Enhancing Stability and Antioxidant Activity of Resveratrol-Loaded Emulsions by Ovalbumin-Dextran Conjugates.

A reliable strategy for improving the stability and shelf life of protein-stabilized systems is by covalently attaching the protein onto a polysaccharide. In this study, ovalbumin (OVA) was modified with dextran (DEX) of different molecular weights by the Maillard reaction, and was used to enhance the stability of emulsions loaded with resveratrol. The surface hydrophobicity, thermal stability, and FT-IR spectroscopy of the OVA-DEX conjugates were evaluated. The results showed that the surface hydrophobicity of OVA decreased, while the thermal stability of OVA was significantly improved after DEX covalent modification. The OVA-DEX1k-stabilized emulsion exhibited high encapsulation efficiency of resveratrol, with the value of 89.0%. In addition, OVA-DEX was considerably more effective in droplet stabilization against different environmental stresses (heat, pH, and ionic strength). After 28 days of storage at 25 °C, the OVA-stabilized emulsion showed faster decomposition of resveratrol, whereas the OVA-DEX-conjugate-stabilized emulsion had approximately 73% retention of resveratrol. Moreover, the antioxidant activity of resveratrol-loaded emulsions stabilized by OVA-DEX was higher during storage under different temperatures. These results proved that the OVA-DEX conjugates had the potential to form stable, food-grade emulsion-based delivery systems against environmental stresses, which strongly supports their potential in the field of food and biomedical applications.

Oral Delivery of Astaxanthin via Carboxymethyl Chitosan-Modified Nanoparticles for Ulcerative Colitis Treatment.

The oral delivery strategy of natural anti-oxidant and anti-inflammatory agents has attracted great attention to improve the effectiveness of ulcerative colitis (UC) treatment. Herein, we developed a novel orally deliverable nanoparticle, carboxymethyl chitosan (CMC)-modified astaxanthin (AXT)-loaded nanoparticles (CMC-AXT-NPs), for UC treatment. The CMC-AXT-NPs were evaluated by appearance, morphology, particle size, ζ-potential, and encapsulation efficiency (EE). The results showed that CMC-AXT-NPs were nearly spherical in shape with a particle size of 34.5 nm and ζ-potential of -30.8 mV, and the EE of CMC-AXT-NPs was as high as 95.03%. The CMC-AXT-NPs exhibited preferable storage stability over time and well-controlled drug-release properties in simulated intestinal fluid. Additionally, in vitro studies revealed that CMC-AXT-NPs remarkably inhibited cytotoxicity induced by LPS and demonstrated superior antioxidant and anti-inflammatory abilities in Raw264.7 cells. Furthermore, CMC-AXT-NPs effectively alleviated clinical symptoms of colitis induced by dextran sulfate sodium salt (DSS), including maintaining body weight, inhibiting colon shortening, and reducing fecal bleeding. Importantly, CMC-AXT-NPs suppressed the expression of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1ß and ameliorated DSS-induced oxidative damage. Our results demonstrated the potential of CMC-modified nanoparticles as an oral delivery system and suggested these novel AXT nanoparticles could be a promising strategy for UC treatment.

Type I photodynamic antimicrobial therapy: Principles, progress, and future perspectives.

