Micafungin protects mouse heart against doxorubicin-induced oxidative injury via suppressing MALT1-dependent k48-linked ubiquitination of Nrf2.

Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 µM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 µM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.

Methyltransferase-like proteins in cancer biology and potential therapeutic targeting.

RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.

Photoinduced Vinylogous Dearomatization.

The first vinylogous dearomatization is reported. Under a photoinduced platform, various benzothiophenes functionalized by ketones at the 3-position could react with 3-methylenechroman-4-ones efficiently, leading to a variety of valuable products that contain the pharmaceutically significant chromones and 2,3-dihydrobenzo[b]thiophenes concurrently. The transformations were revealed to experience hydrogen-atom transfer, dearomatization, olefin migration, and radical cross coupling.

Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica.

BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined. METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP. RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity. CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, which may facilitate its diagnosis, prognosis, and treatment.

[Biodegradation of Polyethylene Microplastic: A Review].

Over the recent decades, global plastic production has grown dramatically due to the huge demands of consumption. As a consequence, large amounts of plastic waste have accumulated in the environment and will be cleaved into microplastics. Due to the low bioavailability, the microplastics will exist in the environment persistently and cause massive environmental stress. Plastic pollution is currently one of the biggest environmental concerns. Recent studies have shown the possibility to obtain degrading microorganisms of microplastics from the natural environment. Some microorganisms can break down microplastics into water and carbon dioxide. This paper reviewed the current research on biodegradation of polyethylene (PE), which is the most abundant microplastic type in the environment, and discussed the quantification methods of the degradation effect. Given that current biodegradation efficiency is relatively limited, further research is required.

Effects of hyperbaric oxygen on NLRP3 inflammasome activation in the brain after carbon monoxide poisoning.

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1ß and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air - i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by FluoroMyelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1ßß and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1ß and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Polymer-Based Device Fabrication and Applications Using Direct Laser Writing Technology.

Polymer materials exhibit unique properties in the fabrication of optical waveguide devices, electromagnetic devices, and bio-devices. Direct laser writing (DLW) technology is widely used for micro-structure fabrication due to its high processing precision, low cost, and no need for mask exposure. This paper reviews the latest research progresses of polymer-based micro/nano-devices fabricated using the DLW technique as well as their applications. In order to realize various device structures and functions, different manufacture parameters of DLW systems are adopted, which are also investigated in this work. The flexible use of the DLW process in various polymer-based microstructures, including optical, electronic, magnetic, and biomedical devices are reviewed together with their applications. In addition, polymer materials which are developed with unique properties for the use of DLW technology are also discussed.

[Correlation of insulin resistance with male reproductive hormone levels and semen parameters].

OBJECTIVE: To investigate the influence of insulin resistance on male reproductive hormones and semen quality. METHODS: Using the electrochemiluminescence method, we measured the levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2) and testosterone (T) in the serum of 83 infertile males. We detected the levels of fasting plasma glucose (FPG) and fasting insulin (FINS) and calculated the insulin resistance index presented as homeostasis model assessment of insulin resistance (HOMA-IR). Based on HOMA-IR, we divided the patients into three tertile groups, T1 (HOMA-IR 0.36－0.55, n = 27), T2 (HOMA-IR 0.56－0.80, n = 28) and T3 (HOMA-IR 0.81－1.97, n = 28), obtained their semen parameters by computer-assisted semen analysis (CASA) and analyzed the correlation of HOMA-IR with male reproductive hormone levels and semen parameters. RESULTS: With the elevation of HOMA-IR, the patients of the T1, T2 and T3 groups showed significant decreases in the serum T level (ï¼»14,26 ± 4.27ï¼½ vs ï¼»14.75 ± 5.00ï¼½ vs ï¼»11.62 ± 3.68ï¼½ nmol/L, P <0.05) and the percentage of progressively motile sperm (PMS) (ï¼»51.04 ± 15.10ï¼½% vs ï¼»48.04 ± 16.24ï¼½% vs ï¼»37.84 ± 18.23ï¼½%, P <0.05). HOMA-IR was correlated negatively with the serum T level (r = －0.333, P = 0.002), semen volume (r = －0.23, P = 0.029) and PMS (r = －0.27, P = 0.015), and so was FINS with the serum T level (r = －0.327, P = 0.003) and PMS (r = －0.315, P = 0.004), while the semen volume was correlated positively with the levels of serum T (r = 0.221, P = 0.048) and FSH (r = 0.222, P = 0.047). Multivariate linear regression analysis showed that HOMA-IR was an independent influencing factor for PMS and the body mass index (BMI) was that for the semen volume and total sperm count. CONCLUSIONS: Insulin resistance may reduce semen quality by changing the levels of male reproductive hormones.

[Correlation of seminal plasma zinc alpha-2 glycoprotein with semen quality in obese males].

