Periodontitis is an inflammatory disease induced by plaque microorganisms. In the clinic, antibiotic assistant periodontal mechanical therapy is the most effective therapy for the treatment of periodontitis. However, the drug resistance of the antibiotics and the repeated coming and diminishing of the disorder of oxidation-reduction balance in the inflammatory tissue could not meet the high requirements for periodontic health control in long periods. Deuterohemin-ala-his-thr-val-glu-lys (DhHP-6) is a biomimetic oxidase-mimicking enzyme that simulates the reactive oxygen radical scavenger function of heme by synthesizing the new molecular material following the key structure and amino acid sequence of heme. In this article, we report the antioxidant and anti-inflammatory properties of DhHP-6 by building a inflammatory model for human gingival fibroblasts (HGFs) stimulated by lipolysaccharide (LPS) and its effects on periodontitis in Wistar rats. DhHP-6 reduced the oxidative stress of HGFs by increasing the amount of the reductase species of glutathione (GSH) and catalase (CAT) while decreasing the amount of oxidase species of malonaldehyde (MDA) and reactive oxygen species (ROS). DhHP-6 had a dose-dependent protective effect on alveolar bone absorption in rats with periodontitis, enhanced antioxidant capacity, and reduced inflammation. As determined by Micro-CT scanning, DhHP-6 reduced alveolar bone loss and improved the bone structure of the left maxillary first molar of rats. There were no obvious morphological and histological differences in the rat organs with or without DhHP-6 treatment. These results suggest that DhHP-6 can be used to treat periodontitis by increasing the expression levels of antioxidant enzymes and antioxidants in systemic and local tissues, thereby reducing levels of oxidation products and cyto-inflammatory factors. The synergistic antioxidant and anti-inflammatory effects of DhHP-6 suggest that there are promising applications of this biomimetic enzyme molecular material for the next generation of agents for periodontitis therapy.

Abdominal obesity (AO) has been regarded as the most dangerous type of obesity. The Conicity-index (C-index) had a high ability to discriminate underlying AO. The purpose of this study was to determine the ability of C-index to predict all-cause mortality among non-cancer Chinese older people.

Renal tubulointerstitial fibrosis is the hallmark of chronic kidney disease (CKD) and the best predictor of renal survival. However, current treatments for CKD remain extremely limited. Therefore, novel therapeutic targets are urgently needed to either stop or reverse CKD progression. The present study was designed to explore the potential role of GPR87, a member of the G protein-coupled receptors (GPCRs) family, in the pathogenesis of tubulointerstitial fibrosis. It was found that GPR87 was significantly induced in the kidney, especially in tubular areas, from different mouse models of renal fibrosis, including unilateral ureteral obstruction (UUO) nephropathy, aristolochic acid nephropathy, and diabetic nephropathy, respectively. Tubule-specific GPR87 deletion dramatically ameliorated tubulointerstitial fibrosis in UUO mice. Mechanistically, GPR87 accelerated glycolysis and mitochondrial injury by YAP-hexokinase-2 signaling, thereby promoting renal fibrosis. Importantly, the upregulation of GPR87 was also found in the kidney from patients with various CKD, indicating that the induction of GPR87 may be a common feature of human kidney diseases. Collectively, our studies for the first time demonstrate that GPR87 plays a pivotal role in renal fibrosis at least in part by accelerating glycolysis and mitochondrial injury, suggesting that targeting GPR87 may represent a novel therapeutic strategy for patients with CKD.