The emergence of drug-resistant bacteria has significantly diminished the efficacy of existing antibiotics in the treatment of bacterial infections. Consequently, the need for finding a strategy capable of effectively combating bacterial infections has become increasingly urgent. Photodynamic therapy (PDT) is considered one of the most promising emerging antibacterial strategies due to its non-invasiveness, low adverse effect, and the fact that it does not lead to the development of drug resistance. However, bacteria at the infection sites often exist in the form of biofilm instead of the planktonic form, resulting in a hypoxic microenvironment. This phenomenon compromises the treatment outcome of oxygen-dependent type-II PDT. Compared to type-II PDT, type-I PDT is not constrained by the oxygen concentration in the infected tissues. Therefore, in the treatment of bacterial infections, type-I PDT exhibits significant advantages over type-II PDT. In this review, we first introduce the fundamental principles of type-I PDT in details, including its physicochemical properties and how it generates reactive oxygen species (ROS). Next, we explore several specific antimicrobial mechanisms utilized by type-I PDT and summarize the recent applications of type-I PDT in antimicrobial treatment. Finally, the limitations and future development directions of type-I photosensitizers are discussed. STATEMENT OF SIGNIFICANCE: The misuse and overuse of antibiotics have accelerated the development of bacterial resistance. To achieve the effective eradication of resistant bacteria, pathfinders have devised various treatment strategies. Among these strategies, type I photodynamic therapy has garnered considerable attention owing to its non-oxygen dependence. The utilization of non-oxygen-dependent photodynamic therapy not only enables the effective elimination of drug-resistant bacteria but also facilitates the successful eradication of hypoxic biofilms, which exhibits promising prospects for treating biofilm-associated infections. Based on the current research status, we anticipate that the novel type I photodynamic therapy agent can surmount the biofilm barrier, enabling efficient treatment of hypoxic biofilm infections.

Long-read sequencing reveals the structural complexity of genomic integration of HPV DNA in cervical cancer cell lines.

BACKGROUND: Cervical cancer (CC) causes more than 311,000 deaths annually worldwide. The integration of human papillomavirus (HPV) is a crucial genetic event that contributes to cervical carcinogenesis. Despite HPV DNA integration is known to disrupt the genomic architecture of both the host and viral genomes in CC, the complexity of this process remains largely unexplored. RESULTS: In this study, we conducted whole-genome sequencing (WGS) at 55-65X coverage utilizing the PacBio long-read sequencing platform in SiHa and HeLa cells, followed by comprehensive analyses of the sequence data to elucidate the complexity of HPV integration. Firstly, our results demonstrated that PacBio long-read sequencing effectively identifies HPV integration breakpoints with comparable accuracy to targeted-capture Next-generation sequencing (NGS) methods. Secondly, we constructed detailed models of complex integrated genome structures that included both the HPV genome and nearby regions of the human genome by utilizing PacBio long-read WGS. Thirdly, our sequencing results revealed the occurrence of a wide variety of genome-wide structural variations (SVs) in SiHa and HeLa cells. Additionally, our analysis further revealed a potential correlation between changes in gene expression levels and SVs on chromosome 13 in the genome of SiHa cells. CONCLUSIONS: Using PacBio long-read sequencing, we have successfully constructed complex models illustrating HPV integrated genome structures in SiHa and HeLa cells. This accomplishment serves as a compelling demonstration of the valuable capabilities of long-read sequencing in detecting and characterizing HPV genomic integration structures within human cells. Furthermore, these findings offer critical insights into the complex process of HPV16 and HPV18 integration and their potential contribution to the development of cervical cancer.

Analysis of subsets and localization of macrophages in skin lesions and peripheral blood of patients with keloids.

Keloids are a type of abnormal fibrous proliferation disease of the skin, characterized by local inflammation that lacks clear pathogenesis and satisfactory treatment. The phenomenon of distinct phenotypes, including M1 and M2 macrophages, is called macrophage polarization. Recently, macrophage polarization has been suggested to play a role in keloid formation. This study aimed to evaluate the relation between macrophage polarization and keloids and identify novel effective treatments for keloids. Differentially expressed genes were identified via RNA sequencing of the skin tissue of healthy controls and patients with keloids and validated using quantitative PCR. Multiplex immunofluorescence microscopy was used to detect different phenotypes of macrophages in keloid tissues. Finally, quantitative PCR validation of differentially expressed genes and flow cytometry were used to analyze macrophages in the peripheral blood of healthy controls and patients with keloids. Total and M2 macrophages were significantly increased in the local skin tissue and peripheral blood of patients with keloids compared with healthy controls. In addition, inflammation- and macrophage polarization-related differentially expressed genes in keloid tissue showed similar expression patterns in the peripheral blood. This study highlighted an increased frequency of total macrophages and M2 polarization in the local skin tissue and peripheral blood of patients with keloids. This systematic macrophage polarization tendency also indicates a potential genetic predisposition to keloids. These findings suggest the possibility of developing new diagnostic and therapeutic indicators for keloids focusing on macrophages.

