How Advanced are Nanocarriers for Effective Subretinal Injection?

Subretinal injection (SR injection) is a commonly used method of ocular drug delivery and has been mainly applied for the treatment of neovascular age-associated macular degeneration (nAMD) and sub-macular hemorrhage (SMH) caused by nAMD, as well as various types of hereditary retinopathies (IRD) such as Stargardt's disease (STGD), retinitis pigmentosa (RP), and a series of fundus diseases such as Leber's congenital dark haze (LCA), choroidal defects, etc. The commonly used carriers of SR injection are mainly divided into viral and non-viral vectors. Leber's congenital amaurosis (LCA), choroidal agenesis, and a series of other fundus diseases are also commonly treated using SR injection. The commonly used vectors for SR injection are divided into two categories: viral vectors and non-viral vectors. Viral vectors are a traditional class of SR injection drug carriers that have been extensively studied in clinical treatment, but they still have many limitations that cannot be ignored, such as poor reproduction efficiency, small loading genes, and triggering of immune reactions. With the rapid development of nanotechnology in the treatment of ocular diseases, nanovectors have become a research hotspot in the field of non-viral vectors. Nanocarriers have numerous attractive properties such as low immunogenicity, robust loading capacity, stable structure, and easy modification. These valuable features imply greater safety, improved therapeutic efficacy, longer duration, and more flexible indications. In recent years, there has been a growing interest in nanocarriers, which has led to significant advancements in the treatment of ocular diseases. Nanocarriers have not only successfully addressed clinical problems that viral vectors have failed to overcome but have also introduced new therapeutic possibilities for certain classical disease types. Nanocarriers offer undeniable advantages over viral vectors. This review discusses the advantages of subretinal (SR) injection, the current status of research, and the research hotspots of gene therapy with viral vectors. It focuses on the latest progress of nanocarriers in SR injection and enumerates the limitations and future perspectives of nanocarriers in the treatment of fundus lesions. Furthermore, this review also covers the research progress of nanocarriers in the field of subretinal injection and highlights the value of nanocarrier-mediated SR injection in the treatment of fundus disorders. Overall, it provides a theoretical basis for the application of nanocarriers in SR injection.

Extreme temperature events, functional dependency, and cardiometabolic multimorbidity: Insights from a national cohort study in China.

BACKGROUND: Extreme temperature events (ETEs), including heatwaves and cold spells, are attracting increasing attention because of their impacts on human health. However, the association between ETEs and cardiometabolic multimorbidity (CMM) and the role of functional dependency in this relationship remain unclear. METHODS: A prospective cohort study was conducted using data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2020, considering 12 definitions each for heatwaves and cold spells, and three levels of functional dependency. Mixed Cox models with time-varying variables were used to comprehensively assess the independent and combined effects of ETEs and functional dependency on CMM. Additionally, subgroup analyses were conducted to investigate whether the relationship between ETEs and CMM was modified by the baseline characteristics. RESULTS: Heatwave and cold spell exposures were associated with an increased risk of CMM (HR range: 1.028-1.102 and 1.046-1.187, respectively). Compared to participants with normal functional abilities, the risk of CMM increased with higher levels of functional dependency (HR range: 1.938-2.185). ETEs exposure and functional dependency are jointly associated with CMM risk. Participants with high-intensity ETEs exposure and high functional dependency had the greatest risk of developing CMM. Participants aged 60 and above were more susceptible to the effects of ETEs on CMM. Additionally, urban residents and those in northern regions were more vulnerable to heatwaves. CONCLUSION: Both ETEs exposure and functional dependency increase the risk of developing CMM. Participants with functional dependency exposed to high-intensity ETEs faced the highest risk of developing CMM. These findings highlight the significant impact of ETEs on CMM and the importance of protecting vulnerable populations during periods of extreme temperature.

Layer-by-layer self-assembly coatings on strontium titanate nanotubes with antimicrobial and anti-inflammatory properties to prevent implant-related infections.

