To determine the effect of a pleiotropic MMP-inhibitor, a novel chemically-modified curcumin 2.24 (CMC2.24), on the clinical and biological measures of naturally-occurring periodontitis in the beagle dog.

Objective: To explore relationships between PET/CT characteristics of cold-activated brown adipose tissue (BAT), measures of adiposity and metabolic markers.Methods: We conducted a post-hoc analysis of a study which utilized PET/CT to characterize BAT. 25 men ages 18-24 (BMI 19.4 to 35.9 kg/m2) were studied. Fasting blood samples were collected. Body composition was measured using DXA. An individualized cooling protocol was utilized to activate BAT prior to imaging with PET/CT.Results: There was an inverse relationship between fasting serum glucose and BAT volume (r = -0.40, p = 0.048). A marginally significant inverse relationship was also noted between fasting glucose and total BAT activity (r = -0.40, p = 0.05). In addition, a positive correlation was observed between serum FGF21 and SUVmax (r = 0.51, p = 0.01). No significant correlations were noted for measures of BAT activity or volume and other indicators of adiposity or glucose metabolism.Conclusions: The presence of active BAT may be associated with lower fasting glucose in young men. BAT activity may also be correlated with levels of FGF21, suggesting that BAT may lower glucose levels via an FGF21 dependent pathway. Further studies are needed to clarify mechanisms by which BAT may impact glucose metabolism.

Eosinophils play a critical role in the pathogenesis of allergic airway inflammation. However, the relative importance of eosinophil activation and pathogenicity in driving the progression of disease severity of allergic rhinitis (AR) remains to be defined. We aimed to assess the relation of activated and pathogenic eosinophils with disease severity of patients with AR. Peripheral blood and nasal samples were collected from patients with mild (n = 10) and moderate-severe (n = 21) house dust mite AR and healthy control subjects (n = 10) recruited prospectively. Expressions of activation and pathogenic markers on eosinophils in the blood and nose were analyzed by flow cytometry. The eosinophilic cation protein- (ECP-) releasing potential and the pro-Th2 function of blood eosinophils were compared between the mild and moderate-severe patients and healthy controls. Our results showed that the numbers of activated (CD44+ and CD69+) and pathogenic (CD101+CD274+) eosinophils in the blood and nose as well as blood eosinophil progenitors were increased in moderate-severe AR compared with the mild patients and healthy controls. In addition, the levels of activated and pathogenic eosinophils in the blood were positively correlated with the total nasal symptom score and serum ECP and eosinophil peroxidase (EPX) levels in patients with AR. Furthermore, the blood eosinophils obtained from the moderate-severe patients exhibited a higher potential of releasing ECP and EPX induced by CCL11 and of promoting Th2 responses than those from the mild patients and healthy controls. In conclusion, patients with moderate-severe AR are characterized by elevated levels of activated and pathogenic eosinophils, which are associated with higher production of ECP, EPX, and IL-4 in the peripheral blood.

Phosphatidylcholine-specific phospholipase Cγ1 (PLCγ1) is involved in regulating cell metabolism. However, little is known how PLCγ1 directs BMSC differentiation. Here, we investigated the role of PLCγ1 in rat BMSC differentiation into osteoblasts and chondrocytes. The results of Alizarin red and Alcian blue staining showed that PLCγ1 inhibitor U73122 significantly enhanced the mineralization capacity and proteoglycan deposition of BMSCs. The results of qPCR technique and Western blot analysis showed that long-term treatment of U73122 enhanced COL1A1 and OPG mRNA levels and Collagen 1A1, BMP2, and p-Smad1/5/9 protein levels and that short-term treatment of U73122 enhanced COL2A1 and SOX9 mRNA levels and Collagen 2, SOX9, Aggrecan, TGF-β3, and p-Smad2/3 protein levels. Decreased p-mTOR and p-P38 contributed to enhanced osteogenic potentials of BMSCs and increased p-P38 contributed to enhanced chondrogenic potentials of BMSCs. The scaffold transplantation with U73122+BMSC was more efficacious than BMSC alone for osteochondral defect repair in a rat model. Therefore, suppressing PLCγ1 could improve the capacity to effectively use BMSCs for cell therapy of osteochondral defect.

