Hydrogel-based immunoregulation of macrophages for tissue repair and regeneration.

The rational design of hydrogel materials to modulate the immune microenvironment has emerged as a pivotal approach in expediting tissue repair and regeneration. Within the immune microenvironment, an array of immune cells exists, with macrophages gaining prominence in the field of tissue repair and regeneration due to their roles in cytokine regulation to promote regeneration, maintain tissue homeostasis, and facilitate repair. Macrophages can be categorized into two types: classically activated M1 (pro-inflammatory) and alternatively activated M2 (anti-inflammatory and pro-repair). By regulating the physical and chemical properties of hydrogels, the phenotypic transformation and cell behavior of macrophages can be effectively controlled, thereby promoting tissue regeneration and repair. A full understanding of the interaction between hydrogels and macrophages can provide new ideas and methods for future tissue engineering and clinical treatment. Therefore, this paper reviews the effects of hydrogel components, hardness, pore size, and surface morphology on cell behaviors such as macrophage proliferation, migration, and phenotypic polarization, and explores the application of hydrogels based on macrophage immune regulation in skin, bone, cartilage, and nerve tissue repair. Finally, the challenges and future prospects of macrophage-based immunomodulatory hydrogels are discussed.

A Bionic Thermosensitive Sustainable Delivery System for Reversing the Progression of Osteoarthritis by Remodeling the Joint Homeostasis.

Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti-inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease-modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral-biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)-based nanoparticles (NPs) are integrated into poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self-assembled ChS and ε-poly-l-lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin-1ß (IL-1ß)-mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS-based hydrogel system offers a potential strategy to regulate the chondrocyte-macrophage crosstalk, thus re-establishing the anti-inflammatory and immunomodulatory microenvironment for OA therapy.

Case report: Recurrent pontine stroke and leukoencephalopathy in a patient with de novo mutation in COL4A1.

This report presents a case of pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) in a 35 year-old male patient. The patient exhibited a consistent history of recurrent ischemic strokes, concentrated primarily in the pons region, accompanied by concurrent manifestations of leukoencephalopathy and microbleeds. Genetic evaluation revealed a heterozygous missense mutation consistent with c.3431C>G, p. Thr1144Arg substitution within exon 40 of the COL4A1 gene. This mutation was also identified in the patient's mother, affirming an autosomal dominant inheritance model. Our findings serve as testament to the potential role of mutation in the exon 40 of COL4A1 in the pathogenesis and progression of PADMAL, contributing to ongoing efforts aimed at better understanding the genetic basis of this debilitating disorder.

Icaritin ameliorates RANKL-mediated osteoclastogenesis and ovariectomy-induced osteoporosis.

A rapidly aging society and longer life expectancy are causing osteoporosis to become a global epidemic. Over the last five decades, a number of drugs aimed at reducing bone resorption or restoring bone mass have been developed, but their efficacy and safety are limited. Icaritin (ICT) is a natural compound extracted from anti-osteoporosis herb Epimedium spp. and has been shown to inhibit osteoclast differentiation. However, the molecular mechanism by which ICT weaken RANKL-induced osteoclast differentiation has not been completely investigated. Here, we evaluated the anti-osteoclastogenic effect of ICT in vitro and the potential drug candidate for treating osteoporosis in vivo. In vitro study, ICT was found to inhibit osteoclast formation and bone resorption function via downregulating transcription factors activated T cell cytoplasm 1 (NFATc1) and c-fos, which further downregulate osteoclastogenesis-specific gene. In addition, the enhanced mitochondrial mass and function required for osteoclast differentiation was mitigated by ICT. The histomorphological results from an in vivo study showed that ICT attenuated the bone loss associated with ovariectomy (OVX). Based on these results, we propose ICT as a promising new drug strategy for osteoporosis that inhibits osteoclast differentiation.

Production, Biosynthesis, and Commercial Applications of Fatty Acids From Oleaginous Fungi.

