 7-day incubation. Electrochemical tests using linear polarization resistance and potentiodynamic polarization supported the weight loss data trend. These findings suggest that conductive magnetic nanowires can be employed to identify EET-MIC. The use of insoluble 2 µm long nanowires proved that the extracellular section of the electron transfer process is a bottleneck in SRB MIC of carbon steel.

Revealing roles of S-layer protein (SlpA) in Clostridioides difficile pathogenicity by generating the first slpA gene deletion mutant.

Clostridioides difficile infection (CDI) with high morbidity and high mortality is an urgent threat to public health, and C. difficile pathogenesis studies are eagerly required for CDI therapy. The major surface layer protein, SlpA, was supposed to play a key role in C. difficile pathogenesis; however, a lack of isogenic slpA mutants has greatly hampered analysis of SlpA functions. In this study, the whole slpA gene was successfully deleted for the first time via CRISPR-Cas9 system. Deletion of slpA in C. difficile resulted in smaller, smother-edged colonies, shorter bacterial cell size, and aggregation in suspension. For life cycle, the mutant demonstrated lower growth (changes of optical density at 600 nm, OD600) but higher cell density (colony-forming unit, CFU), decreased toxins production, and inhibited sporulation. Moreover, the mutant was more impaired in motility, more sensitive to vancomycin and Triton X-100-induced autolysis, releasing more lactate dehydrogenase. In addition, SlpA deficiency led to robust biofilm formation but weak adhesion to human host cells.IMPORTANCEClostridioides difficile infection (CDI) has been the most common hospital-acquired infection, with a high rate of antibiotic resistance and recurrence incidences, become a debilitating public health threat. It is urgently needed to study C. difficile pathogenesis for developing efficient strategies as CDI therapy. SlpA was indicated to play a key role in C. difficile pathogenesis. However, analysis of SlpA functions was hampered due to lack of isogenic slpA mutants. Surprisingly, the first slpA deletion C. difficile strain was generated in this study via CRISPR-Cas9, further negating the previous thought about slpA being essential. Results in this study will provide direct proof for roles of SlpA in C. difficile pathogenesis, which will facilitate future investigations for new targets as vaccines, new therapeutic agents, and intervention strategies in combating CDI.

Mitigation of galvanized steel biocorrosion by Pseudomonas aeruginosa biofilm using a biocide enhanced by trehalase.

Pseudomonas aeruginosa is a facultative bacterium that is pathogenic. It is ubiquitous in the environment including air handling systems. It causes microbiologically influenced corrosion (MIC) aerobically and anaerobically. In this work, P. aeruginosa was grown as a nitrate reducing bacterium (NRB) in Luria-Bertani medium with KNO3 at 37 °C. Trehalase, an enzyme which plays a crucial role in biofilm formation was found to enhance the treatment of P. aeruginosa biofilm and its MIC against galvanized steel by tetrakis-hydroxymethyl phosphonium sulfate (THPS) green biocide. After a 7-d incubation, 30 ppm (w/w) trehalase reduced sessile cell count by 0.8-log, and it also reduced galvanized steel weight loss by 14%, compared to 2.3-log and 39%, respectively for the 30 ppm THPS treatment. The combination of 30 ppm THPS + 30 ppm trehalase reduced sessile cell count further by 0.1-log and weight loss by 13% compared to using THPS alone. Electrochemical corrosion measurements supported weight loss results. The injection of 20 ppm riboflavin into a 3-d P. aeruginosa broth failed to accelerate the corrosion rate, suggesting that nitrate reducing P. aeruginosa MIC of galvanized steel did not belong to extracellular electron transfer-MIC, because Zn was hydrolyzed after the microbe damaged the passive film.

Electrochemical Assessment of Mitigation of Desulfovibrio ferrophilus IS5 Corrosion against N80 Carbon Steel and 26Cr3Mo Steel Using a Green Biocide Enhanced by a Nature-Mimicking Biofilm-Dispersing Peptide.

