Six polymorphisms in the lncRNA H19 gene and the risk of cancer: a systematic review and meta-analysis.

BACKGROUND: Numerous studies have demonstrated long noncoding RNA (lncRNA) play an important role in the occurrence and progression of cancer, and single nucleotide polymorphisms (SNPs) located in lncRNA are considered to affect cancer suspensibility. Herein, a meta-analysis was carried out to better assess the relationship of H19 polymorphisms and cancer susceptibility. METHODS: A literature search was conducted through using PubMed, EMBASE, and Web of Science databases to obtain relevant publications before Aug 23, 2022. The reference lists of the retrieved studies were also investigated to identify additional relevant articles. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to appraise the risk of various cancers. RESULTS: There appeared to be a remarkable correlation between the rs2107425 variation and decreased cancer risk among Caucasians. Nevertheless, the rs217727 polymorphism was significantly associated with an increased risk of lung cancer, hepatocellular carcinoma and oral squamous cell carcinoma. Also, we found a significant correlation between the rs2839698 polymorphism and increased cancer risk among Asians, gastric cancer, hepatocellular carcinoma, hospital-based control and larger simple size subgroups, respectively. Similarly, the rs3741219 mutation was notably related to cancer risk in higher quality score. As for rs3024270 polymorphism, the homozygous model was markedly linked to cancer risk in overall analysis and population-based controls. There was no significant association between the rs3741216 polymorphism and cancer risk. CONCLUSION: H19 rs2839698 and rs3024270 were closely associated with overall cancer risk. H19 rs2107425 was related to lower cancer risk among Caucasians, while the rs2839698 was related to increased cancer risk among Asians. Our results supported that H19 SNPs were significantly correlated with cancer risk.

Acute liver injury induced by carbon tetrachloride reversal by Gandankang aqueous extracts through nuclear factor erythroid 2-related factor 2 signaling pathway.

The aims of this study were to evaluated the effect and underlying mechanism of Gandankang (GDK) aqueous extract in alleviating the acute liver injury induced by carbon tetrachloride (CCl4) in vivo and in vitro. Mice were divided into 5 groups (n = 8) for acute (Groups: control, 0.3 % CCl4, BD (Bifendate), 1.17, 2.34 and 4.68 mg/kg GDK) liver injury study. 10 µL/g CCl4 with corn oil were injected interperitoneally (i.p) expect the control group. HepG2 cells were used in vitro study. The results showed GDK can effectively inhibit liver damage and restore the structure and function of the liver. In mechanism, GDK inhibited CCl4-induced liver fibrosis and blocked the NF-κB pathway to effectively inhibit the hepatic inflammatory response; and inhibited CCl4-induced oxidative stress by upregulating the Keap1/Nrf2 pathway-related proteins and promoting the synthesis of several antioxidants. Additionally, it inhibited ferroptosis in the liver by regulating the expression of ACSl4 and GPX4. GDK reduced lipid peroxide generation in vitro by downregulating the production of reactive oxygen species and Fe2+ aggregation, thereby inhibiting ferroptosis and alleviating CCl4-induced hepatocyte injury. In conclusion, we describe the potential complex mechanism underlying the effect of GDK against acute liver injury.

Sequential Dual Delivery System Based on siCOX-2-Loaded Gold Nanostar and Thermal-Sensitive Liposomes Overcome Hypoxia-Mediated Multidrug Resistance in Tumors.

Reversing hypoxia-mediated multidrug resistance (MDR) presents a unique challenge in clinical chemotherapy. Here, a sequential dual delivery system composited with Cyclooxygenase-2 siRNA (siCOX-2) in poly-d-arginine (9R)/2-deoxyglucose (DG)-loaded gold nanostar (GNS) (siCOX-2@RDG) and paclitaxel (PTX)-loaded thermosensitive liposome (PTSL) was proposed to conquer the hypoxia-mediated MDR in tumors. As a result, the prepared siCOX-2@RDG exhibited a starlike morphology with a uniform particle size of 194.36 ± 1.44 nm and a ζ-potential of -11.83 ± 2.01 mV. In vitro, PTSL displayed expected thermal-responsive release properties. As expected, siCOX-2@RDG displayed exceptional DG-mediated hypoxia-targeting capability both in vitro and in vivo and downregulated the expression of COX-2 successfully. Meanwhile, GNS-triggered hyperthermia elevated the cellular uptake of PTSL in PTX-resistant HepG2(HepG2/PTX) cells in vitro and enhanced the permeability of tumor tissues, thus elevating the valid retention of PTX into solid tumors. Finally, we demonstrated that the sequential dual systems composed of siCOX-2@RDG and PTSL could reverse hypoxia-mediated MDR and exhibit excellent synergistic antitumor effects both in vitro and in vivo, prolonging the survival of tumor-bearing mice. The devised sequential dual systems, composed of two independent nanosystems, have a promising potential to overcome hypoxia-mediated MDR in clinical practice.