Oleaginous fungi (including fungus-like protists) are attractive in lipid production due to their short growth cycle, large biomass and high yield of lipids. Some typical oleaginous fungi including Galactomyces geotrichum, Thraustochytrids, Mortierella isabellina, and Mucor circinelloides, have been well studied for the ability to accumulate fatty acids with commercial application. Here, we review recent progress toward fermentation, extraction, of fungal fatty acids. To reduce cost of the fatty acids, fatty acid productions from raw materials were also summarized. Then, the synthesis mechanism of fatty acids was introduced. We also review recent studies of the metabolic engineering strategies have been developed as efficient tools in oleaginous fungi to overcome the biochemical limit and to improve production efficiency of the special fatty acids. It also can be predictable that metabolic engineering can further enhance biosynthesis of fatty acids and change the storage mode of fatty acids.

Accuro ultrasound-based system with computer-aided image interpretation compared to traditional palpation technique for neuraxial anesthesia placement in obese parturients undergoing cesarean delivery: a randomized controlled trial.

PURPOSE: Recently, a new handheld ultrasound-based device, called Accuro, has been commercialized with a real-time automated interpretation of lumbar ultrasound images. We hypothesized that the handheld ultrasound device would improve the efficacy and safety of combined spinal-epidural anesthesia (CSEA) for cesarean delivery in obese parturients. METHODS: Eighty parturients with a body mass index > 30 kg∙m-2 scheduled for elective cesarean delivery were randomly allocated equally (palpation group and ultrasound group). The primary outcome was the first insertion success rate. Secondary outcomes were the time taken to identify the needle puncture site, duration of CSEA procedure, the total time, the rate of parturients who require needle redirections, the number of skin punctures, changes in the intended interspace, and the incidence of complications. RESULTS: Compared to the palpation group, the first insertion success rate was significantly higher (72.5% vs. 40.0%; P = 0.003), and time taken to identify the needle puncture site was less (30 [26-36] vs. 39 [32-49] seconds; P = 0.001) in the ultrasound group. The rate of parturients who required needle redirections (40.0% vs. 72.5%; P = 0.003) and the incidence of paresthesia were both lower (7.5% vs. 45.0%; P < 0.001). The other outcomes had no significant difference between groups. The mean difference between the epidural depth measured by the handheld ultrasound and needle depth was - 0.29 cm [95% limit of agreement, - 0.52 to - 0.05]. CONCLUSIONS: Our study suggests using the Accuro ultrasound device can enhance the efficacy and safety of CSEA in obese parturients when executed by experienced anesthesiologists, and its automated estimation of epidural depth is accurate.

Cloning, Secretory Expression and Characterization of a Unique pH-Stable and Cold-Adapted Alginate Lyase.

Cold-adapted alginate lyases have unique advantages for alginate oligosaccharide (AOS) preparation and brown seaweed processing. Robust and cold-adapted alginate lyases are urgently needed for industrial applications. In this study, a cold-adapted alginate lyase-producing strain Vibrio sp. W2 was screened. Then, the gene ALYW201 was cloned from Vibrio sp. W2 and expressed in a food-grade host, Yarrowia lipolytica. The secreted Alyw201 showed the activity of 64.2 U/mL, with a molecular weight of approximate 38.0 kDa, and a specific activity of 876.4 U/mg. Alyw201 performed the highest activity at 30 °C, and more than 80% activity at 25-40 °C. Furthermore, more than 70% of the activity was obtained in a broad pH range of 5.0-10.0. Alyw201 was also NaCl-independent and salt-tolerant. The degraded product was that of the oligosaccharides of DP (Degree of polymerization) 2-6. Due to its robustness and its unique pH-stable property, Alyw201 can be an efficient tool for industrial production.

Mortality of Alzheimer's Disease Patients: A 10-Year Follow-up Pilot Study in Shanghai.