One way to effectively address endophyte infection and loosening is the creation of multifunctional coatings that combine anti-inflammatory, antibacterial, and vascularized osteogenesis. This study started with the preparation of strontium-doped titanium dioxide nanotubes (STN) on the titanium surface. Next, tannic acid (TA), gentamicin sulfate (GS), and pluronic F127 (PF127) were successfully loaded into the STN via layer-by-layer self-assembly, resulting in the STN@TA-GS/PF composite coatings. The findings demonstrated the excellent hydrophilicity and bioactivity of the STN@TA-GS/PF coating. STN@TA-GS/PF inhibited E. coli and S. aureus in vitro to a degree of roughly 80.95 % and 92.45 %, respectively. Cellular investigations revealed that on the STN@TA-GS/PF surface, the immune-system-related RAW264.7, the vasculogenic HUVEC, and the osteogenic MC3T3-E1 showed good adhesion and proliferation activities. STN@TA-GS/PF may influence RAW264.7 polarization toward the M2-type and encourage MC3T3-E1 differentiation toward osteogenesis at the molecular level. Meanwhile, the STN@TA-GS/PF coating achieved effective removal of ROS within HUVEC and significantly promoted angiogenesis. In both infected and non-infected bone defect models, the STN@TA-GS/PF material demonstrated strong anti-inflammatory, antibacterial, and vascularization-promoting osteogenesis properties. In addition, STN@TA-GS/PF had good hemocompatibility and biosafety. The three-step process used in this study to modify the titanium surface for several purposes gave rise to a novel concept for the clinical design of antimicrobial coatings with immunomodulatory properties.

Effects of different sizes of ambient particulate matter and household fuel use on physical function: National cohort study in China.

BACKGROUND: Impact of outdoor and household air pollution on physical function remains unelucidated. This study examined the influence of various ambient particulate sizes (PM1, PM2.5, and PM10) and household fuel usage on physical function. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) spanning 2011 and 2015 were utilized. The physical functional score was computed by summing scores from four tests: grip strength, gait speed, chair stand test, and balance. Multivariate linear and linear mixed-effects models were used to explore the separate and combined effects of PM1, PM2.5, PM10 and household fuel use on physical function in the cross-sectional and longitudinal analyses, respectively, and to further observe the effects of fuel cleanup on physical function in the context of air pollution exposure. RESULTS: Both cross-sectional and longitudinal analyses revealed negative correlations between PM1 (ß = -0.044; 95% CI: -0.084, -0.004), PM2.5 (ß = -0.024; 95% CI: -0.046, -0.001), PM10 (ß = -0.041; 95% CI: -0.054, -0.029), and physical function, with a more pronounced impact observed for fine particulate matter (PM1). Cleaner fuel use was associated with enhanced physical function compared to solid fuels (ß = 0.143; 95% CI: 0.070, 0.216). The presence of air pollutants and use of solid fuels had a negative impact on physical function, while cleaner fuel usage mitigated the adverse effects of air pollutants, particularly in areas with high exposure. CONCLUSION: This study underscores the singular and combined detrimental effects of air pollutants and solid fuel usage on physical function. Addressing fine particulate matter, specifically PM1, and prioritizing efforts to improve household fuel cleanliness in regions with elevated air pollution levels are crucial for preventing physical disability.

Effect of PCI on ophthalmic artery hemodynamics in patients with acute coronary syndrome.

