Mucoadhesive liposomal delivery system synergizing anti-inflammation and anti-oxidation for enhanced treatment against dry eye disease.

Dry eye disease (DED) is a common and frequent ocular surface disease worldwide, which can cause severe ocular surface discomfort and blurred vision. Inflammation and reactive oxygen species (ROS) play decisive roles in the development of DED. However, existing treatments usually focus on anti-inflammation while ignore the role of ROS in DED. Ever worse, the clinical preparations are easily cleared by nasolacrimal ducts, resulting in poor therapeutic effect. To circumvent these obstacles, here we designed a phenylboronic acid (PBA) modified liposome co-loading immunosuppressant cyclosporin A (CsA) and antioxidant crocin (Cro). The CsA/Cro PBA Lip achieved mucoadhesion through the formation of covalent bonds between PBA and the sialic acid residues on mucin, and consequently improved the retention of drugs on the ocular surface. By inhibiting ROS production and blocking NF-κB inflammatory pathway, CsA/Cro PBA Lip successfully promoted the healing of damaged corneal epithelium, eventually achieving the goal of relieving DED. CsA/Cro PBA Lip is proven a simple yet effective dual-drug delivery system, exhibiting superior antioxidant and anti-inflammatory effects both in vitro and in vivo. This approach holds great potential in the clinical treatment of DED and other related mucosal inflammations.

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The global pandemic of coronavirus disease 2019 (COVID-19) poses a serious threat to human health, leading to a relatively high mortality in patients with severe or critical conditions in particular. Hyperglycemia is one of the high-risk factors for poor prognosis in these patients. Patients with COVID-19 are more likely to develop hyperglycemia, regardless of whether there is a previous history of diabetes mellitus. Glucocorticoid therapy is an important part of the anti-inflammatory regimen for COVID-19. However, the use of glucocorticoid significantly increases the occurrence of hyperglycemic events in COVID-19 patients, ultimately leading to poor prognosis. Timely monitoring of blood glucose and early intervention for hyperglycemia contribute to the improvement in the outcome of COVID-19 patients. In this paper, we comprehensively reviewed the potential mechanisms of COVID-19 and concomitant hyperglycemia. We reviewed the latest findings on the blood glucose management strategies for COVID-19 patients with concomitant hyperglycemia, aiming to optimize the management of hyperglycemia in COVID-19 patients and improve the outcome of the disease.

Diagnosis, Treatment, and Associated Factors Among Patients with HCV Infection - Jiangsu Province, China, 2004-2020.

What is already known on this topic?: The global efforts to address the hepatitis C virus (HCV) are progressing, but there are still significant gaps in the diagnosis and treatment of HCV, leading to an increasing number of deaths related to HCV. What is added by this report?: An extensive investigation was conducted to assess HCV RNA diagnosis, treatment uptake, and associated factors among individuals infected with HCV within Jiangsu Province. The study encompassed a large geographical area and utilized a substantial sample size. What are the implications for public health practice?: Implementing focused interventions to improve the timely diagnosis of HCV RNA and increase the uptake of HCV treatment could effectively reduce the future burden of HCV-related health problems, deaths, and healthcare expenses. This is essential for achieving the global target of eliminating hepatitis C.

An aging-related immune landscape in the hematopoietic immune system.

BACKGROUND: Aging is a holistic change that has a major impact on the immune system, and immunosenescence contributes to the overall progression of aging. The bone marrow is the most important hematopoietic immune organ, while the spleen, as the most important extramedullary hematopoietic immune organ, maintains homeostasis of the human hematopoietic immune system (HIS) in cooperation with the bone marrow. However, the overall changes in the HIS during aging have not been described. Here, we describe a hematopoietic immune map of the spleen and bone marrow of young and old mice using single-cell sequencing and flow cytometry techniques. RESULTS: We observed extensive, complex changes in the HIS during aging. Compared with young mice, the immune cells of aged mice showed a marked tendency toward myeloid differentiation, with the neutrophil population accounting for a significant proportion of this response. In this change, hypoxia-inducible factor 1-alpha (Hif1α) was significantly overexpressed, and this enhanced the immune efficacy and inflammatory response of neutrophils. Our research revealed that during the aging process, hematopoietic stem cells undergo significant changes in function and composition, and their polymorphism and differentiation abilities are downregulated. Moreover, we found that the highly responsive CD62L + HSCs were obviously downregulated in aging, suggesting that they may play an important role in the aging process. CONCLUSIONS: Overall, aging extensively alters the cellular composition and function of the HIS. These findings could potentially give high-dimensional insights and enable more accurate functional and developmental analyses as well as immune monitoring in HIS aging.

Microphthalmia and anterior segment dysgenesis due to a double gene variant in GJA8 and CRYGC.