BACKGROUND: Identifying risk factors and mortality of individuals with Alzheimer's disease (AD) could have important implications for the clinical management of AD. OBJECTIVE: This pilot study aimed to examine the overall mortality of AD patients over a 10-year surveillance period in Shanghai, China. This study is an extension of our previous investigation on mortality of neurodegenerative diseases. METHODS: One hundred and thirty-two AD patients recruited from the memory clinics of two hospitals in Shanghai in 2007 were followed up until December 31, 2017 or death, representing a follow-up period of up to 10 years. Overall standardized mortality ratios (SMRs) were calculated, and predictors for survival at recruitment were estimated. RESULTS: Sixty-seven patients had died by December 31, 2017, and the SMR at 10 years of follow-up was 1.225 (95% confidence interval 0.944-1.563). Employing Cox's proportional hazard modeling, lower Mini-Mental State Examination score, and comorbid diabetes predicted poor survival in this cohort. CONCLUSION: This pilot study suggests a similar survival trend of patients with AD compared to the general population in Shanghai urban region. Poor cognitive status and comorbid diabetes had a negative impact on the survival of AD patients.

Dysregulated Urinary Arginine Metabolism in Older Adults With Amnestic Mild Cognitive Impairment.

Background: Urine samples, which capture an individual's metabolic profile, are ideal for the exploration of non-invasive biomarkers to confirm the amnestic mild cognitive impairment (aMCI) status of patients vs. unimpaired ones. Objective: We aimed to detect differentially metabolized amino acids, which are important objectives in metabolomics, garnering particular attention in biomedical pathogenesis from the urine of aMCI patients, which may give clinicians the possibility to intervene with early treatments that curb Alzheimer's disease (AD). Methods: The study included 208 subjects, 98 of whom were aMCI patients, and 110 who were control subjects without dementia. Urine samples were taken from each participant and supernatant was obtained for analysis. The concentrations of amino acids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Urinary arginine levels in aMCI patients are obviously lower than in normal controls (q < 0.2 and p < 0.05). Meanwhile, aMCI patients had significant reduced urinary global arginine bioavailability ratio (GABR), and GABR in urine displayed a positive correlation with the score of CMMSE. Conclusion: Urinary dysregulated arginine metabolism that may serve as a helpful clinical diagnostic biomarker for aMCI in older adults.

Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease.

Causative mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) account for a majority of cases of familial Alzheimer disease (FAD) inherited in an autosomal-dominant pattern. For the sake of characterizing mutations, index patients from 148 families with FAD were enrolled from mainland China. Sanger sequencing of the genes APP, PSEN1, and PSEN2 was performed to characterize the mutation spectrum of the Chinese population. Thirteen of 148 (8.8%) individuals had possible pathogenic APP, PSEN1, or PSEN2 variants, including 2 (15.4%) APP variants, 8 (61.5%) PSEN1 variants, and 3 (23.1%) PSEN2 variants. PSEN1 variants represented the largest proportion in Chinese FAD, and PSEN2 variants are responsible for late-onset FAD in China. Analysis of genetic-clinical correlations permitted the conclusion that FAD phenotypes were mainly influenced by specific genetic defects.

Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

Sevoflurane is one of the most commonly used volatile anaesthetics for children, but the safety of prolonged or repeated clinical use of sevoflurane in infants or children is controversial. Here, we investigated the effects of sevoflurane on rats in early life and the time scale of those effects. Our behavioral results indicated that repeated short-term exposure of new-born rats to sevoflurane caused learning and memory impairment, while a single exposure of rats to sevoflurane was relatively safe. Further mechanistic investigation revealed that repeated sevoflurane exposure impaired long-term potentiation (LTP), downregulated the expression of certain synaptogenesis-related proteins (GluR1, PSD95) and upregulated proteins related to endoplasmic reticulum (ER) stress in the hippocampus. An ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the changes in the levels of synaptic plasticity proteins. Our results provide new evidence for the clinical concerns regarding repeated sevoflurane anesthesia.

