Association between bilirubin levels and risk of stroke: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between bilirubin levels and stroke risk. DESIGN: Systematic review and meta-analysis, reported in accordance with Meta-analysis Of Observational Studies in Epidemiology guidelines. DATA SOURCES: The PubMed, Embase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure Databases were searched from inception up to 27 February 2022. ELIGIBILITY CRITERIA: Cohort studies assessing the dose-response relationship between bilirubin levels and risk of stroke were eligible for inclusion. There were no language restrictions. DATA EXTRACTION AND SYNTHESIS: All data from eligible studies were collected and assessed by two independent investigators. We generated pooled relative risks (RRs) with 95% CIs. We used a restricted cubic spline model for the dose-response analyses. Subsequent subgroup analyses were conducted according to stroke outcomes, follow-up duration, geographical area and size of the cohort. RESULTS: Nine articles including results from 11 cohort studies with 7835 cases of stroke and 263 596 participants met the inclusion criteria. The summarised RR of stroke comparing the highest and lowest bilirubin level was 0.85 (95% CI 0.72 to 0.99). The dose-response analysis indicated that a 15 µmol/L increment of bilirubin level was associated with an 18% lower risk of stroke (RR=0.82, 95% CI 0.67 to 0.99). For ischaemic stroke, the RR was 0.76 (95% CI 0.58 to 0.99). Significant publication bias was not detected. CONCLUSIONS: Elevated bilirubin levels were associated with a decreased risk of stroke among adults. PROSPERO REGISTRATION NUMBER: CRD42017071497.

BORIS variant SF2(C2/A4) promotes the malignant development of liver cancer by activating epithelial-mesenchymal transition and hepatic stellate cells.

The underlying mechanisms of metastasis and recurrence of liver cancer remain largely unknown. Here, we found that Brother of the Regulator of Imprinted Sites (BORIS) variant SF2(C2/A4) was highly expressed in high metastatic potential hepatocellular carcinoma (HCC) cells and clinical tumor samples, related to the formation of satellite nodules. Its over expression promoted self-renewal, the expression of tumor stem cell markers, chemoresistance, wound healing rate, invasion and metastasis of HepG2 and Hep3B cells; reinforced epithelial-mesenchymal transition (EMT), decreased the expression of E-cadherin and increased N-cadherin and Vimentin. Subcellular localization experiment showed that BORIS SF2(C2/A4) was localized in nucleus and cytoplasm. Further double luciferase reporter gene experiment confirmed that it bound to TWIST1 gene promoter and significantly increased latter expression. BORIS SF2(C2/A4) knock down induced apoptosis of HCCLM3 and PLC/PRF/5 cells, and increased the protein content of cleaved caspase 3. Additionally, BORIS SF2(C2/A4) over expression increased the expression of fibroblast growth factor 2 (FGF2) in HepG2 and Hep3B cells. FGF2 expressed higher in HCC tumor tissues than in paired peri-tumor tissues, and its expression was positively correlated with BORIS SF2(C2/A4). Interestingly, high expression of FGF2 is also associated with the formation of satellite nodules. Moreover, using the medium from BORIS SF2(C2/A4) overexpressed cell lines to coculture hepatic stellate cell (HSCs) line LX-2, the latter could be activated and increased the expression of CD90 and PIGF, which is consistent with the effect of adding bFGF alone. These results indicate that BORIS SF2(C2/A4) plays a role in deterioration of liver cancer by regulating TWIST1 to induce EMT, and by FGF2 to activate HSCs.

The Antigenic Membrane Protein (Amp) of Rice Orange Leaf Phytoplasma Suppresses Host Defenses and Is Involved in Pathogenicity.