AKT/GSK-3ß signaling is altered through downregulation of mTOR during cerebral Ischemia/Reperfusion injury.

PURPOSE: Cellular responses following cerebral ischemia/reperfusion injury are critical to recovery and survival after ischemic stroke. Understanding of these cellular responses can help the design of therapies to protect brain tissue and promote recovery after stroke. One of these cellular responses may be mediated by the AKT (protein kinase B) signal transduction pathway. This study was aimed to investigate the cerebral ischemia-induced alterations of AKT signaling and the upstream molecular pathways. METHODS: We modeled cerebral ischemia by middle cerebral artery occlusion in 2-3-month-old male C57BL/6J mice and then analyze the brain samples by using quantitative Western blots and phosphorylation/activation-dependent kinase antibodies. Cerebral ischemia was confirmed by staining of brain slices with 1% 2,3,5-triphenyltetrazolium chloride (TTC) and Nissl, as well as neurological assessments of the mice 24 h after ischemia-reperfusion surgery. RESULTS: We found marked downregulation of AKT within 12 h of cerebral ischemia/reperfusion, which leads to overactivation of glycogen synthase kinase-3ß (GSK-3ß). Furthermore, we found that the downregulation of AKT was mediated by downregulation of mTORC2 (the complex 2 of the mechanistic target of rapamycin) instead of its common upstream kinases, phosphatidylinositol 3-kinase and phosphoinositide-dependent kinase-1. CONCLUSION: Our findings provide new insight into the cellular responses to ischemia/reperfusion brain injury and will help develop new treatments targeting the AKT signaling pathway for the treatment of ischemic stroke.

Timely and Appropriate Administration of Inhaled Argon Provides Better Outcomes for tMCAO Mice: A Controlled, Randomized, and Double-Blind Animal Study.

BACKGROUND: Inhaled argon (iAr) has shown promising therapeutic efficacy for acute ischemic stroke and has exhibited impressive advantages over other inert gases as a neuroprotective agent. However, the optimal dose, duration, and time point of iAr for acute ischemic stroke are unknown. Here, we explored variable iAr schedules and evaluated the neuroprotective effects of acute iAr administration on lesion volume, brain edema, and neurological function in a mouse model of cerebral ischemic/reperfusion injury. METHODS: Adult ICR (Institute of Cancer Research) mice were randomly subjected to sham, moderate (1.5 h), or severe (3 h) transient middle cerebral artery occlusion (tMCAO). One hour after tMCAO, the mice were randomized to variable iAr protocols or air. General and focal deficit scores were assessed during double-blind treatment. Infarct volume, overall recovery, and brain edema were analyzed 24 h after cerebral ischemic/reperfusion injury. RESULTS: Compared with those in the tMCAO-only group, lesion volume (p < 0.0001) and neurologic outcome (general, p < 0.0001; focal, p < 0.0001) were significantly improved in the group administered iAr 1 h after stroke onset (during ischemia). Short-term argon treatment (1 or 3 h) significantly improved the infarct volume (1 vs. 24 h, p < 0.0001; 3 vs. 24 h, p < 0.0001) compared with argon inhalation for 24 h. The concentration of iAr was confirmed to be a key factor in improving focal neurological outcomes relative to that in the tMCAO group, with higher concentrations of iAr showing better effects. Additionally, even though ischemia research has shown an increase in cerebral damage proportional to the ischemia time, argon administration showed significant neuroprotective effects on infarct volume (p < 0.0001), neurological deficits (general, p < 0.0001; focal, p < 0.0001), weight recovery (p < 0.0001), and edema (p < 0.0001) in general, particularly in moderate stroke. CONCLUSIONS: Timely iAr administration during ischemia showed optimal neurological outcomes and minimal infarct volumes. Moreover, an appropriate duration of argon administration was important for better neuroprotective efficacy. These findings may provide vital guidance for using argon as a neuroprotective agent and moving to clinical trials in acute ischemic stroke.