Background: To investigate the pathophysiology of age-related hearing loss (ARHL) and the mechanism of resveratrol (RSV) in prevention and treatment of ARHL. Methods: C57BL/6 mice of different ages were used in this study. Auditory brainstem response (ABR) was performed to assess hearing and identify abnormalities. Surface preparation and hair cell-specific marker Myo VIIa were employed to evaluated cochlear hair cell losses. Scanning electron microscopy (SEM) was to observe the microstructure of the organ of Corti (OC). The expression of related proteins in the RIPK1/RIPK3/MLKL pathway in cochlear tissue was detected by immunofluorescence. Results: In old mice (15 months), the ABR threshold increased significantly compared with the young mice. After 50 mg/kg RSV intervention, the hearing threshold of the old mice was significantly reduced at 8 kHz and 12 kHz as well as click. 100 mg/kg RSV led to a statistically significant reduction in hearing threshold only at clicks, whereas 300 mg/kg RSV showed no difference at all frequencies tested. In terms of cochlear hair cell loss, the damage of OHC and IHC was severe in old mice, but the damage was evidently reduced in RSV 50 mg/kg group. Notably, in the RSV 300 mg/kg group, the loss and disorientation of both the OHCs and IHCs were aggravated. Under SEM, a large number of OHCs were lost in the old group, but increased significantly in the RSV 50 mg/kg group, and even the OHCs were more seriously damaged in the RSV 300 mg/kg group. Furthermore, immunofluorescence showed that 50 mg/kg RSV significantly reduced the expression of RIPK3, RIPK1, and MLKL in the cochlea during aging, especially in necroptosis-sensitive regions OCs and SGN. Conclusion: Low-dose RSV inhibited RIPK3-mediated necroptosis in aging cochlea and delayed the onset of ARHL, which was a promising therapeutic strategy for ARHL.

Action potentials (APs) in neurons are generated at the axon initial segment (AIS). AP dynamics, including initiation and propagation, are intimately associated with neuronal excitability and neurotransmitter release kinetics. Most learning and memory studies at the single-neuron level have relied on the use of animal models, most notably rodents. Here, we studied AP initiation and propagation in cultured hippocampal neurons from Sprague-Dawley (SD) rats and C57BL/6 (C57) mice with genetically encoded voltage indicator (GEVI)-based voltage imaging. Our data showed that APs traveled bidirectionally in neurons from both species; forward-propagating APs (fpAPs) had a different speed than backpropagating APs (bpAPs). Additionally, we observed distinct AP propagation characteristics in AISs emerging from the somatic envelope compared to those originating from dendrites. Compared with rat neurons, mouse neurons exhibited higher bpAP speed and lower fpAP speed, more distally located ankyrin G (AnkG) in AISs, and longer Nav1.2 lengths in AISs. Moreover, during AIS plasticity, AnkG and Nav1.2 showed distal shifts in location and shorter lengths of labeled AISs in rat neurons; in mouse neurons, however, they showed a longer AnkG-labeled length and more distal Nav1.2 location. Our findings suggest that hippocampal neurons in SD rats and C57 mice may have different AP propagation speeds, different AnkG and Nav1.2 patterns in the AIS, and different AIS plasticity properties, indicating that comparisons between these species must be carefully considered.

Hypericum perforatum L. has a long history in many countries of being used as a herbal medicine. It is also widely used in Chinese herbal medicine for the treatment of infections. Hypericin, a main component extracted from Hypericum perforatum L., has attracted the attention of many researchers for its remarkable antiviral, antitumor and antidepressant effects.

Allergic asthma is associated with allergen-induced airway hyperresponsiveness and inflammatory cell infiltration. While moderate-to-severe asthma with refractory symptoms is difficult to treat, methane is protective against organ damage. In this study, an asthmatic mouse model was established. Airway resistance under acetylcholine stimulation in asthmatic mice and histology of lung tissue injury were determined. EOS infiltration was determined by flow cytometry. Enzyme-linked immunosorbent assays (ELISAs) were performed for the determination of relevant cytokine levels in asthmatic mice with or without methane treatment. The potential mechanisms of methane under anti-IL-10 antibody intraperitoneal intervention were assessed by ELISA and flow cytometry. Pulmonary T regulatory cells (Tregs) were analyzed by flow cytometry, and anti-CD25 antibody was used to block them. Immunoblot analysis was performed to evaluate if methane played a role in the asthmatic lungs via the NF-κB and MAPKs pathways. The results showed that methane significantly improved airway compliance, relieved asthma-induced lung injury, and reduced EOS accumulation and inflammatory mediators in the lungs of ovalbumin-treated asthmatic mice. Anti-IL-10 treatment diminished the ameliorating effect of methane on asthma. In addition, methane enhanced pulmonary Tregs in asthma, which could be blocked by the anti-CD25 antibody. Further analysis revealed that methane decreased p-p65/p65 and p-p38/p38 expression. In conclusion, methane is a readily available and inexpensive molecule potentially suitable for human use, which can alleviate asthma-induced lung injury and EOS infiltration through the IL-10 pathway by increasing Tregs and decreasing NF-κB and p38 MAPK in a mouse model.