Phytoplasmas are uncultivable, phloem-limited, phytopathogenic bacteria that represent a major threat to agriculture worldwide. Phytoplasma membrane proteins are in direct contact with hosts and presumably play a crucial role in phytoplasma spread within the plant as well as by the insect vector. Three highly abundant types of immunodominant membrane proteins (IDP) have been identified within the phytoplasmas: immunodominant membrane protein (Imp), immunodominant membrane protein A (IdpA), and antigenic membrane protein (Amp). Although recent results indicate that Amp is involved in host specificity by interacting with host proteins such as actin, little is known about the pathogenicity of IDP in plants. In this study, we identified an antigenic membrane protein (Amp) of rice orange leaf phytoplasma (ROLP), which interacts with the actin of its vector. In addition, we generated Amp-transgenic lines of rice and expressed Amp in tobacco leaves by the potato virus X (PVX) expression system. Our results showed that the Amp of ROLP can induce the accumulation of ROLP and PVX in rice and tobacco plants, respectively. Although several studies have reported interactions between major phytoplasma antigenic membrane protein (Amp) and insect vector proteins, this example demonstrates that Amp protein can not only interact with the actin protein of its insect vector but can also directly inhibit host defense responses to promote the infection. The function of ROLP Amp provides new insights into the phytoplasma-host interaction.

Spatio-temporal dynamic diversity of bacterial alkaline phosphatase phoD gene and its environmental drivers in sediments during algal blooms: A case study of shallow Lake Taihu.

Bacterial alkaline phosphatase encoded by the phoD gene is essential for phosphorus (P) cycling in ecosystems. Until now, knowledge of the phoD gene diversity in shallow lake sediments is still lacking. In this study, from early to late stage of cyanobacterial blooms, we investigated the dynamic changes of the abundance of phoD gene (hereafter phoD abundance) and phoD-harboring bacterial community composition (hereafter phoD-harboring BCC) in sediments from different ecological regions of Lake Taihu, the third-largest shallow freshwater lake in China, as well as explored their environmental driving factors. Results showed that phoD abundance in the sediments of Lake Taihu showed spatiotemporal heterogeneity. The highest abundance was found in macrophyte-dominated area (mean 3.25*106copies/g DW), where Haliangium and Aeromicrobium were identified as the major contributors. Due to the negative impact of Microcystis species, phoD abundance decreased significantly (by 40.28% on average) during cyanobacterial blooms in all other regions except the estuary area. The phoD abundance in sediment was positively correlated with total organic carbon (TOC) and total nitrogen (TN). However, the relationship between phoD abundance and alkaline phosphatase activity (APA) varied with time, showing positive correlation (R2 = 0.763, P < 0.01) in the early stage of cyanobacterial blooms, but not (R2 = -0.052, P = 0.838) in the later stage. The predominant phoD-harboring genera in sediments were Kribbella, Streptomyces and Lentzea, all of which belong to Actinobacteria. Non-metric multidimensional scaling (NMDS) analysis revealed that the spatial heterogeneity of phoD-harboring BCC in the sediments of Lake Taihu was significantly higher than the temporal heterogeneity. TP and sand were the principle environmental factors affecting the phoD-harboring BCC in the sediments of the estuary area, while DO, pH, organic phosphorus (Po) and diester phosphorus were the key driving factors for other lake regions. We concluded that the C, N, and P cycles in sediments might work in concert. This study extends the understanding of the phoD gene diversity in shallow lake sediments.

Low energy multiple blue light-emitting diode light Irradiation promotes melanin synthesis and induces DNA damage in B16F10 melanoma cells.

Visible light is present everywhere in our lives. Widespread use of computers and smartphones has increased the daily time spent in front of screens. What effect does this visible light have on us? Recent studies have shown that short-wavelength blue light (400-450nm) irradiation, similar to UV, inhibits the cell proliferation and differentiation, induces the intracellular oxidative stress, promotes the cell apoptosis and causes some other negative effects. However, it's unusual that directly face to such short-wavelength and high-energy blue light in daily life. Therefore, the effects of blue light with longer wavelength (470nm), lower energy (1, 2 J/cm2) and multiple times (simulated daily use) exposure on cells have been studied in this experiment. In our results, low energy density multiple blue light inhibited cell proliferation and metastatic capability with a weak phototoxicity. Blue light also promoted intracellular reactive oxygen species and caused DNA damage. Furthermore, the melanin synthesis was also promoted by low energy density multiple blue light exposure. Together, these results indicate that longer wavelength and low energy density blue light multiple exposure is still harmful to our cells. Furthermore, prolonged exposure to screens likely induces dull skin through induction of melanin synthesis. These results further mentioned us should paid more attention to controlling the daily use of digital device.