Caregivers' attitude toward disclosure of Alzheimer's disease diagnosis in Urban China.

BACKGROUND: Disclosing the diagnosis of Alzheimer's disease (AD) to a patient is controversial. There is significant stigma associated with a diagnosis of AD or dementia in China, but the attitude of the society toward disclosure of such a diagnosis had not been formally evaluated prior to our study. Therefore, we aimed to evaluate the attitude toward disclosing an AD diagnosis to patients in China with cognitive impairment from their caregivers, and the factors that may affect their attitude. METHODS: We designed a 17-item questionnaire and administered this questionnaire to caregivers, who accompanied patients with cognitive impairment or dementia in three major hospitals in Shanghai, China. The caregiver's attitude toward disclosing the diagnosis of AD as evaluated by the questionnaire was compared to that of disclosing the diagnosis of terminal cancer. RESULTS: A majority (95.7%) of the 175 interviewed participants (mean 14.2 years of education received) wished to know their own diagnosis if they were diagnosed with AD, and 97.6% preferred the doctor to tell their family members if they were diagnosed with AD. If a family member of the participants suffered from AD, 82.9% preferred to have the diagnosis disclosed to the patient. "Cognitive impairment" was the most accepted term by caregivers to disclose AD diagnosis in Chinese. CONCLUSION: This study suggests most of the well-educated individuals in a Chinese urban area favored disclosing the diagnosis when they or their family members were diagnosed with AD.

The Apelin-APJ axis is an endogenous counterinjury mechanism in experimental acute lung injury.

BACKGROUND: Although the mechanisms and pathways mediating ARDS have been studied extensively, less attention has been given to the mechanisms and pathways that counteract injury responses. This study found that the apelin-APJ pathway is an endogenous counterinjury mechanism that protects against ARDS. METHODS: Using a rat model of oleic acid (OA)-induced ARDS, the effects of ARDS on apelin and APJ receptor expressions and on APJ receptor binding capacity were examined. The protective effect of activating the apelin-APJ pathway against OA- or lipopolysaccharide (LPS)-induced ARDS was evaluated. RESULTS: ARDS was coupled to upregulations of the apelin and APJ receptor. Rats with OA-induced ARDS had higher lung tissue levels of apelin proprotein and APJ receptor expressions; elevated plasma, BAL fluid (BALF), and lung tissue levels of apelin-36 and apelin-12/13; and an increased apelin-APJ receptor binding capacity. Upregulation of the apelin-APJ system has important pathophysiologic function. Stimulation of the apelin-APJ signaling using receptor agonist apelin-13 alleviated, whereas inhibition of the apelin-APJ signaling using receptor antagonist [Ala]-apelin-13 exacerbated, OA-induced lung pathologies, extravascular lung water accumulation, capillary-alveolar leakage, and hypoxemia. The APJ receptor agonist inhibited, and the APJ receptor antagonist augmented, OA-induced lung tissue and BALF levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, and plasma and lung tissue levels of malondialdehyde. Postinjury treatment with apelin-13 alleviated lung inflammation and injury and improved oxygenation in OA- and LPS-induced lung injury. CONCLUSIONS: The apelin-APJ signaling pathway is an endogenous anti-injury and organ-protective mechanism that is activated during ARDS to counteract the injury response and to prevent uncontrolled lung injury.

Altered neurotransmitter levels with post-traumatic stress disorder.

AIM: The aim of this study was to observe the changes in the monoamine neurotransmitter levels of patients with post-traumatic stress disorder (PTSD) and explore whether the neurotransmitter level is correlated with the severity of PTSD. MATERIAL AND METHODS: A total of 15 PTSD patients without any physical injuries were enrolled into the study. Another 15 cases of pre-restoration patients were recruited as controls who experienced traumatic events but did not experience PTSD or had a Posttraumatic stress disorder Check List-Civilian version (PCL-C) score lower than 12 points. The levels of plasma monoamine neurotransmitters, including norepinephrine, 5-hydroxytryptamine, and dopamine, were tested using enzyme-linked immunosorbent assays. RESULTS: No significant differences were found between the monoamine neurotransmitter levels of the PTSD and the control groups (p > 0.05). A correlation study confirmed that the monoamine neurotransmitter levels and the PCL-C scores of the PTSD group were not significantly correlated (p > 0.05). CONCLUSION: No neurotransmitter changes are seen in PTSD caused by simple mental trauma, and the PCL-C scores do not associate with PTSD.