The incidence and prevalence of inflammatory bowel disorders (IBD) are increasing around the world due to bacterial infection, abnormal immune response, etc. The conventional medicines for IBD treatment possess serious side effects. Periplaneta americana (P. americana), a traditional Chinese medicine, has been used to treat arthritis, fever, aches, inflammation, and other diseases. This study aimed to evaluate the anti-inflammatory effects of oligosaccharides from P. Americana (OPA) and its possible mechanisms in vivo. OPA were purified and biochemical characterization was analyzed by HPGPC, HPLC, FT-IR, and GC-MS. Acute colitis mice model was established, the acute toxicity and anti-inflammatory activity were tested in vivo. The results showed OPA with molecular mass of 1.0 kDa were composed of 83% glucose, 6% galactose, 11% xylose, and the backbone was (1→4)-Glcp. OPA had potent antioxidant activities in vitro and significantly alleviated the clinical symptoms of colitis, relieved colon damage without toxic side effects in vivo. OPA exhibited anti-inflammatory activity by regulating Th1/Th2, reducing oxidative stress, preserving intestinal barrier integrity, and inhibiting TLR4/MAPK/NF-κB pathway. Moreover, OPA protected gut by increasing microbial diversity and beneficial bacteria, and reducing pathogenic bacteria in feces. OPA might be the candidate of complementary and alternative medicines of IBD with low-cost and high safety.

Metformin is the most widely used anti-diabetic medication worldwide. However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4α (HNF4α). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4α also has an indispensable role in the regulation of expression of gluconeogenic genes. Consistently, H19 overexpression in a human liver cell line leads to decreased methylation and increased expression of Hnf4α, with concomitant activation of the gluconeogenic program. Mechanistically, we show that the methylation change of Hnf4α is induced by H19-mediated regulation of S-adenosylhomocysteine hydrolase. We also provide evidence that altered H19 expression is a direct effect of metformin in the fetal liver. Our results suggest that metformin from the mother can directly act upon the fetal liver to modify Hnf4α expression, a key factor for both liver development and function, and that perturbation of this H19/Hnf4α-mediated pathway may contribute to the fetal origin of adult metabolic abnormalities.

Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model.

Chronic kidney disease caused by X-linked Alport syndrome (XLAS) is relatively rare. However, due to the nonspecific pathologic and clinical manifestations of this disease, it is easily misdiagnosed. Genetic testing is crucial in identifying suspected cases. In addition, the results of genetic testing are an important indicator of patient prognosis. This study demonstrated a novel pathogenic COL4A5 splicing site variant in a Chinese family with XLAS.

An imbalance in ROS (reactive oxidative species) and the antioxidant barrier regulates the process of tumorigenesis. GSH has a key effect in preventing cells from oxidative damage by scavenging ROS. The role of CHAC2, an enzyme regulating GSH, in lung adenocarcinoma remains unknown. Here, RNA sequencing data analysis and immunohistochemistry (IHC) assays of lung adenocarcinoma and normal lung tissues were used to verify the expression of CHAC2. The effect of CHAC2 on the proliferation abilities of lung adenocarcinoma cells was examined using a series of overexpression or knockout assays. RNA sequencing and IHC results showed that the expression level of CHAC2 in lung adenocarcinoma was higher than that in normal lung tissues. CCK-8, colony formation and subcutaneous xenograft experiments in BALB/c nude mice showed that in vitro and in vivo CHAC2 promoted the growth capacity of lung adenocarcinoma cells. Subsequent immunoblot, immunohistochemistry and flow cytometry experiments showed that CHAC2 increased ROS by reducing GSH in lung adenocarcinoma and that the elevated ROS activated the MAPK pathway. Our investigation identified a new role for CHAC2 and elucidated the mechanism by which CHAC2 promotes lung adenocarcinoma progression.