Purpose: We aimed to explore the effects of percutaneous coronary intervention (PCI) on the ophthalmic artery (OA) hemodynamics in patients with acute coronary syndrome (ACS). Methods: A total of 73 participants (Group0: healthy controls, Group1: Patients with ACS underwent PCI < 3 months, Group2: Patients with ACS underwent PCI ≥ 3 months) were enrolled. Computed tomographic angiography images were used to construct three-dimensional models of participants' OAs. Numerical simulations based on computational fluid dynamics were used to acquire hemodynamic parameters. Results: The angle between the OA and internal carotid artery in Group2 was significantly larger compared with Group0 and Group1 (P = 0.003 and P = 0.044). Hemodynamic simulation showed a significantly slower OA blood velocity in Group1 than in the control (P < 0.001) and Group2 (P = 0.033). Lower wall shear stress was found in Group1 than that in control (P = 0.040). Patients after PCI had a higher wall pressure than healthy controls (P = 0.012 and P = 0.004). Mass flow ratios were decreased in Group1 and Group2 (P = 0.021 and P = 0.002). The hemodynamic parameters of OA were correlated with several clinical indicators. Conclusions: The OA blood flow velocity of patients with ACS after PCI initially slowed down, which increased the risk of plaque formation, and then showed an increasing trend. There was a correlation between OA hemodynamic parameters and clinical indexes related to cardiac stress. Ischemia-reperfusion injury and changes in blood flow status after PCI may affect OA morphology and hemodynamics, leading to ocular lesions. Trial registration: ChiCTR2100050428.

YTHDC1 inhibits osteoclast differentiation to alleviate osteoporosis by enhancing PTPN6 messenger RNA stability in an m6A-hUR-dependent manner.

YTHDC1 has been confirmed to mediate osteoporosis (OP) progression by regulating osteogenic differentiation. However, whether YTHDC1 mediates osteoclast differentiation and its molecular mechanism remains unclear. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the levels of YTHDC1, PTPN6, NFATc1, TRAP, RUNX2, alkaline phosphatase, and HUR. YTHDC1 knockout mice was constructed by CRISPR/Cas9 system, and the OP mice model was established by ovariectomy. Hematoxylin and eosin staining and micro-computed tomography were used to evaluate bone formation and bone mass. Mouse primary bone marrow macrophage cells were isolated and induced into osteoclasts. TRAP-positive cells were detected using TRAP staining. MeRIP-qPCR, RIP-qPCR assay, RNA affinity isolation assay, and co-immunoprecipitation assay were used to confirm the interactions among YTHDC1, PTPN6, and HUR. YTHDC1 expression was reduced and positively correlated with lumbar bone mineral density in OP patients. In the ovariectomy model of YTHDC1 knockout mice, bone formation was reduced, bone histomorphology was changed, and osteoclastic-related factor (NFATc1 and TRAP) levels were enhanced. Overexpression YTHDC1 inhibited osteoclast differentiation. YTHDC1 increased PTPN6 messenger RNA stability in an m6A-dependent manner. Moreover, YTHDC1 interacted with HUR to positively regulate PTPN6 expression. PTPN6 knockdown promoted osteoclast differentiation, and this effect was reversed by overexpressing HUR or YTHDC1. YTHDC1 was involved in regulating OP progression through inhibiting osteoclast differentiation by enhancing PTPN6 messenger RNA stability in an m6A-HUR-dependent manner.

[Changes of non-structural carbohydrates and nitrogen contents of needles and twigs in Pinus sylvestris var. mongolica plantations along an aridity gradient]. / 沿干旱梯度樟子松人工林针叶和枝条非结构性碳水化合物及氮含量的变化.

With six Pinus sylvestris var. mongolica plantations (Huinan, Xifeng, Fujia, Zhanggutai, Naiman and Wulanaodu) along an aridity gradient in the Horqin sandy land, we examined the changes in non-structural carbohydrates (NSCs) and nitrogen (N) contents of current and one-year-old needles and twigs, to explore the carbon supply and demand status as well as the nutrient accumulation strategies of P. sylvestris var. mongolica under drought. The results showed that the contents of NSCs and soluble sugars in needles and twigs of P. sylvestris var. mongolica plantations significantly decreased with increasing aridity. From the most humid site (Huinan) to the most aridity site (Wulanaodu), the soluble sugar contents in current and one-year old needles of P. sylvestris var. mongolica decreased from 12.8% and 12.5% to 9.0% and 9.5%, respectively. The soluble sugar contents in current-year old twigs decreased from 15.6% to 9.2%. With increasing aridity, the starch contents in needles and twigs remained relatively stable, soluble sugars/starch ratio in current and one-year old needles decreased, the N contents in current and one-year old twigs significantly increased. The P. sylvestris var. mongolica plantations in the Horqin sandy land consumed soluble sugar storage under drought, resulting in a risk of mortality from 'carbon starvation'. P. sylvestris var. mongolica tended to maintain stable starch storage and accumulate N in twigs to cope with long-term drought stress.