Jasmonic acid negatively regulates branch growth in pear.

The quality of seedlings is an important factor for development of the pear industry. A strong seedling with few branches and suitable internodes is ideal material as a rootstock for grafting and breeding. Several branching mutants of pear rootstocks were identified previously. In the present study, 'QAU-D03' (Pyrus communis L.) and it's mutants were used to explore the mechanism that affects branch formation by conducting phenotypic trait assessment, hormone content analysis, and transcriptome analysis. The mutant plant (MP) showed fewer branches, shorter 1-year-old shoots, and longer petiole length, compared to original plants (OP), i.e., wild type. Endogenous hormone analysis revealed that auxin, cytokinin, and jasmonic acid contents in the stem tips of MP were significantly higher than those of the original plants. In particular, the jasmonic acid content of the MP was 1.8 times higher than that of the original plants. Transcriptome analysis revealed that PcCOI1, which is a transcriptional regulatory gene downstream of the jasmonic acid signaling pathway, was expressed more highly in the MP than in the original plants, whereas the expression levels of PcJAZ and PcMYC were reduced in the MP compared with that of the original plants. In response to treatment with exogenous methyl jasmonate, the original plants phenotype was consistent with that of the MP in developing less branches. These results indicate that jasmonic acid negatively regulates branch growth of pear trees and that jasmonic acid downstream regulatory genes play a crucial role in regulating branching.

Perfusion index for early identification of regional anesthesia effectiveness: a narrative review.

Regional anesthesia (RA) is a common and irreplaceable technique in clinical, which can be used in different surgery sites and control of acute and chronic pain, especially for outpatients, pediatrics and the elderly. RA demands are increasing during COVID-19 pandemic because many surgeries could be performed under RA to reduce the risk of cross-infection between patients and health care workers. Early and accurate identification of the effects of RA can help physicians make timely decisions about whether to supplement analgesics or switch to general anesthesia, which will save time and improve patient satisfaction in a busy operating room. Perfusion index (PI) is a parameter derived from photoplethysmography (PPG) and represents the ratio of pulsatile and non-pulsatile blood flow at monitoring sites. It reflects local perfusion and is mainly affected by stroke volume and vascular tone. With characteristics of non-invasive, rapid, simple, and objective, PI is widely used in clinical practice, such as fluid responsiveness prediction, nociceptive assessment, etc. Recently, many studies have assessed the accuracy of PI in early prediction of RA success, including brachial plexus block, sciatic nerve block, neuraxial anesthesia, paravertebral block, caudal block and stellate ganglion block. Successful RA often parallels increased PI. In this narrative review, we describe the principles and influencing factors of PI, and introduce the effects of PI on early identification of RA effectiveness.

An enriched environment improves long-term functional outcomes in mice after intracerebral hemorrhage by mechanisms that involve the Nrf2/BDNF/glutaminase pathway.

Post-stroke depression exacerbates neurologic deficits and quality of life. Depression after ischemic stroke is known to some extent. However, depression after intracerebral hemorrhage (ICH) is relatively unknown. Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective effects in animal models, but its impact after ICH is unknown. In this study, we investigated the effect of EE on long-term functional outcomes in mice subjected to collagenase-induced striatal ICH. Mice were subjected to ICH with the standard environment (SE) or ICH with EE for 6 h/day (8:00 am-2:00 pm). Depressive, anxiety-like behaviors and cognitive tests were evaluated on day 28 with the sucrose preference test, tail suspension test, forced swim test, light-dark transition experiment, morris water maze, and novel object recognition test. Exposure to EE improved neurologic function, attenuated depressive and anxiety-like behaviors, and promoted spatial learning and memory. These changes were associated with increased expression of transcription factor Nrf2 and brain-derived neurotrophic factor (BDNF) and inhibited glutaminase activity in the perihematomal tissue. However, EE did not change the above behavioral outcomes in Nrf2-/- mice on day 28. Furthermore, exposure to EE did not increase BDNF expression compared to exposure to SE in Nrf2-/- mice on day 28 after ICH. These findings indicate that EE improves long-term outcomes in sensorimotor, emotional, and cognitive behavior after ICH and that the underlying mechanism involves the Nrf2/BDNF/glutaminase pathway.