INTRODUCTION: To report a family with severe ocular disorder caused by double gene variants in causative genes of autosomal dominant cataracts, GJA8 and CRYGC. CASE PRESENTATION: A 5-month-old boy with poor vision and enophthalmos was referred to our hospital. Further ocular examination showed horizontal nystagmus, iris abnormalities with pinpoint pupils, and extreme microphthalmia with axial right and left eye lengths of 13.48 mm and 13.75 mm, respectively. Digenic heterozygous variants (c.269T > G, p.Leu90Arg in CRYGC and c.151G > A, p.Asp51Asn in GJA8) have been detected based on the whole exome sequencing. His mother, who carried variant in CRYGC (c.269T > G, p.Leu90Arg), had nuclear cataract, microcornea and nystagmus, while his father, who carried variant in GJA8 (c.151G > A, p.Asp51Asn), showed bilateral membranous cataract, microphthalmia, sclerocornea, glaucoma, and nystagmus. CONCLUSIONS: To our knowledge, this is the first report of a patient with variants in two cataract-related genes. Importantly, patient with double heterozygous variants in two dominantly inherited genes may suffer more serious phenotypes than those with heterozygous variant in a single dominantly inherited gene. Whole exome or genome sequencing is necessary for a genetic diagnosis in case of multiple gene variants.

Identification of co-expressed gene networks promoting CD8+ T cell infiltration and having prognostic value in uveal melanoma.

Current immunotherapies are unsatisfactory against uveal melanoma (UM); however, elevated CD8+ T cell infiltration level indicates poor prognosis in UM. Here, we aimed to identify co-expressed gene networks promoting CD8+ T cell infiltration in UM and created a prognostic hazard model based on the identified hub genes. Raw data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Stromal-immune comprehensive score (ESTIMATE) was used to evaluate the immune-infiltration landscape of the tumor microenvironment. Single-Sample Gene Set Enrichment Analysis (ssGSEA) and Weighted Correlation Network Analysis (WGCNA) were used to quantify CD8+ T cell infiltration level and identify hub genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to analyze the biological processes. Least absolute shrinkage and selection operator (LASSO) Cox regression were used to establish a prognostic model, which was further validated. Finally, pan-cancer analysis evaluated these genes to be associated with CD8+ T cell infiltration in other tumors. In conclusion, the proposed four-gene (PTPN12, IDH2, P2RX4, and KDELR2) prognostic hazard model had satisfactory prognostic ability. These hub genes may promote CD8+ T cell infiltration in UM through antigen presentation, and CD8+ T cell possibly function as Treg, resulting in poor prognosis. These findings might facilitate the development of novel immunotherapies.

Advances in the applications of mesenchymal stem cell-conditioned medium in ocular diseases.

Mesenchymal stem cell-conditioned medium (MSC-CM), also known as secretome, is secreted by MSC and contains a variety of bioactive factors with anti-inflammatory, anti-apoptotic, neuroprotection, and proliferation effects. Increasing evidence proved that MSC-CM plays an important role in various diseases, including skin, bone, muscle, and dental diseases. However, the role of MSC-CM in ocular diseases is not quite clear, Therefore, this article reviewed the composition, biological functions, preparation, and characterization of MSC-CM and summarized current research advances in different sources of MSC-CM in corneal and retinal diseases, including dry eye, corneal epithelial damage, chemical corneal injury, retinitis pigmentosa (RP), anterior ischemic optic neuropathy (AION), diabetic retinopathy (DR), and other retinal degenerative changes. For these diseases, MSC-CM can promote cell proliferation, reduce inflammation and vascular leakage, inhibit retinal cell degeneration and apoptosis, protect corneal and retinal structures, and further improves visual function. Hence, we summarize the production, composition and biological functions of MSC-CM and focus on describing its mechanisms in the treatment of ocular diseases. Furthermore, we look at the unexplored mechanisms and further research directions for MSC-CM based therapy in ocular diseases.

Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis.

BACKGROUND: Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear. METHODS: To this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing. RESULTS: We found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD. CONCLUSIONS: Our study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases.

γδ T cells in autoimmune uveitis pathogenesis: A promising therapeutic target.

Autoimmune uveitis is a non-infectious, inflammatory intraocular disease that affects the uveal and adjacent tissues. It frequently causes varying degrees of visual loss. Evidence for the strong association between activated γδ T cells and the development of autoimmune uveitis is growing. The innate and adaptive immune response are connected in the early phases by the γδ T cells that contain the γ and δ chains. γδ T cells can identify antigens in a manner that is not constrained by the MHC. When activated by various pathways, γδ T cells can not only secrete pro-inflammatory factors early on (such as IL-17), but they can also promote Th17 cells responses, which ultimately exacerbates autoimmune uveitis. Therefore, we review the mechanisms by which γδ T cells affect autoimmune uveitis in different activation and disease states. Moreover, we also prospect for immunotherapies targeting different γδ T cell-related action pathways, providing a reference for exploring new drug for the treatment of autoimmune uveitis.