Effects of the periodic fasting-mimicking diet on health, lifespan, and multiple diseases: a narrative review and clinical implications.

Dietary restriction and fasting have been recognized for their beneficial effects on health and lifespan and their potential application in managing chronic metabolic diseases. However, long-term adherence to strict dietary restrictions and prolonged fasting poses challenges for most individuals and may lead to unhealthy rebound eating habits, negatively affecting overall health. As a result, a periodic fasting-mimicking diet (PFMD), involving cycles of fasting for 2 or more days while ensuring basic nutritional needs are met within a restricted caloric intake, has gained widespread acceptance. Current research indicates that a PFMD can promote stem cell regeneration, suppress inflammation, extend the health span of rodents, and improve metabolic health, among other effects. In various disease populations such as patients with diabetes, cancer, multiple sclerosis, and Alzheimer's disease, a PFMD has shown efficacy in alleviating disease symptoms and improving relevant markers. After conducting an extensive analysis of available research on the PFMD, it is evident that its advantages and potential applications are comparable to other fasting methods. Consequently, it is proposed in this review that a PFMD has the potential to fully replace water-only or very-low-energy fasting regimens and holds promise for application across multiple diseases.

The relationship between APOE genotype, CSF Tau and cognition across the Alzheimer's disease spectrum, moderation and mediation role of insula network connectivity.

AIMS: To investigate whether insula network connectivity modulates the relationship between apolipoprotein E (APOE) ε4 genotype, cerebrospinal fluid (CSF) biomarkers (Aß, Tau, and pTau) and cognition across Alzheimer's disease (AD) spectrum. METHODS: Forty-six cognitive normal (CN), 35 subjective memory complaint (SMC), 41 mild cognitive impairment (MCI), and 32 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were obtained. Multivariable linear regression analyses were conducted to investigate the main effects and interaction of the APOE genotype and disease status on the insula functional connectivity (IFC) network. Mediation and moderation analysis were performed to investigate whether IFC strengths regulate the association between APOE genotype, CSF biomarkers and cognition. Additionally, the support vector machine (SVM) model integrating APOE genotype, CSF biomarkers, and neuroimaging biomarkers (insula volumes and altered regional IFCs) was used to classify the AD spectrum. RESULTS: The interactive effect of the APOE genotype and disease on the insula network was found in the left medial superior frontal gyrus (SFGmed.L), right anterior medial prefrontal cortex (aMPFC.R), and bilateral thalamus (THA.B). The functional connectivities (FCs) in the left insula (LIns) connecting with the left posterior middle temporal gyrus (pMTG.L), SFGmed.L, and right lingual gyrus (LING.R) were correlated with cognition. LIns-SFGmed.L and LIns-pMTG.L FCs could moderate the effects of Tau on cognition. Furthermore, LIns-SFGmed.L FC may suppress the association between APOE genotype and cognition. More importantly, the integrated biomarkers from the SVM model yielded strong powers for classifying the AD spectrum. CONCLUSIONS: Insula functional connectivity regulated the association between APOE genotype, CSF Tau and cognition and provided stage-dependent biomarkers for early differentiation of the AD spectrum. The present study used a cross-sectional design. Follow-up studies are needed to validate the relationship.

Bile acid signalling and its role in anxiety disorders.

Anxiety disorder is a prevalent neuropsychiatric disorder that afflicts 7.3%~28.0% of the world's population. Bile acids are synthesized by hepatocytes and modulate metabolism via farnesoid X receptor (FXR), G protein-coupled receptor (TGR5), etc. These effects are not limited to the gastrointestinal tract but also extend to tissues and organs such as the brain, where they regulate emotional centers and nerves. A rise in serum bile acid levels can promote the interaction between central FXR and TGR5 across the blood-brain barrier or activate intestinal FXR and TGR5 to release fibroblast growth factor 19 (FGF19) and glucagon-like peptide-1 (GLP-1), respectively, which in turn, transmit signals to the brain via these indirect pathways. This review aimed to summarize advancements in the metabolism of bile acids and the physiological functions of their receptors in various tissues, with a specific focus on their regulatory roles in brain function. The contribution of bile acids to anxiety via sending signals to the brain via direct or indirect pathways was also discussed. Different bile acid ligands trigger distinct bile acid signaling cascades, producing diverse downstream effects, and these pathways may be involved in anxiety regulation. Future investigations from the perspective of bile acids are anticipated to lead to novel mechanistic insights and potential therapeutic targets for anxiety disorders.