Mori fructus aqueous extracts attenuate carbon tetrachloride-induced renal injury via the Nrf2 pathway and intestinal flora.

Mori fructus aqueous extracts (MFAEs) have been used as a traditional Chinese medicine for thousands of years with the function of strengthening the liver and tonifying the kidney. However, its inner mechanism to alleviative renal injury is unclear. To investigate the attenuation of MFAEs on nephrotoxicity and uncover its potential molecular mechanism, we established a nephrotoxicity model induced by carbon tetrachloride (CCl4). The mice were randomly divided into control group, CCl4 model group (10% CCl4), CCl4 + low and high MFAEs groups (10% CCl4 + 100 mg/kg and 200 mg/kg MFAEs). We found that MFAEs decreased the kidney index of mice, restored the pathological changes of renal structure induced by CCl4, reduced cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (Kim-1) blood urea nitrogen and creatinine contents in serum, promoted the nuclear transportation of Nrf2 (nuclear factor erythroid derived 2 like 2), elevated the expression of HO-1 (heme oxygenase 1), GPX4 (glutathione peroxidase 4), SLC7A11 (solute carrier family 7 member 11), ZO-1 (zonula occludens-1) and Occludin, suppressed the expression of Keap1 (kelch-like ECH-associated protein 1), HMGB1 (High Mobility Group Protein 1), ACSL4 (acyl-CoA synthetase long chain family member 4) and TXNIP (thioredoxin interacting protein), upregulated the flora of Akkermansia, Anaerotruncus, Clostridium_sensu_stricto, Ihubacter, Alcaligenes, Dysosmobacter, and downregulated the flora of Clostridium_XlVa, Helicobacter, Paramuribaculum. Overlapped with Disbiome database, Clostridium_XlVa, Akkermansia and Anaerotruncus may be the potential genera treated with renal injury. It indicated that MFAEs could ameliorate kidney injury caused by CCl4 via Nrf2 signaling.

Alpha lipoic acid antagonizes cytotoxicity of cobalt nanoparticles by inhibiting ferroptosis-like cell death.

As a main element in the hard metal industry, cobalt is one of the major components of human metal implants. Cobalt-containing implants, especially joint prostheses used for artificial joint replacement, can be corroded due to the complex physiological environment in vivo, producing a large number of nanoscale cobalt particles (Cobalt Nanoparticles, CoNPs). These CoNPs can be first accumulated around the implant to cause adverse local reactions and then enter into the blood vessels followed by reaching the liver, heart, brain, kidney, and other organs through systematic circulation, which leads to multi-system toxicity symptoms. To ensure the long-term existence of cobalt-containing implants in the body, it is urgently required to find out a safe and effective detoxification drug. Herein, we have demonstrated that CoNPs could induce the ferroptosis-like cell death through the enhancement of intracellular reactive oxygen species (ROS) level, cytoplasmic Fe2+ level, lipid peroxidation, and consumption of reduced glutathione (GSH) as well as inhibition of glutathione peroxidase 4 (GPX4) activity. Importantly, α-lipoic acid (ALA), a natural antioxidant with the capability to scavenge free radicals and chelate toxic metals, was found to efficiently alleviate the adverse effects of CoNPs. The present study illustrates a new mechanism of CoNPs mediated by ferroptosis-like cytotoxicity and discloses an effective method for the detoxification of CoNPs by employing the natural antioxidant of ALA, providing a basis for further in vivo detoxification study.

CARE Dose 4D combined with sinogram-affirmed iterative reconstruction improved the image quality and reduced the radiation dose in low dose CT of the small intestine.