As vaccine resources were distributed unevenly worldwide, sometimes there might have been shortages or delays in vaccine supply; therefore, considering the use of heterogeneous booster doses for Coronavirus disease 2019 (COVID-19) might be an alternative strategy. Therefore, we aimed to review the data available to evaluate and compare the effectiveness and safety of heterologous booster doses with homologous booster doses for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. We searched relevant studies up to 27 April 2022. Random-effects inverse variance models were used to evaluate the vaccine effectiveness (VE) and its 95% confidence interval (CI) of COVID-19 outcomes and odds ratio (OR) and its CI of safety events. The Newcastle-Ottawa quality assessment scale and Cochrane Collaboration's tool were used to assess the quality of the included cohort studies. A total of 23 studies involving 1,726,506 inoculation cases of homologous booster dose and 5,343,580 inoculation cases of heterologous booster dose was included. The VE of heterologous booster for the prevention of SARS-CoV-2 infection (VEheterologous = 96.10%, VEhomologous = 84.00%), symptomatic COVID-19 (VEheterologous = 56.80%, VEhomologous = 17.30%), and COVID-19-related hospital admissions (VEheterologous = 97.40%, VEhomologous = 93.20%) was higher than homologous booster. Compared with homologous booster group, there was a higher risk of fever (OR = 1.930, 95% CI, 1.199-3.107), myalgia (OR = 1.825, 95% CI, 1.079-3.089), and malaise or fatigue (OR = 1.745, 95% CI, 1.047-2.906) within 7 days after boosting, and a higher risk of malaise or fatigue (OR = 4.140, 95% CI, 1.729-9.916) within 28 days after boosting in heterologous booster group. Compared with homologous booster group, geometric mean neutralizing titers (GMTs) of neutralizing antibody for different SARS-CoV-2 variants and response rate of antibody and gama interferon were higher in heterologous booster group. Our findings suggested that both homologous and heterologous COVID-19 booster doses had great effectiveness, immunogenicity, and acceptable safety, and a heterologous booster dose was more effective, which would help make appropriate public health decisions and reduce public hesitancy in vaccination.

Little is known about the long-term consequences of asymptomatic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to review the data available to explore the long-term consequences of asymptomatic SARS-CoV-2 infection in the real world. We searched observational cohort studies that described the long-term health effects of asymptomatic SARS-CoV-2 infections. Random-effects inverse-variance models were used to evaluate the pooled prevalence (PP) and its 95% confidence interval (CI) of long-term symptoms. Random effects were used to estimate the pooled odds ratios (OR) and its 95%CI of different long-term symptoms between symptomatic and asymptomatic infections. Five studies involving a total of 1643 cases, including 597 cases of asymptomatic and 1043 cases of symptomatic SARS-CoV-2 infection were included in this meta-analysis. The PPs of long-term consequences after asymptomatic SARS-CoV-2 infections were 17.13% (95%CI, 7.55−26.71%) for at least one symptom, 15.09% (95%CI, 5.46−24.73%) for loss of taste, 14.14% (95%CI, −1.32−29.61%) for loss of smell, and 9.33% (95%CI, 3.07−15.60) for fatigue. Compared with symptomatic SARS-CoV-2 infection, asymptomatic infection was associated with a significantly lower risk of developing COVID-19-related sequelae (p < 0.05), with 80% lower risk of developing at least one symptom (OR = 0.20, 95%CI, 0.09−0.45), 81% lower risk of fatigue (OR = 0.19, 95%CI, 0.08−0.49), 90% lower risk of loss of taste/smell (OR = 0.10, 95%CI, 0.02−0.58). Our results suggested that there were long-term effects of asymptomatic SARS-CoV-2 infection, such as loss of taste or smell, fatigue, cough and so on. However, the risk of developing long-term symptoms in asymptomatic SARS-CoV-2 infected persons was significantly lower than those in symptomatic SARS-CoV-2 infection cases.

Early detection of subclinical myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) is essential for preventing heart failure. This study aims to search for predictors of left ventricular (LV) myocardial deformation and tissue abnormalities in T2DM patients with preserved ejection fraction by using CMR T1 mapping and feature tracking.