MIC (microbiologically influenced corrosion) is problematic in many industries, especially in the oil and gas industry. In this work, N80 carbon steel for pipelines was tested with 26Cr3Mo chromium pipeline steel for comparison in SRB (sulfate-reducing bacterium) MIC mitigation using a THPS (tetrakis hydroxymethyl phosphonium sulfate)-based commercial biocide (Biotreat 5475 with 75-80% THPS by mass). Peptide A, a nature-mimicking synthetic cyclic peptide (cys-ser-val-pro-tyr-asp-tyr-asn-trp-tyr-ser-asn-trp-cys) with biofilm dispersal ability was used as a biocide enhancer. Metal coupons covered with 3-d old Desulfovibrio ferrophilus IS5 biofilms were immersed in different biocide solutions. After 1-h treatment, 200 ppm Biotreat 5475, 200 ppm Biotreat 5475 + 200 nM (360 ppb) Peptide A, and 400 ppm Biotreat 5475 achieved 0.5-log, 1.7-log and 1.9-log reductions in sessile cell count on N80, and 0.7-log, 1.7-log, and 1.8-log on 26Cr3Mo, respectively. The addition of 200 nM Peptide A cut the THPS biocide dosage by nearly half. Biocide injection tests in electrochemical glass cells after 1 h exhibited 15%, 70%, and 72% corrosion inhibition efficiency (based on corrosion current density) on N80, and 27%, 79%, 75% on 26Cr3Mo, respectively. Linear polarization resistance and electrochemical impedance spectrometry results also indicated antimicrobial efficacies.

The role of red blood cell distribution width (RDW) in the diagnosis of pediatric sepsis.

BACKGROUND: Early diagnosis of pediatric sepsis is difficult, so it is necessary to find a reliable auxiliary diagnostic method. The purpose of the study was to assess the role of RDW in the diagnosis of pediatric sepsis. METHODS: We did a case control study reviewing pediatric inpatients (≥28 days, < 18 years old) who were diagnosed with sepsis between April 2020 and November 2022. According to the sepsis-3 and Pediatric Sequential Organ Failure Assessment (pSOFA) scoring standards, 66 septic inpatients of the pediatric intensive care unit (PICU) were included in the sepsis group and 66 non-septic inpatients of the PICU were included by using the random sampling method during the same period as the control group. RESULTS: RDW values in the sepsis group were higher than those in the control group (P < 0.001). The cut-off value, sensitivity, specificity and area under curve of RDW for sepsis were 39.15, 0.955, 0.758 and 0.943,respectively. CONCLUSIONS: Our study confirms that RDW may have a good value on the early diagnosis of pediatric sepsis.

Microbiologically influenced corrosion of titanium by Desulfovibrio vulgaris biofilm under organic carbon starvation.

Desulfovibrio vulgaris biofilm was pre-grown on Ti coupons for 7 d and then the biofilm covered coupons were incubated again with fresh culture media with 10 % (reduced) and 100 % (normal) carbon source levels, respectively. After the pre-growth, sessile D. vulgaris cell count reached 107 cells/cm2. The sessile cell counts were 2 × 107 and 4.2 × 107 cells/cm2 for 10 % and 100 % carbon sources, respectively after the subsequent 7 d starvation test. The maximum pit depth after the 7 d pre-growth was 4.7 µm. After the additional 7 d of the starvation test, the maximum pit depth increased to 5.1 µm for 100 % carbon source vs 6.2 µm for 10 % carbon source. Corrosion current density (icorr) from potentiodynamic polarization data at the end of the 7 d starvation test for 10 % carbon source was more than 3 times of that for 100 % carbon source, despite a reduced sessile cell count with 10 % carbon source. The polarization resistance (Rp) started to decrease within minutes after 20 ppm (w/w) riboflavin (electron mediator) injection. The carbon starvation data and riboflavin corrosion acceleration data both suggested that D. vulgaris utilized elemental Ti as an electron source to replace carbon source as the electron donor during carbon source starvation.