OBJECTIVE: Multislice computed tomography (MSCT) has been used for diagnosis of small intestinal diseases. However, the radiation dose is a big problem. This study was to investigate whether CARE Dose 4D combined with sinogram-affirmed iterative reconstruction (SAFIRE) can provide better image quality at a lower dose for imaging small intestinal diseases compared to MSCT. METHODS: The noise reduction ability of SAFIRE was assessed by scanning the plain water mold using SOMATOM Definition Flash double-source spiral CT. CT images at each stage of radiography for 239 patients were obtained. The patients were divided into groups A and B were based on different tube voltage and current or the image recombination methods. The images were restructured using with filtered back projection (FBP) and SAFIRE (S1-S5). The contrast noise ratio (CNR), CT Dose index (CTDI), subjective scoring, and objective scoring were compared to obtain the best image and reformation parameters at different stages of CT. RESULTS: Twenty-six restructuring patterns of tube voltage and current were obtained by FBP and SAFIRE. The average radiation dose using CARE Dose 4D combined with SAFIRE (S4-S5) reduced approximately 74.85% compared to conditions where the tube voltage of 100 kV and tube current of 131 mAs for patients with MSCT small intestinal CT enterography at plain CT scan, arterial stage, small intestine, and portal venous phase. The objective and subjective scoring were all significantly different among groups A and B at each stage. CONCLUSIONS: Combination of CARE Dose 4D and SAFIRE is shown to decrease the radiation dose while maintaining image quality.

Elevated serum levels of interleukin-37 correlate with poor prognosis in gastric cancer.

BACKGROUND: interleukin-37 (IL-37) is as a natural suppressor of the innate inflammatory and immune responses. It has also been reported to be involved in carcinogenesis and metastasis. The present case-control study was designed to investigate the role of serum levels of IL-37 in patients with gastric cancer. METHODS: serum IL-37 levels were determined using the enzyme-linked immunosorbent assay in 180 patients diagnosed with gastric cancer and 100 healthy controls. The association between IL-37 levels and clinical factors was assessed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters in gastric cancer. RESULTS: serum IL-37 levels in gastric cancer patients (5.606 ± 0.837 pg/ml) were significantly higher than those in healthy controls (2.364 ± 0.210 pg/ml, p < 0.001). High serum IL-37 levels were related to a poorly differentiated histologic type (p = 0.046) and advanced T stage (p = 0.003). The Kaplan-Meier survival analysis indicated that the high-IL-37 group had a poorer overall survival and progression-free survival (overall survival [OS]: 39.0 months vs 13.0 months, p < 0.001, progression-free survival [PFS]: 25.0 months vs 10.0 months, p < 0.001). Multivariate analyses showed serum IL-37 to be an independent prognostic factor for gastric cancer patients (OS: hazard ratios [HR] = 1.842, 95% CI: 1.190-2.854, p = 0.006; PFS: HR = 1.547, 95% CI: 1.014-2.359, p = 0.043). CONCLUSIONS: in conclusion, serum IL-37 levels were associated with poor overall survival and progression-free survival in gastric cancer patients. IL-37 may be a potential predictor of prognosis in gastric cancer.

Antifungal Agents: Design, Synthesis, Antifungal Activity and Molecular Docking of Phloroglucinol Derivatives.

Pseudoaspidinol is a phloroglucinol derivative with Antifungal activity and is a major active component of Dryopteris fragrans. In our previous work, we studied the total synthesis of pseudoaspidinol belonging to a phloroglucinol derivative and investigated its antifungal activity as well as its intermediates. However, the results showed these compounds have low antifungal activity. In this study, in order to increase antifungal activities of phloroglucinol derivatives, we introduced antifungal pharmacophore allylamine into the methylphloroglucinol. Meanwhile, we remained C1⁻C4 acyl group in C-6 position of methylphloroglucinol using pseudoaspidinol as the lead compound to obtain novel phloroglucinol derivatives, synthesized 17 compounds, and evaluated antifungal activities on Trichophyton rubrum and Trichophyton mentagrophytes in vitro. Molecular docking verified their ability to combine the protein binding site. The results indicated that most of the compounds had strong antifungal activity, in which compound 17 were found to be the most active on Trichophyton rubrum with Minimum Inhibitory Concentration (MIC) of 3.05 µg/mL and of Trichophyton mentagrophytes with MIC of 5.13 µg/mL. Docking results showed that compounds had a nice combination with the protein binding site. These researches could lay the foundation for developing antifungal agents of clinical value.

Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke.