Hyaluronic acid-based nanoparticles to deliver drugs to the ocular posterior segment.

Ocular posterior segment diseases such as uveitis, X-linked juvenile retinoschisis, or age-related macular degeneration usually result in progressive and irreversible vision loss. Although intravitreal injection is the main way to deliver drugs to the posterior eye, it still has shortcomings as an invasive operation. Nanocontrolled drug delivery technology is a promising option to avoid frequent injections. Due to the particularity of the human intraocular structure, drugs have unique pharmacokinetic characteristics in the eye. Various nanoparticles have been successfully investigated in experimental studies for vitreous injection, with advantages and drawbacks. Here, we introduce an ideal nanopolymer modifier to build nanodelivery systems in vitreous cavities. Hyaluronic acid (HA) is a natural polysaccharide with a broad molecular weight range, negatively charged surface, ligand-receptor binding capabilities, and hyaluronidase breakdown capability. Advances in CD44 receptor targeting for HA-based nanoparticles can improve mobility and penetration in the vitreous and retina, stabilize the nanoparticles, and regulate drug release. This review summarizes the intravitreal administration of nanoplatforms based on HA and the benefits of HA in drug delivery systems.

Malondialdehyde levels in diabetic retinopathy patients: a systematic review and meta-analysis.

BACKGROUND: It remains unclear whether circulating malondialdehyde (MDA) levels change in people with diabetic retinopathy (DR). This systematic review compared circulating MDA levels in diabetic people with and without DR. METHODS: PubMed, Medline (Ovid), Embase (Ovid), and Web of Science were searched for case-control studies conducted before May 2022 in English that compared circulating MDA levels in people with and without DR. The following MeSH search terms were used: ("malondialdehyde" or "thiobarbituric acid reactive substances [TBARS]" or "lipid peroxidation" or "oxidative stress") and "diabetic retinopathy." Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of the included studies. Random-effects pairwise meta-analysis pooled the effect size with standardized mean difference (SMD) and 95% confidence intervals (CIs). RESULTS: This meta-analysis included 29 case-control studies with 1680 people with DR and 1799 people with diabetes but not DR. Compared to people without DR, the circulating MDA levels were higher in those with DR (SMD, 0.897; 95% CI, 0.631 to 1.162; P  < 0.001). The study did not identify credible subgroup effects or publication bias and the sensitivity analysis confirmed the robustness of the study. CONCLUSIONS: Circulating MDA levels are higher in people with DR compared to those without. Future comparative studies that use more specific methods are required to draw firm conclusions. REGISTRATION: PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022352640.

Spatiotemporal Changes in Pulmonary Tuberculosis Incidence in a Low-Epidemic Area of China in 2005-2020: Retrospective Spatiotemporal Analysis.

BACKGROUND: In China, tuberculosis (TB) is still a major public health problem, and the incidence of TB has significant spatial heterogeneity. OBJECTIVE: This study aimed to investigate the temporal trends and spatial patterns of pulmonary tuberculosis (PTB) in a low-epidemic area of eastern China, Wuxi city, from 2005 to 2020. METHODS: The data of PTB cases from 2005 to 2020 were obtained from the Tuberculosis Information Management System. The joinpoint regression model was used to identify the changes in the secular temporal trend. Kernel density analysis and hot spot analysis were used to explore the spatial distribution characteristics and clusters of the PTB incidence rate. RESULTS: A total of 37,592 cases were registered during 2005-2020, with an average annual incidence rate of 34.6 per 100,000 population. The population older than 60 years had the highest incidence rate of 59.0 per 100,000 population. In the study period, the incidence rate decreased from 50.4 to 23.9 per 100,000 population, with an average annual percent change of -4.9% (95% CI -6.8% to -2.9%). The incidence rate of pathogen-positive patients increased during 2017-2020, with an annual percent change of 13.4% (95% CI 4.3%-23.2%). The TB cases were mainly concentrated in the city center, and the incidence of hot spots areas gradually changed from rural areas to urban areas during the study period. CONCLUSIONS: The PTB incidence rate in Wuxi city has been declining rapidly with the effective implementation of strategies and projects. The populated urban centers will become key areas of TB prevention and control, especially in the older population.

Prevalence of syphilis and chlamydia trachomatis infection among men who have sex with men in Jiangsu province, China: A cross-sectional survey.