Structural transition of parenthood among Chinese nulliparous couples with planned pregnancies, 2013-2019.

BACKGROUND: The postponement of parenthood is a global public health issue that has received attention of many public health experts. However, few studies have investigated the postponement in marriage age, marriage and conception interval, and pregnancy age in terms of demographic and regional heterogenicities. METHODS: This is a cross-sectional, registry-based study, and a total of 13 894 601 nulliparous couples who participated in the National Free Pre-Pregnancy Check-ups Project and became pregnant during 2013-2019 were included. We calculated annual percentage change and forest plots for marriage age, marriage and conception interval, and pregnancy age. RESULTS: Late marriage (marriage age ≥ 35 years), long marriage and conception interval (marriage and conception interval ≥ 2 years), and advanced pregnancy (pregnancy age ≥ 35 years) increased from 1.20%, 22.01%, and 1.88% in 2013 to 1.69%, 32.75%, and 2.79% in 2019, respectively. The corresponding annual percentage changes were 6.55%, 8.44%, and 8.17%. Participants without higher education had a higher annual percentage change, but comparable prevalence for long marriage and conception interval with participants with higher education. Participants residing in second- or new first-tier cities, and the northeast of China who had a higher prevalence of parenthood postponement also had higher corresponding annual percentage changes. CONCLUSIONS: Structural postponement of parenthood with demographic and regional heterogenicities was observed among Chinese nulliparous couples with planned pregnancies during 2013-2019. Inclusive and comprehensive parenting support should be developed and implemented in mainland China to minimize the negative health effects arising from the postponement, especially for couples without higher education and living in new first/second-tier cities or the northeast China.

High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a rare devastating subclassification of Alzheimer's disease (AD). EOAD affects individuals <65 years old, and accounts for 5%-10% of all AD cases. Previous studies on EOAD primarily focused on familial forms, whereas research on sporadic EOAD (sEOAD), which represents 85%-90% of EOAD cases, is limited. In this prospective cohort study, participants were recruited between 2018 and 2023 and included patients with sEOAD (n = 110), late-onset AD (LOAD, n = 89), young controls (YC, n = 50), and older controls (OC, n = 25). All AD patients fulfilled the diagnostic criteria based on biomarker evidence. Familial EOAD patients or non-AD dementia patients were excluded. Single molecule array technology was used to measure fluid biomarkers, including cerebrospinal fluid (CSF) and plasma amyloid beta (Aß) 40, Aß42, phosphorylated tau (P-tau) 181, total tau (T-tau), serum neurofilament light chain and glial fibrillary acidic protein (GFAP). Patients with sEOAD exhibited more severe executive function impairment and bilateral precuneus atrophy (P < 0.05, family-wise error corrected) than patients with LOAD. Patients with sEOAD showed elevated CSF and plasma P-tau181 levels (154.0 ± 81.2 pg/mL, P = 0.002; and 6.1 ± 2.3 pg/mL, P = 0.046). Moreover, precuneus atrophy was significantly correlated with serum GFAP levels in sEOAD (P < 0.001). Serum GFAP levels (area under the curve (AUC) = 96.0%, cutoff value = 154.3 pg/mL) displayed excellent diagnostic value in distinguishing sEOAD patients from the control group. These preliminary findings highlight the crucial role of tau protein phosphorylation in the pathogenesis and progression of sEOAD.

Association of marine PUFAs intakes with cardiovascular disease, all-cause mortality, and cardiovascular mortality in American adult male patients with dyslipidemia: the U.S. National Health and Nutrition Examination Survey, 2001 to 2016.