BACKGROUND AND PURPOSE: Our previous study has defined a role of TP53-induced glycolysis and apoptosis regulator in neuroprotection against ischemic injury through increasing the flow of pentose phosphate pathway. We hypothesized that the pentose phosphate pathway product nicotinamide adenine dinucleotide phosphate (NADPH) could be a novel drug for treatment of ischemic stroke. METHODS: The NADPH was given before, at the onset, or after stroke onset with single or repeated intravenous (mice and rats) or intraperitoneal injections (monkey). The short- and long-term therapeutic effects of NADPH were evaluated in male adult ICR mice (total=614) with transient middle cerebral artery occlusion, in male adult Sprague-Dawley rats (total=114) with permanent middle cerebral artery occlusion, and in male adult rhesus monkey (total=12) with thrombotic middle cerebral artery occlusion. RESULTS: Administration of NADPH led to a dramatic increase in the levels of ATP and reduced form of glutathione, whereas it decreased the levels of reactive oxygen species. NADPH significantly reduced infarct volume, improved poststroke survival, and recovery of neurological functions in mouse and rat models of stroke. Robust neuroprotection of a single dose of NADPH was seen when it was administered within 5 hours after reperfusion; however, repeat administration of NADPH twice a day for 7 days starting 24 hours after the onset of stroke also offered therapeutic effects. Pretreatment with NADPH also significantly improved the outcome of stroke insult. CONCLUSIONS: Administration of exogenous NADPH significantly protected neurons against ischemia/reperfusion-induced injury in 2 rodent stroke models. Thus, NADPH might be a promising drug candidate for treatment of ischemic stroke.

A TIGAR-regulated metabolic pathway is critical for protection of brain ischemia.

TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases the flow of pentose phosphate pathway (PPP), which generates NADPH and pentose. We hypothesized that TIGAR plays a neuroprotective role in brain ischemia as neurons do not rely on glycolysis but are vulnerable to oxidative stress. We found that TIGAR was highly expressed in brain neurons and was rapidly upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. Overexpression of TIGAR in normal mice with lentivirus reduced ischemic neuronal injury, whereas lentivirus-mediated TIGAR knockdown aggravated it. In cultured primary neurons, increasing TIGAR expression reduced oxygen and glucose deprivation (OGD)/reoxygenation-induced injury, whereas decreasing its expression worsened the injury. The glucose 6-phosphate dehydrogenase was upregulated in mouse and cellular models of stroke, and its upregulation was further enhanced by overexpression of TIGAR. Supplementation of NADPH also reduced ischemia/reperfusion brain injury and alleviated TIGAR knockdown-induced aggravation of ischemic injury. In animal and cellular stroke models, ischemia/reperfusion increased mitochondrial localization of TIGAR. OGD/reoxygenation-induced elevation of ROS, reduction of GSH, dysfunction of mitochondria, and activation of caspase-3 were rescued by overexpression of TIGAR or supplementation of NADPH, while knockdown of TIGAR aggravated these changes. Together, our results show that TIGAR protects ischemic brain injury via enhancing PPP flux and preserving mitochondria function, and thus may be a valuable therapeutic target for ischemic brain injury.

Anti-miR-362-3p Inhibits Migration and Invasion of Human Gastric Cancer Cells by Its Target CD82.

AIM: This study was to investigate the effects and mechanisms of miR-362-3p on regulation of gastric cancer (GC) cell metastasis potential. METHODS: We detected miR-362-3p level in GC and adjacent normal tissues and investigated the relationship with clinicopathological factors. Next, we analyzed the level of miR-362-3p expression and CD82 in different differentiated GC cells compared with a normal gastric mucosa cell by RT-PCR and Western blot. Dual-luciferase reporter assay and Western blot confirmed a direct interaction between miR-362-3p and CD82 3'UTR. After miR-362-3p and CD82 were silenced in GC cells, we compared the transfected GC cells migration and invasion capacity by transwell assay. In addition, we detected the effects on cells angiogenesis by tube formation assay. Western blot was used to detect the impact of CD82 and miR-362-3p on epithelial-to-mesenchymal transition markers in treated GC cells. RESULTS: Level of miR-362-3p expression was much higher in GC cells than in normal gastric mucosa cell, and miR-362-3p expression negatively correlated with CD82 mRNA expression in these cell lines. Furthermore, miR-362-3p expression induced [corrected] GC cell metastasis capacity by suppression of CD82 expression. Level of miR-362-3p may mediate E-cadherin, N-cadherin, and vimentin expression in GC cells. CONCLUSION: This study illuminated that downregulation of miR-362-3p along with the upregulation of CD82 in GC cells resulted in the inhibition of GC migration and invasion. Thus, our results suggested that miR-362-3p or CD82 can be exploited as a new potential target for control of GC in the future.

Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

BACKGROUND: Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. METHODS: To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 µg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-ß/Smad signaling pathway and oxidative stress were examined. RESULTS: The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1ß and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-ß/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. CONCLUSIONS: The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

O-GlcNAcylation in ischemic diseases.

Protein glycosylation is an extensively studied field, with the most studied forms being oxygen or nitrogen-linked N-acetylglucosamine (O-GlcNAc or N-GlcNAc) glycosylation. Particular residues on proteins are targeted by O-GlcNAcylation, which is among the most intricate post-translational modifications. Significantly contributing to an organism's proteome, it influences numerous factors affecting protein stability, function, and subcellular localization. It also modifies the cellular function of target proteins that have crucial responsibilities in controlling pathways related to the central nervous system, cardiovascular homeostasis, and other organ functions. Under conditions of acute stress, changes in the levels of O-GlcNAcylation of these proteins may have a defensive function. Nevertheless, deviant O-GlcNAcylation nullifies this safeguard and stimulates the advancement of several ailments, the prognosis of which relies on the cellular milieu. Hence, this review provides a concise overview of the function and comprehension of O-GlcNAcylation in ischemia diseases, aiming to facilitate the discovery of new therapeutic targets for efficient treatment, particularly in patients with diabetes.

Characterization of three cryptic plasmids from Lactobacillus plantarum G63 that was isolated from Chinese pickle.

Three plasmids from Lactobacillus plantarum G63, pG6301, pG6302 and pG6303, were sequenced and have molecular sizes of 3516-bp, 9112-bp and 10047-bp, respectively. We determined the replicons of these plasmids. The pG6301 plasmid carried a replication gene that functioned by the rolling-circle replication mechanism. The Rep protein of pG6302 shared extremely low similarity with a reported plasmid, pLME300, which replicated by a bi-directional mechanism. Both the Rep protein and OriV analyses indicated a similar replication mechanism in pG6302. Conversely, we found neither the Rep protein nor OriV when we analyzed the whole sequence of pG6303. This finding may illustrate a novel replication mechanism. Additionally, the transposon, a mobilization element, was analyzed and compared to a similar insertion sequence (IS) element. A predicted lysozyme gene, pG6303 guhA, was heterologously expressed, but no activity was detected. The pG6302 and pG6303 plasmids contain new replicons and may be useful vector candidates for future molecular manipulation of L. plantarum.

Neuroprotective effect of 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-ß-D-pyranoside against sodium nitroprusside-induced neurotoxicity in HT22 cells.

2-(4-Methoxyphenyl) ethyl-2-acetamido-2-deoxy-ß-D-pyranoside (GlcNAc-Sal), the salidroside analog was synthesized and shown to inhibit hypoglycemia and serum limitation induced apoptosis in PC12 cells. This study investigated the protective effects of GlcNAc-Sal on sodium nitroprusside (SNP)-induced cytotoxicity in HT22 cells. Cell viability tests and Hoechst 33342 staining comfirmed that GlcNAc-Sal pretreatment attenuated SNP-stimulated apoptotic cell death in HT22 cells in a concentration-dependent manner. The measurements of reactive oxygen species (ROS), nitric oxide (NO) production and apoptosis-related gene and protein expression suggest that the protection of GlcNAc-Sal, shown in this study, might be mediated by inhibiting intracellular ROS and NO production, and regulating apoptosis-related gene and protein expression during SNP stimulation. Perhaps, this study might contribute to the development of GlcNAc-Sal as an agent for preventing and/or treating a variety of NO-induced brain diseases.

Association of vitamin D receptor polymorphisms with colorectal cancer susceptibility: A systematic meta-analysis.