Overexpression of vascular endothelial growth factor enhances the neuroprotective effects of bone marrow mesenchymal stem cell transplantation in ischemic stroke.

Although bone marrow mesenchymal stem cells (BMSCs) might have therapeutic potency in ischemic stroke, the benefits are limited. The current study investigated the effects of BMSCs engineered to overexpress vascular endothelial growth factor (VEGF) on behavioral defects in a rat model of transient cerebral ischemia, which was induced by middle cerebral artery occlusion. VEGF-BMSCs or control grafts were injected into the left striatum of the infarcted hemisphere 24 hours after stroke. We found that compared with the stroke-only group and the vehicle- and BMSCs-control groups, the VEGF-BMSCs treated animals displayed the largest benefits, as evidenced by attenuated behavioral defects and smaller infarct volume 7 days after stroke. Additionally, VEGF-BMSCs greatly inhibited destruction of the blood-brain barrier, increased the regeneration of blood vessels in the region of ischemic penumbra, and reducedneuronal degeneration surrounding the infarct core. Further mechanistic studies showed that among all transplant groups, VEGF-BMSCs transplantation induced the highest level of brain-derived neurotrophic factor. These results suggest that BMSCs transplantation with vascular endothelial growth factor has the potential to treat ischemic stroke with better results than are currently available.

SuHAN: Substructural hierarchical attention network for molecular representation.

Recently, molecular representation and property exploration, with the combination of neural network, play a critical role in the field of drug design and discovery for assisting in drug related research. However, previous research in molecular representation relies heavily on artificial extraction of features based on biological experiments which may result in a manually introduced noise of molecular information with high cost in time and money. In this paper, a novel method named Substructural Hierarchical Attention Network (SuHAN) is proposed to discover inherent characteristics of molecules for representation learning. Specifically, SuHAN is composed of the cascaded layer: atom-level layer and substructure-level layer. Molecule in the SMILES format is divided into several substructural fragments by predefined partition rules, and then they are fed into atom-level layer and substructure-level layer successively to obtain feature representation from different perspective: atomic view and substructural view. In this way, the prominent structural features that may be omitted in global extraction are excavated from a fine-grained viewpoint and fused to reconstruct representative pattern in an overall view. Experiments on biophysics and physiology datasets demonstrate that our model is competitive with a significant improvement of both accuracy and stability in performance. We confirmed that the substructural segments and progressive hierarchical networks lead to an effective molecular representation for downstream tasks. These results provide a novel perspective about reconstructing overall pattern through local prominent structure.

Association between loneliness and dementia risk: A systematic review and meta-analysis of cohort studies.

Loneliness has been reported to be associated with an increased risk of dementia; however, the extent of this relationship remains controversial. This study aimed to assess the strength of the relationship between loneliness and dementia using a meta-analysis approach. PubMed, EMBASE, and China National Knowledge Internet databases were systematically searched for potentially included studies from inception up to 17 February 2022. A meta-analysis was performed using a random-effects model to assess pooled relative risks (RRs) and 95% confidence intervals (CIs). A literature search identified 16 cohort studies (published in 15 articles), among which 4,625 dementia cases and 62,345 individuals were selected for further meta-analysis. Loneliness was associated with an increased risk of Alzheimer's disease (AD) (RR: 1.72, 95% CI: 1.32-2.23; P < 0.001) and dementia (RR: 1.23, 95% CI: 1.16-1.31; P < 0.00001). However, no significant association between loneliness and risk of mild cognitive impairment (MCI) (RR: 1.34, 95% CI: 0.97-1.87; P = 0.080) or vascular dementia (VaD) (RR: 1.01, 95% CI: 0.51-1.99; P = 0.973) was observed. Results revealed that loneliness might increase the risk of Alzheimer's disease and dementia. Early interventions that limit loneliness may reduce risk of dementia and Alzheimer's disease.