BACKGROUND: The relationship between marine polyunsaturated fatty acid (PUFA) intake and cardiovascular disease and mortality in dyslipidemic patients is unclear. Men with dyslipidemia have a higher risk of cardiovascular disease than women, and PUFA supplementation may be more beneficial in men. OBJECTIVE: The purpose of this study was to assess the relationship between different types of marine polyunsaturated fatty acids intakes and cardiovascular disease, all-cause mortality, and cardiovascular mortality in adult U.S. males with dyslipidemia. METHODS: The study ultimately included 11,848 adult men with dyslipidemia who were screened from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2016. This was linked to the 2019 National Death Index (NDI) records to establish a prospective cohort. In the study, a logistic regression model was established to assess the relationship between PUFA intake and prevalent CVD, and a Cox proportional hazards regression model was established to assess the relationship between PUFA intake and death. RESULTS: In the fully adjusted models, compared with participants in the lowest tertile, participants with the highest DPA intake were associated with a lower risk of CVD (CVD: OR = 0.71, 95%CI: 0.55, 0.91; angina: OR = 0.54, 95%CI: 0.38, 0.79; stroke: OR = 0.62, 95%CI: 0.43, 0.89), but not with three subtypes of congestive heart failure, coronary heart disease, and myocardial infarction. And the highest tertile level of DPA intake can reduce all-cause mortality (HR = 0.77, 95%CI: 0.64, 0.91) and CVD mortality (HR = 0.68, 95%CI: 0.52, 0.90). CONCLUSIONS: Cardiovascular disease risk, all-cause mortality, and CVD mortality were inversely associated with dietary DPA intake but not EPA and DHA intakes in U.S. male participants with dyslipidemia.

Correction: A H2O2 self-sufficient nanoplatform with domino effects for thermal-responsive enhanced chemodynamic therapy.

[This corrects the article DOI: 10.1039/C9SC05506A.].

A 2-week time-restricted feeding attenuates psoriasis-like lesions with reduced inflammatory cytokines and immunosenescence in mice.

Psoriasis, a well-established T-cell mediated dermatosis, exhibits a robust correlation with obesity and systemic inflammation, manifesting psoriasis skin lesions and premature immunosenescence within the peripheral blood and lesion. Intermittent fasting (IF) has exhibited various beneficial effects in reducing inflammation, resisting oxidative stress and slowing ageing, as well as losing weight. A form of IF known as time-restricted feeding (TRF) restricts daily caloric intake within 4-8 h. Nonetheless, the advantageous impacts of TRF on psoriasis still require further verification. We measured the acanthosis in Imiquimod (IMQ)-induced psoriasis mice and evaluated their pathological phenotypes. Our study examined the effects of a 2-week TRF on body weight and metabolic parameters. The subsets of T cells in spleens and skin lesions were accessed by flow cytometry. Cytokines and senescence-associated genes were evaluated by immunofluorescence and RT-qPCR. RNA sequencing was conducted on skin lesions. According to our findings, a 2-week TRF attenuates psoriasis-like lesions in mice with reduced inflammatory cytokines and mitigated immunosenescence. TRF increased the counts of CD4+ Treg cells in skin lesions while reducing the counts of Th2 and Th17 cells in spleens. Furthermore, the administration of TRF resulted in a decrease in the population of CD4+ senescent T cells in both the dermis and spleens, concomitant with the expression of senescence-associated genes in spleen CD4+ T cells. The outcomes mentioned above provide valuable evidence in support of TRF for the management of psoriasis.

Nitric Oxide-Assisted Photodynamic Therapy for Enhanced Penetration and Hypoxic Bacterial Biofilm Elimination.