Reduction of SIRT1-Mediated Epigenetic Upregulation of Nav1.7 Contributes to Oxaliplatin-Induced Neuropathic Pain.

BACKGROUND: Clinically, neuropathic pain is a severe side effect of oxaliplatin chemotherapy, which usually leads to dose reduction or cessation of treatment. Due to the unawareness of detailed mechanisms of oxaliplatin-induced neuropathic pain, it is difficult to develop an effective therapy and limits its clinical use. OBJECTIVES: The aim of the present study was to identify the role of sirtuin 1 (SIRT1) reduction in epigenetic regulation of the expression of voltage-gated sodium channels 1.7 (Nav1.7) in the dorsal root ganglion (DRG) during oxaliplatin-induced neuropathic pain. STUDY DESIGN: Controlled animal study. SETTING: University laboratory. METHODS: The von Frey test was performed to evaluate pain behavior in rats. Real-time quantitative polymerase chain reaction, western blotting, electrophysiological recording, chromatin immunoprecipitation, and small interfering RNA (siRNA) were used to illustrate the mechanisms. RESULTS: In the present study, we found that both the activity and expression of SIRT1 were significantly decreased in rat DRG following oxaliplatin treatment. The activator of SIRT1, resveratrol, not only increased the activity and expression of SIRT1, but also attenuated the mechanical allodynia following oxaliplatin treatment. In addition, local knockdown of SIRT1 by intrathecal injection of SIRT1 siRNA caused mechanical allodynia in naive rats. Besides, oxaliplatin treatment enhanced the action potential firing frequency of DRG neurons and the expression of Nav1.7 in DRG and activation of SIRT1 by resveratrol reversed this effect. Furthermore, blocking Nav1.7 by ProTx II (a selective Nav1.7 channel blocker) reversed oxaliplatin-induced mechanical allodynia. In addition, histone H3 hyperacetylation at the Nav1.7 promoter in DRG of rats following oxaliplatin treatment was significantly suppressed by activation of SIRT1 with resveratrol. Moreover, both the expression of Nav1.7 and histone H3 acetylation at the Nav1.7 promoter were upregulated in the DRG by local knockdown of SIRT1 with SIRT1 siRNA in naive rats. LIMITATIONS: More underlying mechanism(s) of SIRT1 reduction after oxaliplatin treatment needs to be explored in future research. CONCLUSIONS: These findings suggest that reduction of SIRT1-mediated epigenetic upregulation of Nav1.7 in the DRG contributes to the development of oxaliplatin-induced neuropathic pain in rats. The intrathecal drug delivery treatment of activating SIRT1 might be a novel therapeutic option for oxaliplatin-induced neuropathic pain.

Bim- and Bax-mediated mitochondrial pathway dominates abivertinib-induced apoptosis and ferroptosis.

Abivertinib (AC) is a novel epidermal growth factor receptor tyrosine kinase inhibitor with highly efficient antitumor activity. Here, we report the capacity of AC to induce both reactive oxygen species (ROS)-dependent apoptosis and ferroptosis in tumor cells. Our data showed that AC induced iron- and ROS-dependent cytotoxicity in MCF7, HeLa, and A549 cell lines. Flow cytometry analyses showed that AC increased ferrous ions and ROS and induced ferroptosis in MCF-7 cells. This was confirmed by the findings that AC not only decreased solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression but also induced iron- and ROS-dependent aggrandized lipid ROS accumulation and plasma membrane damage. Meanwhile, AC induced nuclear condensation and increased ROS-dependent phosphatidylserine (PS) eversion, caspase-3 activation, and cleaved-PARP expression, suggesting that AC also induced ROS-dependent apoptosis. In addition, mitochondrial depletion significantly inhibited AC-induced cytotoxicity, including ferroptosis and apoptosis, indicating the key role of mitochondria in AC-induced ferroptosis and apoptosis. Moreover, knockout of Bim or Bax not only remarkably inhibited AC-induced apoptosis, but also markedly inhibited AC-triggered downregulation of SLC711 and GPX4, accumulation of lipid ROS, and damage to the plasma membrane. This suggests that Bim and Bax act upstream of SLC7A11 and GPX4 to mediate AC-induced ferroptosis. Collectively, AC induces ferroptosis and apoptosis, in which the Bim- and Bax-mediated mitochondrial pathways play a dominant role.