OBJECTIVE: To investigate the relationship between seminal plasma zinc alpha-2 glycoprotein (ZAG) and semen quality in obese males. METHODS: This study included 130 obese male patients with idiopathic infertility Based on the concentration of seminal plasma ZAG, we divided the patients into three tertile groups: tertile 1 (T1, 73.45－97.15 µg/ml, n = 43), T2 (97.16－115.46 µg/ml, n = 44), and T3 (115.47－220.11 µg/ml, n = 43). We measured the concentrations of seminal plasma zinc (SPZ) and ZAG of the patients by ELISA, obtained the semen parameters, and analyzed the correlation of semen quality with the levels of SPZ and ZAG and the influence of obesity on SPZ, ZAG and semen quality. RESULTS: The mean level of seminal plasma ZAG in the 130 obese male patients was (111.29 ± 26.50) µg/ml. There were statistically significant differences in sperm concentration and total sperm count among the three tertile groups (P < 0.05). The level of seminal plasma ZAG was correlated negatively with the body mass index (BMI), waist circumference (WC), sperm concentration and sperm count (P < 0.01), that of SPZ positively with BMI and WC (P < 0.05) but negatively with semen volume and the percentage of progressively motile sperm (P < 0.05). The level of serum ZAG, however, exhibited no correlation with SPZ, seminal plasma ZAG or semen quality. Obesity was found to be associated with significantly decreased concentration of seminal plasma ZAG and percentage of progressively motile sperm but remarkably increased level of SPZ (P < 0.05). CONCLUSIONS: Obesity may induce the metabolic disorder of SPZ and ZAG, change the microenvironment of seminal plasma, and consequently affect semen quality.

[Correlation of the levels of seminal plasma homocysteine, folate and cobalamin with semen parameters in obese men].

OBJECTIVE: To investigate the correlation of seminal plasma homocysteine (Hcy) and its metabolic factors folate (FA) and cobalamin (VB12) with semen quality in obese men. METHODS: We randomly selected 83 male patients with idiopathic infertility for this study and, according to the body mass index (BMI), divided them into a normal BMI (n = 28), an overweight (n = 28) and an obesity group (n = 27). We determined the levels of Hcy, FA and VB12 in the seminal plasma by ELISA and analyzed their correlation with the semen parameters of the patients in different groups. RESULTS: Compared with the normal BMI group, the obese males showed significant decreases in the semen volume (ï¼»3.23 ± 0.86ï¼½ vs ï¼»2.58 ± 0.77ï¼½ ml, P < 0.05), total sperm count (ï¼»191.35 ± 103.00ï¼½ vs ï¼»121.55 ± 88.08ï¼½ ×106, P < 0.05), percentage of progressively motile sperm (ï¼»52.88 ± 15.58ï¼½ % vs ï¼»38.97 ± 16.52ï¼½ %, P < 0.05), seminal plasma Hcy (ï¼»7.41 ± 1.29ï¼½ vs ï¼»6.62 ± 0.85ï¼½ µmol/L, P < 0.05), and VB12 (ï¼»282.41 ± 30.38ï¼½ vs ï¼»230.07 ± 37.75ï¼½ pmol/L, P < 0.05). There were no statistically significant differences in the semen parameters between the overweight group and the normal BMI or the obese group (P > 0.05), or in sperm concentration or the FA level among the three groups of patients (P > 0.05). The levels of seminal plasma Hcy and VB12 were correlated positively with the semen volume (r = 0.281 and 0.242, P < 0.05) and total sperm count (r = 0.229 and 0.258, P < 0.05) but negatively with BMI (r = －0.293 and －0.238, P < 0.05). No correlation, however, was found either between sperm concentration and the percentage of progressively motile sperm (P > 0.05) or between the FA level and BMI or semen parameters (P > 0.05). CONCLUSIONS: The levels of seminal plasma Hcy and VB12 are correlated with BMI, semen volume and total sperm count, which suggests that the concentrations of seminal plasma Hcy and VB12 may be associated with the fertility of obese men.

Decreased production of higher alcohols by Saccharomyces cerevisiae for Chinese rice wine fermentation by deletion of Bat aminotransferases.

An appropriate level of higher alcohols produced by yeast during the fermentation is one of the most important factors influencing Chinese rice wine quality. In this study, BAT1 and BAT2 single- and double-gene-deletion mutant strains were constructed from an industrial yeast strain RY1 to decrease higher alcohols during Chinese rice wine fermentation. The results showed that the BAT2 single-gene-deletion mutant strain produced best improvement in the production of higher alcohols while remaining showed normal growth and fermentation characteristics. Furthermore, a BAT2 single-gene-deletion diploid engineered strain RY1-Δbat2 was constructed and produced low levels of isobutanol and isoamylol (isoamyl alcohol and active amyl alcohol) in simulated fermentation of Chinese rice wine, 92.40 and 303.31 mg/L, respectively, which were 33.00 and 14.20 % lower than those of the parental strain RY1. The differences in fermentation performance between RY1-Δbat2 and RY1 were minor. Therefore, construction of this yeast strain is important in future development in Chinese wine industry and provides insights on generating yeast strains for other fermented alcoholic beverages.