Precision remodeling of glycans in their native environments is pivotal for understanding glycan-mediated biological events and has important biotechnological implications in fields of clinical diagnosis, glyco-immune checkpoint therapy, and so forth. However, the influence of aglycone-steric diversity on the selectivity of glycan remodeling has been largely overlooked, limiting the application in complex biological scenarios. Here, we report the achievement of aglycone sterics-selective enzymatic glycan remodeling by controlled grafting of functional polymers from glycoenzyme. Through tuning polymer length, a series of enzyme-polymer composites with varying substrate permeability are prepared, which afford an activity pattern-based differentiation strategy for aglycone sterics. This leads to the implementation of glycolipid's partner screening, and aglycone sterics-selective glycan remodeling in a complex biological environment. We further orchestrate the polymer length adjustment with external cues to regulate aglycone-steric selectivity in a multi-faceted fashion, resulting in an unexpected enhancement of glycolipid remodeling, and temporal control of glycan remodeling on live cells.

Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-β1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.

Sevoflurane is identified as an effective candidate drug for acute lung injury (ALI) treatment, but its curing effects and detailed mechanisms have not been fully disclosed. The present study was designed to resolve this academic issue.

There is an urgent need to identify chemotherapeutic agents with improved efficacy and safety against triple-negative breast cancer (TNBC). Ginsenosides can reportedly induce tumor cell death, invasion, and metastasis; however, poor water solubility, low oral absorption rate, and rapid blood clearance limit their clinical application. Utilizing the amphiphilic property of ginsenosides as building blocks of biomaterials, we fabricated a carrier-free nanodrug composed of ginsenosides Rg3 and Rb1 using a nano-reprecipitation method without any additional carriers. After characterizing and demonstrating their uniform morphology and pH-sensitive drug release properties, we observed that Rg3-Rb1 nanoparticles (NPs) exhibited stronger antitumor and anti-invasive effects on TNBCs in vitro than those mediated by free ginsenosides. Consequently, Rg3-Rb1 NPs afforded superior inhibition of tumor growth and reduction of pulmonary metastasis than the Rg3 and Rb1 mixture, with no obvious systematic toxicity in vivo. Collectively, our results provide a proof-of-concept that self-assembled engineered ginsenoside nanodrugs may be efficient and safe for TNBC therapy.

Homologous recombination deficiency (HRD) is a well-known biomarker which could predict poly-ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small-cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)-related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression.

There is genetic diversity of hair types in the Inner Mongolia cashmere goat population. Previous studies have found that fibroblast growth factor 21 (FGF21) and PI3K-AKT signal pathways may be related to different hair types in Inner Mongolia cashmere goats. Therefore, the purpose of this study was to explore the effects of the PI3K-AKT signal pathway on different hair types, the expression of mRNA and protein expression sites of FGF21 in the hair follicles of cashmere goats with different hair types, so as to lay a foundation for understanding the molecular mechanism of different hair types and the role of skin hair follicle development. In this experiment, the skin tissues of long hair type (LHG) and short hair type (SHG) of Inner Mongolia cashmere goat were collected in three key periods of secondary hair follicle growth, namely, anagen (September), catagen (December), and telogen (March). The relative expression of FGF21 and PI3K-AKT signal pathway candidate gene mRNA in different periods and different hair types was detected by real-time fluorescence quantitative technique (qRT-PCR), and the expression site of FGF21 protein was located by immunohistochemical technique. Through qRT-PCR, it was found that the relative expression of FGF21, FGFR1, AKT3, BRCA1, PKN3, SPP1, and GNG4 was significantly different between LHG and SHG. The expression of FGF21 in the skin of LHG was significantly higher than that of SHG in the three periods. Through immunohistochemical test, it was found that FGF21 protein was mainly expressed in primary hair follicle connective tissue sheath, primary hair follicle outer root sheath, secondary hair follicle outer root sheath, and sebaceous glands. It was also found that the expression of LHG skin tissue in the outer root sheath of primary hair follicles was higher than that of SHG in three periods. In summary, it is suggested that the PI3K-AKT signal pathway may play an important role in the formation of different hair types in Inner Mongolia cashmere goats.