Paternal Nicotine/Ethanol/Caffeine Mixed Exposure Induces Offspring Rat Dysplasia and Its Potential "GC-IGF1" Programming Mechanism.

Clinical and animal studies suggest that paternal exposure to adverse environments (bad living habits and chronic stress, etc.) has profound impacts on offspring development; however, the mechanism of paternal disease has not been clarified. In this study, a meta-analysis was first performed to suggest that paternal exposure to nicotine, ethanol, or caffeine is a high-risk factor for adverse pregnancy outcomes. Next, we created a rat model of paternal nicotine/ethanol/caffeine mixed exposure (PME), whereby male Wistar rats were exposed to nicotine (0.1 mg/kg/d), ethanol (0.5 g/kg/d), and caffeine (7.5 mg/kg/d) for 8 weeks continuously, then mated with normal female rats to obtain a fetus (n = 12 for control group, n = 10 for PME group). Then, we analyzed the changes in paternal hypothalamic-pituitary-adrenal (HPA) axis activity, testicular function, pregnancy outcomes, fetal serum metabolic indicators, and multiple organ functions to explore the mechanism from the perspective of chronic stress. Our results demonstrated that PME led to enhanced paternal HPA axis activity, decreased sperm quality, and adverse pregnancy outcomes (stillbirth and absorption, decreased fetal weight and body length, and intrauterine growth retardation), abnormal fetal serum metabolic indicators (corticosterone, glucolipid metabolism, and sex hormones), and fetal multi-organ dysfunction (including hippocampus, adrenal, liver, ossification, and gonads). Furthermore, correlation analysis showed that the increased paternal corticosterone level was closely related to decreased sperm quality, adverse pregnancy outcomes, and abnormal offspring multi-organ function development. Among them, the decreased activity of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis may be the main mechanism of offspring development and multi-organ dysfunction caused by PME. This study explored the impact of common paternal lifestyle in daily life on offspring development, and proposed the GC-IGF1 programming mechanisms of paternal chronic stress-induced offspring dysplasia, which provides a novel insight for exploring the important role of paternal chronic stress in offspring development and guiding a healthy lifestyle for men.

The function of brother of the regulator of imprinted sites in cancer development.

As Douglas Hanahan and Robert Weinberg compiled, there are nine hallmarks of cancer that are conducive to cancer cell development and survival. Previous studies showed that brother of the regulator of imprinted sites (BORIS) might promote cancer progression through these aspects. The competition between BORIS and CCCTC-binding factor (CTCF), which is crucial in the formation of chromatin loops, affects the normal function of CTCF and leads to neoplasia and deformity. In addition, BORIS belongs to the cancer-testis antigen families, which are potential targets in cancer diagnosis and treatment. Herein, we discuss the function and mechanisms of BORIS, especially in cancer development.

Licochalcone A alleviates laser-induced choroidal neovascularization by inhibiting the endothelial-mesenchymal transition via PI3K/AKT signaling pathway.

Choroidal neovascularization (CNV) is a hallmark of wet age-related macular degeneration, which severely impairs central vision. Studies have shown that endothelial-mesenchymal transition (EndMT) is involved in the pathogenesis of CNV. Licochalcone A (lico A), a flavonoid extracted from the root of licorice, shows the inhibition on EndMT, but it remains unclear whether it can suppress the formation of CNV. The aim of this study is to investigate the effects of lico A on laser-induced CNV, and EndMT process in vitro and vivo. We established the model of CNV with a krypton laser in Brown-Norway rats and then intraperitoneally injected lico A. Our experimental results demonstrated that the leakage of CNV was relieved, and the area of CNV was reduced in lico A-treated rats. Cell migration and tube formation in oxidized low-density lipoprotein (Ox-LDL)-stimulated HUVECs were inhibited by lico A and promoted by PI3K activator 740Y-P. The protein expressions of snai1 and α-SMA were increased, and CD31 and VE-cadherin were decreased in the model rats of CNV, but partially reversed after treatment with lico A. The expression of CD31 was decreased and α-SMA was increased in OX-LDL-treated HUVECs, which was further strengthened by 740Y-P, while the expression of CD31 was up-regulated and α-SMA was down-regulated in Lico A treated HUVECs. Our data revealed that EndMT process was alleviated by lico A. Meanwhile, PI3K/AKT signaling pathway was activated in model rat of CNV and Ox-LDL-stimulated HUVECs, which can be suppressed with treatment of lico A. Our experimental results confirmed for the first time that lico A has the potential to alleviate CNV by inhibiting the endothelial-mesenchymal transition via PI3K/AKT signaling pathway.