The presence of a biofilm matrix barrier and hypoxic microenvironment within the biofilm significantly impedes the efficacy of photodynamic therapy for bacterial biofilm infections. Herein, a phototherapeutic nanoagent with type-I photodynamic behavior and nitric oxide (NO) release performance is reported for overcoming biofilm-associated infectious diseases. Sodium nitroprusside (SNP), a NO donor, is loaded onto amino-modified mesoporous silica nanoparticles (MSN) to form MSN@SNP NPs. The resulting nanoparticles are further modified with a porphyrin-based metal-organic framework (Ti-TCPP MOF) to obtain MSN@MOF/SNP NPs (MMS NPs) for phototherapeutic applications. In the hypoxia biofilm microenvironment, the MMS NPs release NO to enhance the biofilm permeability and induce the generation of hydroxyl radical (•OH) and superoxide anion radical (O2 •- ) via Type-I photodynamic pathway under laser irradiation. Subsequently, the biofilm-associated infections are effectively eliminated through reactive oxygen species (ROS) and NO gas synergistic therapy. In addition, NO also stimulates collagen deposition and promotes angiogenesis in vivo. Therefore, the MMS NPs efficiently treat biofilm-related infections, providing an alternative approach to combat biofilm-associated infectious diseases.

Blood-based biomarkers for Alzheimer's disease: a multicenter-based cross-sectional and longitudinal study in China.

Discrepancies in diagnostic biomarkers for Alzheimer's Disease (AD) may arise from racial disparities, risk factors, or lifestyle differences. Moreover, there has been a lack of systematic and multicenter studies to evaluate baselines of the AD biomarkers in Chinese populations. Thus, there is an urgent need for research to investigate the effectiveness of blood biomarkers for AD, specifically in the Chinese Han population, using a multicenter approach. In the present multicenter-based cross-sectional and longitudinal study, we evaluated 817 blood samples from 6 different clinical centers. We measured plasma amyloid beta (Aß)-40, Aß42, phosphorylated tau 181 (pTau), total tau (tTau), serum neurofilament light (NFL), and glial fibrillary acidic protein (GFAP). Additionally, 18F-florbetapir positron electron tomography and magnetic resonance imaging were also performed. A combination of the APOE genotype with plasma pTau and serum GFAP demonstrated exceptional performance in distinguishing Aß status. Furthermore, baseline GFAP levels exhibited a strong association with cognitive decline over time and brain atrophy, with higher GFAP levels predicting a faster rate of neurodegeneration. In summary, these results validate the practicality of blood biomarkers in the Chinese Han population, encompassing various regions within China. Additionally, they emphasize the potential of pTau and GFAP as non-invasive methods for detecting and screening AD at an early stage.

Investigation of brain iron levels in Chinese patients with Alzheimer's disease.

Introduction: We aimed (i) to explore the diagnostic value of deep gray matter magnetic susceptibility in Alzheimer's disease (AD) in China and (ii) to analyze its correlation with neuropsychiatric scales. Moreover, we conducted subgroup analysis based on the presence of the APOE-ε4 gene to improve the diagnosis of AD. Methods: From the prospective studies of the China Aging and Neurodegenerative Initiative (CANDI), a total of 93 subjects who could undergo complete quantitative magnetic susceptibility imaging and APOE-ε4 gene detection were selected. Differences in quantitative susceptibility mapping (QSM) values between and within groups, including AD patients, individuals with mild cognitive impairment (MCI), and healthy controls (HCs), both APOE-ε4 carriers and non-carriers, were analyzed. Results: In primary analysis, the magnetic susceptibility values of the bilateral caudate nucleus and right putamen in the AD group and of the right caudate nucleus in the MCI group were significantly higher than those in the HCs group (P < 0.05). In APOE-ε4 non-carriers, there were significant differences in more regions between the AD, MCI, and HCs groups, such as the left putamen and the right globus pallidus (P < 0.05). In subgroup analysis, the correlation between QSM values in some brain regions and neuropsychiatric scales was even stronger. Discussion: Exploration of the correlation between deep gray matter iron levels and AD may provide insight into the pathogenesis of AD and facilitate early diagnosis in elderly Chinese. Further subgroup analysis based on the presence of the APOE-ε4 gene may further improve the diagnostic efficiency and sensitivity.

Recent progress in nanozymes for the treatment of diabetic wounds.