Tandospirone, a third-generation of antianxiety agent with fewer side effects, has been widely used in the treatment of anxiety. Moreover, it is interesting that tandospirone has been found to relieve gastrointestinal symptoms in patients with refractory irritable bowel syndrome who also have psychological dysfunctions. However, the underlying mechanism remains unclear. In this study, using a visceral hypersensitivity rat model induced by chronic water avoidance stress to mimic the symptoms of irritable bowel syndrome, we found that tandospirone relieved anxiety-like behavior and visceral hypersensitivity induced by stress. Meanwhile, stressed rats had increased 5-HT concentration, less 5-HT1A receptor expression, and enhanced theta oscillations in the anterior cingulate cortex (ACC). Furthermore, the power of the theta band in ACC is positively correlated with the level of visceral sensitivity. Activation of 5-HT1A receptors by its agonist, 8-OH-DPAT, to compensate for their effect in ACC reduced the enhancement of theta oscillations in ACC slices in stressed rats, whereas 5-HT1A receptor antagonist, WAY100135, facilitates theta oscillations in slices of normal rats. Tandospirone reduced the enhancement of theta band power in ACC in vitro and in vivo, thus alleviating anxiety-like behavior and visceral hypersensitivity through 5-HT1A receptors in stressed rats. These results suggest a novel mechanism by which tandospirone activates 5-HT1A receptors to relieve stress-induced anxiety and visceral hypersensitivity by suppressing theta oscillation enhancement in ACC.

Colorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety.

To analyze the characteristics of global β-lactamase-producing Enterobacter cloacae including the distribution of β-lactamase, sequence types (STs) as well as plasmid replicons.

Prolonged or excessive stimulation from inhaled toxins may cause oxidative stress and DNA damage that can lead to stress-induced senescence in epithelial cells, which can contribute to several airway diseases. Mounting evidence has shown carbon monoxide (CO) confers cytoprotective effects. We investigated the effects of CO on oxidative stress-induced senescence in human airway epithelium and elucidated the underlying molecular mechanisms. Here, CO pretreatment reduced H2O2-mediated increases in total reactive oxygen species (ROS) production and mitochondrial superoxide in a human bronchial epithelial cell line (BEAS-2B). H2O2 treatment triggered a premature senescence-like phenotype with enlarged and flattened cell morphology accompanied by increased SA-β-gal activity, cell cycle arrest in G0/G1, reduced cell viability, and increased transcription of senescence-associated secretory phenotype (SASP) genes. Additionally, exposure to H2O2 increased protein levels of cellular senescence markers (p53 and p21), reduced Sirtuin 3 (SIRT3) and manganese superoxide dismutase (MnSOD) levels, and increased p53 K382 acetylation. These H2O2-mediated effects were attenuated by pretreatment with a CO-containing solution. SIRT3 silencing induced mitochondrial superoxide production and triggered a senescence-like phenotype, whereas overexpression decreased mitochondrial superoxide production and alleviated the senescence-like phenotype. Air-liquid interface (ALI) culture of primary human bronchial cells, which becomes a fully differentiated pseudostratified mucociliary epithelium, was used as a model. We found that apical and basolateral exposure to H2O2 induced a vacuolated structure that impaired the integrity of ALI cultures, increased goblet cell numbers, decreased SCGB1A1+ club cell numbers, increased p21 protein levels, and increased SASP gene transcription, consistent with our observations in BEAS-2B cells. These effects were attenuated in the apical presence of a CO-containing solution. In summary, we revealed that CO has a pivotal role in epithelial senescence by regulating ROS production via the SIRT3/MnSOD/p53/p21 pathway. This may have important implications in the prevention and treatment of age-associated respiratory pathologies.