Pirfenidone-loaded exosomes derived from pancreatic ductal adenocarcinoma cells alleviate fibrosis of premetastatic niches to inhibit liver metastasis.

Given the metastasis-promoting effect of pancreatic ductal adenocarcinoma (PDAC)-derived exosomes through activation of fibrotic premetastatic niches, targeting and intervening in premetastatic organs to inhibit distant metastasis have challenged researchers and clinicians. Herein, a self-biomimetic drug delivery system based on exosomes derived from PDAC (PF@PCCEs) was constructed to precisely deliver an antifibrotic drug (pirfenidone, PF) to fibrotic premetastatic organs. First, PDAC-derived exosomes were confirmed to remarkably promote liver fibrosis. Then the prepared PF@PCCEs were actively internalized by HSCs (hepatic stellate cells) and subsequently alleviated the activation of HSCs. Delivery of PF to the premetastatic liver affected the niche suitable for the colonization of circulating tumour cells, further suppressing liver metastasis of PDAC. Thus, the strategy for intervening in the formation of fibrotic premetastatic niches to inhibit liver metastasis of PDAC using PF@PCCEs might offer inspiration for the treatment of tumour metastasis.

Tryptophan-5-HT pathway disorder was uncovered in the olfactory bulb of a depression mice model by metabolomic analysis.

Major depression (MD) is a severe mental illness that creates a heavy social burden, and the potential molecular mechanisms remain largely unknown. Lots of research demonstrate that the olfactory bulb is associated with MD. Recently, gas chromatography-mass spectrometry-based metabolomic studies on depressive rats indicated that metabolisms of purine and lipids were disordered in the olfactory bulb. With various physicochemical properties and extensive concentration ranges, a single analytical technique could not completely cover all metabolites, hence it is necessary to adopt another metabolomic technique to seek new biomarkers or molecular mechanisms for depression. Therefore, we adopted a liquid chromatography-mass spectrometry metabonomic technique in the chronic mild stress (CMS) model to investigate significant metabolic changes in the olfactory bulb of the mice. We discovered and identified 16 differential metabolites in the olfactory bulb of the CMS treatments. Metabolic pathway analysis by MetaboAnalyst 5.0 was generated according to the differential metabolites, which indicated that the tryptophan metabolism pathway was the core pathogenesis in the olfactory bulb of the CMS depression model. Further, the expressions of tryptophan hydroxylase (TpH) and aromatic amino acid decarboxylase (AAAD) were detected by western blotting and immunofluorescence staining. The expression of TpH was increased after CMS treatment, and the level of AAAD was unaltered. These results revealed that abnormal metabolism of the tryptophan pathway in the olfactory bulb mediated the occurrence of MD.

Meropenem-loaded Cement Is Effective in Preventing Gram-negative Osteomyelitis in an Animal Model.