MicroRNA-193b is a regulator of amyloid precursor protein in the blood and cerebrospinal fluid derived exosomal microRNA-193b is a biomarker of Alzheimer's disease.

Amyloid precursor protein (APP) has an important function in the generation of Alzheimer's disease (AD). In our previous study, miR­193b was found to be downregulated in the hippocampi of 9­month­old APP/PS1 double­transgenic mice using microRNA (miR) array. In the present study, bioinformatic analyses showed that miR­193b was a miR that was predicted to potentially target the 3'­untranslated region (UTR) of APP. Subsequently, the function of miR­193b on APP was studied. The levels of miR­193b, exosomal miR­193b, Aß, tau, p­tau, HCY and APOE in samples from APP/PS1 double­transgenic mice, mild cognitive impairment (MCI) and dementia of Alzheimer­type (DAT) patients, were measured. The results indicated that overexpression of miR­193b could repress the mRNA and protein expression of APP. The miR­193b inhibitor oligonucleotide induced upregulation of APP. Binding sites of miR­193b in the 3'­UTR of APP were identified by luciferase assay. MCI and DAT patients had lower exosomal miR­193b, but not total miR­193b, in the blood as compared with the controls. DAT patients had lower exosomal miR­193b levels in blood as compared with the MCI group. A decreased exosomal miR­193b expression level was additionally observed in the cerebral spinal fluid (CSF) of DAT patients. Negative correlations were found between exosomal miR­193b and Aß42 in the CSF of DAT patients. In conclusion, these findings showed that miR­193b may function in the development of AD and exosomal miR­193b has potential as a novel, non-invasive, blood­based biomarker of MCI and DAT patients.

MicroRNA-135a and -200b, potential Biomarkers for Alzheimer׳s disease, regulate ß secretase and amyloid precursor protein.

Amyloid precursor protein (APP) and ß-site amyloid precursor protein cleaving enzyme (BACE-1) play important roles in the generation of Alzheimer׳s disease (AD), a progressive neurodegenerative disorder. In the present study, microRNA (miR) microarray was used to analyze the miR expression profiles in the hippocampi from APP/PS1 transgenic and wild type mice. The miRs with significant alteration and putative targets on APP or BACE-1 were retrieved (miR-135a, -200b and -429). The deregulations of these miRs were confirmed in mice and further verified in AD patient samples by qPCR. Primary mouse hippocampal neurons, SH-SY5Y and HEK293 cells were used to study the function of miRs on APP and BACE-1. We found that miR-135a, which was downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, directly interacted with the 3'-UTR of BACE-1 and repressed its expression and activity. On the other hand, miR-200b and -429, which were downregulated significantly in hippocampi from APP/PS1 transgenic mice compared with the wild type control, targeted the 3'-UTR of APP and repressed its expression. Furthermore, Aß42 could downregulate miR-200b expression which may generate a vicious cycle resulted in accumulating Aß42. The levels of miR-135a and -200b in the serum of DAT group were significantly lower than that of control groups (P<0.05). The serum miR-200b level of MCI group was higher than that of DAT group (P<0.05) and lower than that of control group (P<0.05). We also found decreased miR-135a and -200b levels in the cerebrospinal fluid of DAT group compared with the control group (P<0.05). In conclusion, these findings showed that miR-135a, -200b and -429 may take part in the progress of AD; miR-200b was of great potential as noninvasive and easily detected blood-based biomarkers of MCI and DAT patients.