Reduction of SIRT1 Mediates Monosodium Iodoacetate-Induced Osteoarthritic Pain by Upregulating p53 Expression in Rats.

BACKGROUND: Clinically, chronic pain is the most common and disabling symptom of osteoarthritis (OA). OA pain is associated with OA lesion of the knee and the plastic changes in the peripheral and central nervous systems. However, the central mechanisms involved at the spinal cord level are not fully understood. OBJECTIVES: The aim of this study was to identify the mechanism underlying the role of spinal cord Sirtuin 1 (SIRT1) in OA pain induced by intraarticular injection of monosodium iodoacetate (MIA) in rats. STUDY DESIGN: Controlled animal study. METHODS: MIA was injected intraarticularly into the rat knee joint for the induction of OA. The OA lesion of the knee was assessed by histopathological examination. The mechanical allodynia were measured over 21 days post-injection by von Frey filaments. The messenger RNA and protein levels of SIRT1 and p53 were determined by real-time quantitative polymerase chain reaction and western blotting, respectively. Involvement of SIRT1-mediated p53 expression in the development of MIA-persistent pain was studied using intrathecal (i.t.) injection of the SIRT1-activating molecule resveratrol and intraperitoneal (i.p.) injection of the p53 inhibitor pifithrin-mu (PTF-µ). RESULTS: MIA induced mechanical allodynia, decreased the expression of SIRT1, and upregulated the expression of p53 in the spinal dorsal horn. Consecutive i.t. injection of resveratrol or i.p. injection of PTF-µ alleviated the MIA-induced mechanical allodynia. Upregulation of dorsal horn SIRT1 expression by i.t. injection of resveratrol also inhibited the increase of dorsal horn p53 induced by MIA. Moreover, silencing of dorsal horn SIRT1 expression by i.t. administration of small interfering RNA SIRT1 into normal rats induced the mechanical allodynia and upregulation of p53 expression in the dorsal horn. LIMITATIONS: More underlying mechanism(s) of the role of p53 signaling pathway in OA pain need to be explored in future research. CONCLUSIONS: These findings suggest that the reduction of dorsal horn SIRT1 mediated upregulation of p53 expression, which plays a critical role in persistent pain induced by OA. The i.t. drug delivery treatments targeting the spinal cord SIRT1/p53 pathway might be novel therapeutic options for OA-induced persistent pain.

Individual and combined effects of GSTM1, GSTT1, and GSTP1 polymorphisms on lung cancer risk: A meta-analysis and re-analysis of systematic meta-analyses.