Overexpression of circ_0021739 in Peripheral Blood Mononuclear Cells in Women with Postmenopausal Osteoporosis Is Associated with Reduced Expression of microRNA-194-5p in Osteoclasts.

BACKGROUND Postmenopausal osteoporosis, a common disease among elderly women, is linked to estrogen deficiency, mechanical loading, and genotype. Circular RNAs (circRNAs) are formed through reverse splicing of the splice donor at the 3' end and the splice accepter at the 5' end in pre-mRNA and have been shown to be involved in the development of multiple diseases. Based on their high sequence conservation and stability, circRNAs may be useful biomarkers in different diseases. However, the roles of circRNAs in postmenopausal osteoporosis remain incompletely understood. MATERIAL AND METHODS Fifty-three postmenopausal women were assigned to either the postmenopausal osteoporosis group (n=28) or the control group (n=25). Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) analysis was performed to determine the differential expression of circRNAs between the 2 groups. Receiver-operating characteristic (ROC) curve analysis was conducted to evaluate the clinical diagnostic value of circRNA. Prediction of the binding sites between circRNA and miRNAs was conducted using miRanda and RNAhybrid. The function of the circRNA in osteoclastogenesis was determined by circRNA overexpression followed by tartrate-resistant acid phosphatase staining and RT-qPCR analysis. RESULTS Among 4 circRNAs previously identified by RNA-sequencing analysis as differentially expressed in patients with postmenopausal osteoporosis, only hsa_circ_0021739 showed a significant difference in expression between the groups and was downregulated in patients with postmenopausal osteoporosis. The hsa_circ_0021739 expression level was determined to be correlated with the lumbar vertebra, femur, and forearm T-scores. Overexpression of hsa_circ_0021739 decreased the level of hsa-miR-502-5p and inhibited the differentiation of osteoclasts. CONCLUSIONS The circRNA hsa_circ_0021739 is a potential blood biomarker for postmenopausal osteoporosis. In addition, hsa-miR-502-5p is a likely target of hsa_circ_0021739, which acts to regulate the differentiation of osteoclasts.

DDAH2 (-449 G/C) G allele is positively associated with leukoaraiosis in northeastern China: a double-blind, intergroup comparison, case-control study.

Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase (DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this double-blind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, SmaI restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2 (-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models (GG and CG), while 89.13% of healthy control subjects had dominant genetic models (CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls (P = 0.0002). The frequency of G alleles in the leukoaraiosis patients (71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower (χ2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes (Kruskal-Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2 (-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2 (-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of The 2nd Affiliated Hospital of Harbin Medical University of China (approval No. KY2016-177) on July 28, 2016.

Analysis of risk factors in patients with leukoaraiosis.

To investigate the risk factors for leukoaraiosis (LA) and the correlation between risk factors and LA.The study comprised 92 patients with diagnoses of LA (LA group) and 56 non-LA individuals (control group). Data were collected for the following: age, gender, fasting blood glucose, total cholesterol, triglyceride, high- and low-density lipoprotein cholesterol, uric acid, creatinine, and histories of smoking, hypertension, and diabetes. Levels of serum asymmetric dimethylarginine (ADMA) were detected by enzyme-linked immunosorbent assay.Univariate analysis showed statistical significance between the 2 groups in age, histories of hypertension and smoking, uric acid, creatinine, and levels of serum ADMA (P < 0.05). Binary logistic analysis showed that age (P < 0.0001), hypertension (P = 0.0101), and serum ADMA (P = 0.0206) were related to LA. Pearson correlation analysis showed that levels of serum ADMA correlated with uric acid (r = 0.184, P = 0.025) and creatinine (r = 0.169, P = 0.04).Age, hypertension, and levels of serum ADMA were independent risk factors for LA. Serum ADMA levels may be related to uric acid and creatinine.