BACKGROUND: Low-dose antibiotic-loaded acrylic cement is routinely used for preventing skeletal infection or reimplantation in patients with periprosthetic joint infections. However, few reports about the selection of antibiotics in acrylic cement for antigram-negative bacteria have been proposed. QUESTIONS/PURPOSES: (1) Does the addition of antibiotics (tobramycin, meropenem, piperacillin, ceftazidime, ciprofloxacin, and aztreonam) to acrylic cement adversely affect compressive strength before and after elution? (2) Which antibiotics have the highest cumulative release within 28 days? (3) Which antibiotics showed antimicrobial activity within 28 days? (4) Does meropenem-loaded cement improve body weight, temperature, and other inflammatory markers compared with control unloaded cement? METHODS: This is an in vitro study that assessed the mechanical strength, antibiotic elution, and antibacterial properties of antibiotic-loaded cement, combined with an animal study in a rat model that evaluated key endpoints from the animal study. In the in vitro study, we added 2 g of tobramycin (TOB), meropenem (MEM), piperacillin (PIP), ceftazidime (CAZ), ciprofloxacin (CIP), and aztreonam (ATM) to 40 g of acrylic cement. The compressive strength, elution, and in vitro antibacterial properties of the antibiotic-loaded cement were detected. Thirty male rats were randomly divided into two groups: CON (antibiotic-unloaded cement) and MEM (meropenem-loaded cement, which had the most stable antibacterial properties of the six tested antibiotic-loaded cements in vitro within 28 days). The right tibia of all rats underwent arthroplasty and was implanted with the cement, followed by inoculation with Pseudomonas aeruginosa in the knee. General status, serum biomarkers, radiology, microbiological assay, and histopathological tests were assessed over 14 days postoperatively. RESULTS: The compressive strength of all tested antibiotic cement combinations exceeded the 70 MPa threshold (the requirement established in ISO 5833). The cumulative release proportions of the raw antibiotic in cement were 1182.8 ± 37.9 µg (TOB), 355.6 ± 16.2 µg (MEM), 721.2 ± 40.3 µg (PIP), 477.4 ± 37.1 µg (CAZ), 146.5 ± 11.3 µg (CIP), and 372.1 ± 14.5 µg (ATM) within 28 days. Over a 28-day period, meropenem cement demonstrated antimicrobial activities against the four tested gram-negative bacteria (Escherichia coli, P. aeruginosa, Klebsiella pneumoniae, and Proteus vulgaris). Ciprofloxacin cement inhibited E. coli growth, ceftazidime and aztreonam cement inhibited K. pneumonia growth, and tobramycin cement inhibited P. aeruginosa. Only meropenem demonstrated antimicrobial activity against all gram-negative bacteria on agar diffusion bioassay. Rats treated with meropenem cement showed improved body weight (control: 280.1 ± 4.2 g, MEM: 288.5 ± 6.6 g, mean difference 8.4 [95% CI 4.3 to 12.6]; p < 0.001), improved knee width (control: 13.5 ± 0.3 mm, MEM: 11.8± 0.4 mm, mean difference 1.7 [95% CI 1.4 to 2.0]; p < 0.001), decreased inflammatory marker (control: 316.7 ± 45.0 mm, MEM: 116.5 ± 21.8 mm, mean difference 200.2 [95% CI 162.3 to 238.2]; p < 0.001), decreased radiographic scores (control: 17.7 ± 2.0 mm, MEM: 10.7± 1.3 mm, mean difference 7.0 [95% CI 5.4 to 8.6]; p < 0.001), improved bone volume/total volume (control: 8.7 ± 3.0 mm, MEM: 28.5 ± 5 .5 mm, mean difference 19.8 [95% CI 13.3 to 26.2]; p < 0.001), decreased Rissing scale scores of the knee gross pathology (control: 3.3 ± 0.5, MEM: 1.1 ± 0.7, mean difference 2.2 [95% CI 1.7 to 2.7]; p < 0.001), decreased Petty scale scores of knee synovium (control: 2.9 ± 0.4 mm, MEM: 0.7 ± 0.7 mm, mean difference 2.1 [95% CI 1.7 to 2.5]; p < 0.001), and decreased bacterial counts of the bone and soft tissues and negative bacterial cultures of cement (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). CONCLUSION: In this current study, MEM cement had the most stable in vitro antimicrobial activities, effective in vivo activity while having acceptable mechanical and elution characteristics, and it may be an effective prophylaxis against skeletal infection caused by gram-negative bacteria. CLINICAL RELEVANCE: Meropenem-loaded acrylic cement is a potentially effective prevention measure for skeletal infection caused by gram-negative bacteria; however, more related clinical research is needed to further evaluate the safety and efficacy.