BACKGROUND: Recent studies have reported an association between vitamin D receptor (VDR) polymorphisms and colorectal cancer (CRC) risk; however, the results are controversial. This meta-analysis was performed to investigate whether the Cdx-2, Tru9I, FokI, BsmI, TaqI, and ApaI polymorphisms were correlated with CRC susceptibility. METHODS: All potential studies were retrieved by searching the PubMed, EMBASE, and Cochrane Library databases through October 2, 2021. Odds ratios (ORs) with 95% confidence intervals were used to evaluate the correlation between VDR gene Cdx-2, Tru9I, FokI, BsmI, TaqI, and ApaI polymorphisms and CRC risk. RESULTS: In this meta-analysis, the BsmI variant was significantly correlated with a lower risk of CRC, especially in Caucasian population (B vs b: OR 0.94, 95%CI 0.90-0.99; BB vs bb: OR 0.88; 95%CI 0.79-0.97; BB vs Bb/bb: BB vs Bb/bb: OR 0.89; 95%CI 0.81-0.98). A statistically significant result from the FokI polymorphism was observed in colon cancer rather than rectal cancer (Ff vs FF: OR 0.86, 95%CI 0.84-0.93; ff/Ff vs FF: OR 0.88, 95%CI 0.79-0.98; ff vs Ff/FF: OR 0.90, 95%CI 0.82-0.99). Similarly, Cdx-2 polymorphism was found to be associated with decreased CRC risk among Africans (C vs c: OR 0.50, 95%CI 0.33-0.75; CC vs cc: OR 0.09, 95%CI 0.01-0.77; Cc vs cc: OR 0.49, 95%CI 0.30-0.81; CC/Cc vs cc: OR 0.45, 95%CI 0.28-0.74,). CONCLUSION: Our findings indicate that VDR polymorphisms are significantly associated with CRC risk.

Mori fructus aqueous extracts attenuates liver injury by inhibiting ferroptosis via the Nrf2 pathway.

BACKGROUND: Liver fibrosis and hepatocellular carcinogenesis secondary to liver fibrosis are serious liver diseases with no effective treatments. Mori fructus aqueous extracts (MFAEs) have served as successful treatments for many types of liver injury including fibrosis although the molecular mechanisms are unknown at present. PURPOSE: To investigate the effect of MFAEs in alleviating acute and chronic liver injury and tried to decipher the underlying mechanism. METHODS AND RESULTS: Mice were divided into 5 groups (n = 8) for acute (groups: control, 0.3% CCl4, bifendate (BD), 100 and 200 mg/kg MFAEs, 7 d) and chronic (groups: control, 10% CCl4, BD, 100 and 200 mg/kg MFAEs, 4 weeks) liver injury study. Each mouse was injected intraperitoneally with 10 µL/g corn oil containing CCl4 expect the control group. HepG2 cells were used in vitro study. Eighteen communal components were identified by UPLC-LTQ-Orbitrap-MS. We utilized a mouse model for acute and chronic liver injury using CCl4 and MFAEs administration effectively blocked fibrosis and significantly inhibited inflammation in the liver. MFAEs activated the nuclear factor erythroid derived 2 like 2/heme oxygenase 1 (Nrf2/HO-1) pathway and promoted the synthesis of the antioxidants glutathione (GSH), superoxidedismutase (SOD) and glutathione peroxidase (GSH-Px) that resulted in reduced levels of CCl4-induced oxidative stress molecules including reactive oxygen species. These extracts administered to mice also inhibited ferroptosis in the liver by regulating the expression of Acyl-CoA synthetase long chain family member 4 (ACSL4), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thus reducing the occurrence of liver fibrosis. Both in vivo and in vitro tests indicated that the mechanism of MFAEs protection against liver fibrosis was linked to activation of Nrf2 signaling. These effects were blocked in vitro by the addition of a specific Nrf2 inhibitor. CONCLUSION: MFAEs inhibited oxidative stress, ferroptosis and inflammation of the liver by activating Nrf2 signal pathway and provided a significant protective effect against CCl4-induced liver fibrosis.

Deciphering the mechanism of Peptostreptococcus anaerobius-induced chemoresistance in colorectal cancer: the important roles of MDSC recruitment and EMT activation.

Peptostreptococcus anaerobius (P. anaerobius, PA) in intestinal flora of patients with colorectal cancer (CRC) are associated with poor prognosis. Studies have shown that P. anaerobius could promote colorectal carcinogenesis and progression, but whether P. anaerobius could induce chemoresistance of colorectal cancer has not been clarified. Here, both in vitro and in vivo experiments showed that P. anaerobius specifically colonized the CRC lesion and enhanced chemoresistance of colorectal cancer to oxaliplatin by recruiting myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Furthermore, this study revealed that it was the increased secretion of IL-23 by MDSCs that subsequently facilitated the epithelial-mesenchymal transition (EMT) of tumor cells to induce chemoresistance of CRC by activating the Stat3-EMT pathway. Our results highlight that targeting P. anaerobius might be a novel therapeutic strategy to overcome chemoresistance in the treatment of CRC.