Oxaliplatin (OXA)-based chemotherapy demonstrates active efficacy in advanced hepatocellular carcinoma (HCC), while resistance development limits its clinical efficacy. Thus, identifying resistance-related molecules and underlying mechanisms contributes to improving the therapeutic efficacy of HCC patients. MicroRNA-371a-5p (MiR-371a-5p) fulfills an important function in tumor progression. However, little is known about the effect of miR-371a-5p on chemotherapy response. In this study, quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry were used to determine the expression levels of miR-371a-5p, BECN1 and autophagy-related proteins in HCC cells, tissues and serum. The luciferase reporter assay was used to assess the directly suppressive effect of miR-371a-5p on BECN1 mRNA translation. Moreover, gain- and loss-of-function assays and rescue assays were used to evaluate the mediated effect of BECN1-dependent autophagy on the role of miR-371a-5p in the response of HCC cells to OXA. We found that miR-371a-5p was significantly up-regulated in HCC tissues and serum from patients, whereas BECN1 protein was down-regulated in HCC tissues compared to the corresponding controls. We also found that there was a negative correlation between the two molecules in HCC tissues. In addition, we found that miR-371a-5p expression was positively associated with malignant characteristics of HCC and BECN1 protein expression is negatively associated. Contrary to this, we found that miR-371a-5p enhances and BECN1 attenuates the response of HCC cells to OXA. Importantly, the enhanced effect of miR-371a-5p on the response of HCC cells to OXA could be reduced by re-expression of non-targetable BECN1, and then the reduced effect was restored following bafilomycin A treatment. Taken together, we identified a dual role of miR-371a-5p in HCC malignant characteristics and the response of HCC cells to oxaliplatin. Importantly, we reveal that miR-371a-5p enhances oxaliplatin response by target suppression of BECN1-dependent autophagy.

Angiopoietin-like 4 (ANGPTL4) is highly expressed in a variety of neoplasms and promotes cancer progression. Nevertheless, the mechanism of ANGPTL4 in ovarian cancer (OC) metastasis remains unclear. This study aimeds to explore whether ANGPTL4 regulates OC progression and elucidate the underlying mechanism.

The cold-adapted and/or salt-tolerant enzymes from marine microorganisms were confirmed to be meritorious tools to enhance the efficiency of biocatalysis in industrial biotechnology. We purified and characterized a dextranase CeDex from the marine bacterium Cellulosimicrobium sp. THN1. CeDex acted in alkaline pHs (7.5-8.5) and a broad temperature range (10-50°C) with sufficient pH stability and thermostability. Remarkably, CeDex retained approximately 40% of its maximal activities at 4°C and increased its activity to 150% in 4 M NaCl, displaying prominently cold adaptation and salt tolerance. Moreover, CeDex was greatly stimulated by Mg2+, Na+, Ba2+, Ca2+ and Sr2+, and sugarcane juice always contains K+, Ca2+, Mg2+ and Na+, so CeDex will be suitable for removing dextran in the sugar industry. The main hydrolysate of CeDex was isomaltotriose, accompanied by isomaltotetraose, long-chain IOMs, and a small amount of isomaltose. The amino acid sequence of CeDex was identified from the THN1 genomic sequence by Nano LC-MS/MS and classified into the GH49 family. Notably, CeDex could prevent the formation of Streptococcus mutans biofilm and disassemble existing biofilms at 10 U/ml concentration and would have great potential to defeat biofilm-related dental caries.