The slow healing of diabetic wounds has seriously affected human health. Meanwhile, the open wounds are susceptible to bacterial infection. Clinical therapeutic methods such as antibiotic therapy, insulin treatment, and surgical debridement have made great achievements in the treatment of diabetic wounds. However, drug-resistant bacteria will develop after long-term use of antibiotics, resulting in decreased efficacy. To improve the therapeutic effect, increasing drug concentration is a common strategy in clinical practice, but it also brings serious side effects. In addition, hyperglycemia control or surgical debridement can easily bring negative effects to patients, such as hypoglycemia or damage of normal tissue. Therefore, it is essential to develop novel therapeutic strategies to effectively promote diabetic wound healing. In recent years, nanozyme-based diabetic wound therapeutic systems have received extensive attention because they possess the advantages of nanomaterials and natural enzymes. For example, nanozymes have the advantages of a small size and a high surface area to volume ratio, which can enhance the tissue penetration of nanozymes and increase the reactive active sites. Moreover, compared with natural enzymes, nanozymes have more stable catalytic activity, lower production cost, and stronger operability. In this review, we first reviewed the basic characteristics of diabetic wounds and then elaborated on the catalytic mechanism and action principle of different types of nanozymes in diabetic wounds from three aspects: controlling bacterial infection, controlling hyperglycemia, and relieving inflammation. Finally, the challenges, prospects and future implementation of nanozymes for diabetic wound healing are outlined.

Molecules of senescent glial cells differentiate Alzheimer's disease from ageing.

BACKGROUND: Ageing is a major risk factor for Alzheimer's disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain. OBJECTIVES: To identify the biomarkers in the cerebrospinal fluid (CSF) that could help differentiate healthy ageing from neurodegenerative processes. METHODS: Cellular senescence and ageing-related biomarkers were assessed in primary astrocytes and postmortem brains by immunoblotting and immunohistochemistry. The biomarkers were measured in CSF samples from the China Ageing and Neurodegenerative Disorder Initiative cohort using Elisa and the multiplex Luminex platform. RESULTS: The cyclin-dependent kinase inhibitors p16/p21-positive senescent cells in human postmortem brains were predominantly astrocytes and oligodendrocyte lineage cells, which accumulated in AD brains. CCL2, YKL-40, HGF, MIF, S100B, TSP2, LCN2 and serpinA3 are biomarkers closely related to human glial senescence. Moreover, we discovered that most of these molecules, which were upregulated in senescent glial cells, were significantly elevated in the AD brain. Notably, CSF YKL-40 (ß=0.5412, p<0.0001) levels were markedly elevated with age in healthy older individuals, whereas HGF (ß=0.2732, p=0.0001), MIF (ß=0.33714, p=0.0017) and TSP2 (ß=0.1996, p=0.0297) levels were more susceptible to age in older individuals with AD pathology. We revealed that YKL-40, TSP2 and serpinA3 were useful biomarkers for discriminating patients with AD from CN individuals and non-AD patients. DISCUSSION: Our findings demonstrated the different patterns of CSF biomarkers related to senescent glial cells between normal ageing and AD, implicating these biomarkers could identify the road node in healthy path off to neurodegeneration and improve the accuracy of clinical AD diagnosis, which would help promote healthy ageing.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Background: Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. Methods: A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aß40, Aß42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Results: Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aß42 (p = 0.02). Conclusion: Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

m6A methylation: Critical roles in aging and neurological diseases.

N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells, which participates in the functional regulation of various biological processes. It regulates the expression of targeted genes by affecting RNA translocation, alternative splicing, maturation, stability, and degradation. As recent evidence shows, of all organs, brain has the highest abundance of m6A methylation of RNAs, which indicates its regulating role in central nervous system (CNS) development and the remodeling of the cerebrovascular system. Recent studies have shown that altered m6A levels are crucial in the aging process and the onset and progression of age-related diseases. Considering that the incidence of cerebrovascular and degenerative neurologic diseases increase with aging, the importance of m6A in neurological manifestations cannot be ignored. In this manuscript, we focus on the role of m6A methylation in aging and neurological manifestations, hoping to provide a new direction for the molecular mechanism and novel therapeutic targets.