There is an urgent need for cost-effective strategies to produce hydrogen from renewable net-zero carbon sources using renewable energies. In this context, the electrochemical hydrogen evolution reaction can be boosted by replacing the oxygen evolution reaction with the oxidation of small organic molecules, such as ethylene glycol (EG). EG is a particularly interesting organic liquid with two hydroxyl groups that can be transformed into a variety of C1 and C2 chemicals, depending on the catalyst and reaction conditions. Here, a catalyst is demonstrated for the selective EG oxidation reaction (EGOR) to formate on nickel selenide. The catalyst nanoparticle (NP) morphology and crystallographic phase are tuned to maximize its performance. The optimized NiS electrocatalyst requires just 1.395 V to drive a current density of 50 mA cm-2 in 1 m potassium hydroxide (KOH) and 1 m EG. A combination of in situ electrochemical infrared absorption spectroscopy (IRAS) to monitor the electrocatalytic process and ex situ analysis of the electrolyte composition shows the main EGOR product is formate, with a Faradaic efficiency above 80%. Additionally, C2 chemicals such as glycolate and oxalate are detected and quantified as minor products. Density functional theory (DFT) calculations of the reaction process show the glycol-to-oxalate pathway to be favored via the glycolate formation, where the CC bond is broken and further electro-oxidized to formate.

Pain is an under-recognized complaint among head and neck cancer (HNC) survivors. Treatment is hindered by inadequate characterization of pain.

Root rot, mainly caused by Fusarium oxysporum, is the most destructive disease affecting lily (Lilium spp.) production. The WRKY transcription factors (TFs) have important roles during plant immune responses. To clarify the effects of WRKY TFs on plant defense responses to pathogens, a WRKY gene (LrWRKY2) was isolated from Lilium regale Wilson, which is a wild lily species highly resistant to F. oxysporum. The expression of LrWRKY2, which encodes a nuclear protein, is induced by various hormones (methyl jasmonate, ethephon, salicylic acid, and hydrogen peroxide) and by F. oxysporum infection. In this study, LrWRKY2-overexpressing transgenic tobacco plants were more resistant to F. oxysporum than the wild-type plants. Moreover, the expression levels of jasmonic acid biosynthetic pathway-related genes (NtAOC, NtAOS, NtKAT, NtPACX, NtJMT, NtOPR, and NtLOX), pathogenesis-related genes (NtCHI, NtGlu2, and NtPR-1), and antioxidant stress-related superoxide dismutase genes (NtSOD, NtCu-ZnSOD, and MnSOD) were significantly up-regulated in LrWRKY2 transgenic tobacco lines. Additionally, the transient expression of a hairpin RNA targeting LrWRKY2 increased the susceptibility of L. regale scales to F. oxysporum. Furthermore, an F. oxysporum resistance gene (LrCHI2) encoding a chitinase was isolated from L. regale. An electrophoretic mobility shift assay demonstrated that LrWRKY2 can bind to the LrCHI2 promoter containing the W-box element. Yeast one-hybrid assay results suggested that LrWRKY2 can activate LrCHI2 transcription. An examination of transgenic tobacco transformed with LrWRKY2 and the LrCHI2 promoter revealed that LrWRKY2 activates the LrCHI2 promoter. Therefore, in L. regale, LrWRKY2 is an important positive regulator that contributes to plant defense responses to F. oxysporum by modulating LrCHI2 expression.

The anti-tumor and anti-inflammatory effects of limonin have been established, here, we aim to explore whether limonin can induce protective effects against doxorubicin (DOX)-mediated cardiotoxicity which limits its clinical application. We found that limonin attenuated DOX-mediated cytoxicology of myocardial cell line H9C2 by measuring cell viability and reactive oxygen species (ROS) level. Additionally, limonin ameliorates DOX-induced cardiac injury in rat by examining the activity of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) concentration, and histopathological changes. Mechanistically, it was shown that limonin partially abrogated the inhibition of Nuclear factor - like 2 and Sirtuin 2 signaling induced by DOX. Furthermore, limonin-mediated protective effects on DOX-mediated cytoxicology of H9C2 were rescued by a Sirt2-specific inhibitor or siRNA against Sirt2. Thus, this work reveals that limonin can suppress DOX-mediated cardiotoxicity by activating Nrf2 and Sirt2 signaling.