ABSTRACT: Thirty-five previous meta-analyses have been reported on the individual glutathione S-transferase M1 (GSTM1) present/null, glutathione S-transferase T1 (GSTT1) present/null, and glutathione S-transferase P1 (GSTP1) IIe105Val polymorphisms with lung cancer (LC) risk. However, they did not appraise the credibility and explore the combined effects between the 3 genes and LC risk.We performed a meta-analysis and re-analysis of systematic previous meta-analyses to solve the above problems.Meta-analyses of Observational Studies in Epidemiology guidelines were used. Moreover, we employed false-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and the Venice criteria to verify the credibility of current and previous meta-analyses.Significantly increased LC risk was considered as "highly credible" or "positive" for GSTM1 null genotype in Japanese (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.17-1.44, I2 = 0.0%, statistical power = 0.997, FPRP = 0.008, BFDP = 0.037, and Venice criteria: AAB), for GSTT1 null genotype in Asians (OR = 1.23, 95% CI = 1.12-1.36, I2 = 49.1%, statistical power = 1.000, FPRP = 0.051, BFDP = 0.771, and Venice criteria: ABB), especially Chinese populations (OR = 1.31, 95% CI = 1.16-1.49, I2 = 48.9%, Statistical power = 0.980, FPRP = 0.039, BFDP = 0.673, and Venice criteria: ABB), and for GSTP1 IIe105Val polymorphism in Asians (Val vs IIe: OR = 1.28, 95% CI = 1.17-1.42, I2 = 30.3%, statistical power = 0.999, FPRP = 0.003, BFDP = 0.183, and Venice criteria: ABB). Significantly increased lung adenocarcinoma (AC) risk was also considered as "highly credible" or "positive" in Asians for the GSTM1 (OR = 1.35, 95% CI = 1.22-1.48, I2 = 25.5%, statistical power = 0.988, FPRP < 0.001, BFDP < 0.001, and Venice criteria: ABB) and GSTT1 (OR = 1.36, 95% CI = 1.17-1.58, I2 = 30.2%, statistical power = 0.900, FPRP = 0.061, BFDP = 0.727, and Venice criteria: ABB) null genotype.This study indicates that GSTM1 null genotype is associated with increased LC risk in Japanese and lung AC risk in Asians; GSTT1 null genotype is associated with increased LC risk in Chinese, and GSTP1 IIe105Val polymorphism is associated with increased LC risk in Asians.

Bak instead of Bax plays a key role in metformin-induced apoptosis s in HCT116 cells.

Metformin (Met) exhibits anticancer ability in various cancer cell lines. This report aims to explore the exact molecular mechanism of Met-induced apoptosis in HCT116 cells, a human colorectal cancer cell line. Met-induced reactive oxygen species (ROS) increase and ROS-dependent cell death accompanied by plasma membrane blistering, mitochondrial swelling, loss of mitochondrial membrane potential, and release of cytochrome c. Western blotting analysis showed that Met upregulated Bak expression but downregulated Bax expression. Most importantly, silencing Bak instead of Bax inhibited Met-induced loss of mitochondrial membrane potential, indicating the key role of Bak in Met-induced apoptosis. Live-cell fluorescence resonance energy transfer (FRET) analysis showed that Met unlocked the binding of Mcl-1 to Bak, and enhanced the binding of Bim to Bak and subsequent Bak homo-oligomerization. Western blotting analysis showed that Met enhanced AMPK phosphorylation and Bim expression, and compound C, an inhibitor of AMPK, inhibited Met-induced Bim upregulation. Although Met increased the expression of Bcl-xL, overexpression of Bcl-xL did not prevent Met-induced apoptosis. In summary, our data demonstrate for the first time that Met promotes ROS-dependent apoptosis by regulating the Mcl-1-Bim-Bak axis.

Transcription-mediated tissue-specific lignification of vascular bundle causes trade-offs between growth and defence capacity during invasion of Solidago canadensis.

Allocation of more resources to growth but less to defense causing growth vigor of invasive alien plant populations contributes to successful invasion. However, few studies has addressed to relationship between vascular development variation and this mechanism. In this study, a common garden experimentwas established to compare the growth and vascular bundle development between native and introduced populations of Solidago canadensis, which is a wide-distributed invasive species in China. Our results suggested that the rapid growth of introduced populations could be explained by the well-developed and highly lignified xylem; while native populations present more developed and highly lignified phloem, which contributed more resistance to the infection of Sclerotiun rofsii compared with introduced populations. This difference was resulted from tissue-specific tradeoff distribution of lignification related gene expression between xylem and phloem, which is regulated by upstream MYB transcription factors. Our study gives a novel insight of mechanism that explain invasion success: lignin-related gene transcription-mediated tissue-specific lignification of vascular bundle contributes tradeoffs in resource allocation between growth and defence capacity during successful invasion of S. canadensis.