Calpain Inhibitor Calpeptin Improves Alzheimer's Disease-Like Cognitive Impairments and Pathologies in a Diabetes Mellitus Rat Model.

Diabetes mellitus (DM) has been considered an accelerator of Alzheimer's disease (AD), but the cellular and molecular mechanisms underlying this effect are not fully understood. Here, we attempted to determine the role and regulatory mechanism of calpain in the AD-like cognitive decline and pathological changes in rats caused by DM. In the initial stages, our results verified that DM model rats showed cognitive impairment, as well as a loss of neurons, decreased pericyte marker (PDGFR-ß and α-SMA), and calpain-2 expression and amyloid-ß (Aß) deposition in the hippocampal tissues. In high glucose-induced primary pericytes, the cell apoptotic rate was increased, and cell proliferation was inhibited in a time-dependent manner. The protein level of calpain-2 was also upregulated by HG induction, but the level of calpain-1 did not change with HG treatment, which was also observed in DM model rats. Subsequently, some DM model rats were administered calpeptin, an inhibitor of calpain. Our data revealed that calpeptin treatment significantly suppressed calpain-1 and calpain-2 expression in the hippocampal tissues and effectively improved the cognitive impairments of DM model rats. Neuronal loss, Aß accumulation, pericyte loss, inflammation, and oxidative stress injury in the hippocampal tissues of DM model rats were also partly rescued by calpeptin administration. Our work demonstrated that the calpain inhibitor calpeptin could alleviate DM-induced AD-like cognitive impairments and pathological changes in rats, and this effect may be associated with pericytes. Calpeptin may become a promising drug to treat the AD-like complications of DM.

Long noncoding RNA CERS6-AS1 modulates glucose metabolism and tumor progression in hepatocellular carcinoma by promoting the MDM2/p53 signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most serious malignant cancers and has a high fatality rate. However, clinical strategies for the effective treatment of HCC remain lacking. Long non-coding RNAs (lncRNAs) with aberrant expression have been closely correlated with the occurrence and development of HCC. Here we investigated the underlying mechanism of the lncRNA CERS6-AS1 in HCC progression. The expression and prognosis of CERS6-AS1 in HCC patients was explored using The Cancer Genome Atlas. PCR analysis was utilized to measure the expression of CERS6-AS1 in tissues and cell lines. Transwell, wound healing, proliferation and glycolysis assays were conducted to evaluate the function of CERS6-AS1 on HCC cell functions. Bioinformation methods and luciferase assays were used to screen and verify potential target miRNAs and genes. A subcutaneous tumorigenesis model was constructed in nude mice to assess the effect of CERS6-AS1 on tumorigenesis in vivo. CERS6-AS1 was highly expressed in HCC tissues and cell lines. Upregulated CERS6-AS1 expression was remarkably correlated with poor prognosis of HCC patients. High CERS6-AS1 expression facilitated cell growth, invasion and glycolysis of HCC cells. Bioinformatics analyses combining with PCR analysis identified miR-30b-3p as the potential target of CERS6-AS1, and MDM2 mRNA was verified as the target of miR-30b-3p. The expression of miR-30b-3p was negatively correlated with CERS6-AS1, whereas MDM2 was positively associated with CERS6-AS1. Mechanistic studies showed that CERS6-AS1 may sponge miR-30b-3p to elevate MDM2, thus promoting the MDM2-mediated ubiquitin-dependent degradation of the p53 tumor suppressor. MDM2 overexpression or miR-30b-3p inhibitors blocked the inhibitory effect of CERS6-AS1 knockdown on proliferation, migration and glycolysis. CERS6-AS1 depletion reduced tumor formation in the in vivo mouse model. The CERS6-AS1/miR-30b-3p/MDM2/p53 signaling axis may play key roles in regulating HCC progression. CERS6-AS1 may exert as a novel biomarker or therapeutic target for HCC.