Myocardial remodelling is important pathological basis of HF, mitochondrial oxidative stress is a promoter to myocardial hypertrophy, fibrosis and apoptosis. ECH is the major active component of a traditional Chinese medicine Cistanches Herba, plenty of studies indicate it possesses a strong antioxidant capacity in nerve cells and tumour, it inhibits mitochondrial oxidative stress, protects mitochondrial function, but the specific mechanism is unclear. SIRT1/FOXO3a/MnSOD is an important antioxidant axis, study finds that ECH binds covalently to SIRT1 as a ligand and up-regulates the expression of SIRT1 in brain cells. We hypothesizes that ECH may reverse myocardial remodelling and improve heart function of HF via regulating SIRT1/FOXO3a/MnSOD signalling axis and inhibit mitochondrial oxidative stress in cardiomyocytes. Here, we firstly induce cellular model of oxidative stress by ISO with AC-16 cells and pre-treat with ECH, the level of mitochondrial ROS, mtDNA oxidative injury, MMP, carbonylated protein, lipid peroxidation, intracellular ROS and apoptosis are detected, confirm the effect of ECH in mitochondrial oxidative stress and function in vitro. Then, we establish a HF rat model induced by ISO and pre-treat with ECH. Indexes of heart function, myocardial remodelling, mitochondrial oxidative stress and function, expression of SIRT1/FOXO3a/MnSOD signalling axis are measured, the data indicate that ECH improves heart function, inhibits myocardial hypertrophy, fibrosis and apoptosis, increases the expression of SIRT1/FOXO3a/MnSOD signalling axis, reduces the mitochondrial oxidative damages, protects mitochondrial function. We conclude that ECH reverses myocardial remodelling and improves cardiac function via up-regulating SIRT1/FOXO3a/MnSOD axis and inhibiting mitochondrial oxidative stress in HF rats.

Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX). However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine), a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200mg/kg, i.p.) significantly inhibited the generation of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20mg/kg, i.v., 24h). Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity.

Cotton fibers, which are extremely elongated single cells of epidermal seed trichomes and have highly thickened cell walls, constitute the most important natural textile material worldwide. However, the regulation of fiber development is not well understood. Here, we report that GhHUB2, a functional homolog of AtHUB2, controls fiber elongation and secondary cell wall (SCW) deposition. GhHUB2 is ubiquitously expressed, including within fibers. Overexpression of GhHUB2 in cotton increased fiber length and SCW thickness, while RNAi knockdown of GhHUB2 resulted in shortened fibers and thinner cell walls. We found that GhHUB2 interacted with GhKNL1, a transcriptional repressor predominantly expressed in developing fibers, and that GhHUB2 ubiquitinated and degraded GhKNL1 via the ubiquitin-26S proteasome pathway. GhHUB2 negatively regulated GhKNL1 protein levels and lead to the disinhibition of genes such as GhXTH1, Gh1,3-β-G, GhCesA4, GhAGP4, GhCTL1, and GhCOBL4, thus promoting fiber elongation and enhancing SCW biosynthesis. We found that GhREV-08, a transcription factor that participates in SCW deposition and auxin signaling pathway, was a direct target of GhKNL1. In conclusion, our study uncovers a novel function of HUB2 in plants in addition to its monoubiquitination of H2B. Moreover, we provide evidence for control of the fiber development by the ubiquitin-26S proteasome pathway.

With rapid advances in technology, wearable devices as head-mounted display (HMD) have been adopted for various uses in medical science, ranging from simply aiding in fitness to assisting surgery. We aimed to investigate the feasibility and practicability of a low-cost multimodal HMD system in neuroendoscopic surgery.