Background: Epidemics of sexually transmitted infections (STIs) among men who have sex with men (MSM) are major global public health concerns. This study aimed to examine the prevalence of syphilis and chlamydia trachomatis (CT) infection and associated factors among MSM in Jiangsu province, China, hoping to provide updated data for the formulation of relevant policies. Methods: A cross-sectional survey was conducted among MSM from April to July 2021 in four cities in the province. Socio-demographic characteristics and behavioral information were collected through a face-to-face questionnaire interview. Venous blood specimens were collected for HIV, hepatitis C (HCV), and syphilis testing using serological testing methods. First-void urine specimens were collected for CT and Neisseria gonorrhoeae (NG) testing using nucleic acid amplification testing (NAAT) methods. Chi-square tests were used to compare differences in syphilis and CT infection between subgroups of variables. Multivariate logistic regression analysis was used to identify factors associated with syphilis and CT infection. Results: A total of 1,087 participants were enrolled. The prevalence of HIV, HCV, syphilis, CT and NG infection were 6.6, 0.4, 6.3, 4.2, and 0.4%, respectively. MSM recruited online [adjusted odds ratio (aOR) = 2.189, P = 0.020], diagnosed with an STI in the past 12 months (aOR = 3.304, P < 0.001), and living with HIV (aOR = 4.721, P < 0.001) were more likely to have syphilis infection. MSM who were younger than 25 years (aOR = 4.286, P = 0.020), had senior high school level education (aOR = 2.521, P = 0.038), and were recruited via VCT clinics (aOR = 3.455, P = 0.001) were more likely to have CT infection. Conclusions: Our study showed a high prevalence of syphilis and chlamydia among MSM in Jiangsu province, China. STI screening, diagnosis, and treatment services promotion should be a top priority on the prevention agenda.

A neutrophil-mediated carrier regulates tumor stemness by inhibiting autophagy to prevent postoperative triple-negative breast cancer recurrence and metastasis.

Recurrence and metastasis after resection are still the main challenges in clinical treatment of breast cancer. Residual tumor and cancer stem-like cells are the primary culprits of recurrence and metastasis. Recent research studies indicate that autophagy is a cytoprotective mechanism of tumors, which maintains the stemness of cancer cells and promotes tumor proliferation and metastasis. Here, we constructed a "Trojan horse" using neutrophils as the carrier (PH-RL@NEs) to prevent the recurrence and metastasis of postoperative breast cancer. Neutrophils, as a "Trojan horse," can quickly respond to postoperative inflammation and accurately deliver drugs to the residual tumor site. The inflammation-triggered "Trojan horse" was then opened to release the liposomes containing the chemotherapeutic drug paclitaxel (PTX) and the autophagy inhibitor hydroxychloroquine (HCQ). We found that HCQ could effectively inhibit tumor cell autophagy, interfere with tumor epithelial-mesenchymal transition, and reduce the tumor stem cell-like population. In the orthotopic 4T1 postoperative recurrence models, PTX and HCQ synergistically killed tumors and regulated the stemness of tumor cells, thereby significantly inhibiting tumor recurrence and metastasis. Our work proved that the inhibition of autophagy to reduce tumor stemness is feasible and effective, which opens up a new prospect for postoperative tumor treatment. STATEMENT OF SIGNIFICANCE: The present study aimed to solve the issues of postoperative recurrence and metastasis of breast cancer and low efficiency of drug administration after surgery. For this purpose, we constructed neutrophils containing hydroxychloroquine (HCQ) and paclitaxel (PTX) co-loaded liposomes (PH-RL@NEs), which for the first time regulated the stemness of tumor cells by inhibiting autophagy, thereby inhibiting postoperative recurrence and metastasis of breast cancer cells. The results showed that PH-RL@NEs enhanced the targeted drug delivery efficiency, with the help of postoperative inflammation chemotaxis of neutrophils. HCQ effectively inhibited autophagy of tumor cells and reduced tumor stem cell-like cells, thus improving the therapeutic effect in the 4T1 in situ postoperative recurrence model.

Anticancer nanomedicines harnessing tumor microenvironmental components.

INTRODUCTION: Small-molecular drugs are extensively used in cancer therapy, while they have issues of nonspecific distribution and consequent side effects. Nanomedicines that incorporate chemotherapeutic drugs have been developed to enhance the therapeutic efficacy of these drugs and reduce their side effects. One of the promising strategies is to prepare nanomedicines by harnessing the unique tumor microenvironment (TME). AREAS COVERED: The TME contains numerous cell types that specifically express specific antibodies on the surface. The physicochemical environment is characterized with a low pH, hypoxia, and a high redox potential resulting from tumor-specific metabolism. Therefore, intelligent nanomedicines designed based on the characteristics of the tumor microenvironment can be divided into two groups: the first group which is rapidly responsive to extracellular chemical/biological factors in the TME and the second one which actively and/or specifically targets cellular components in the TME. EXPERT OPINION: In this paper, we review recent progress of nanomedicines by harnessing the TME and illustrate the principles and advantages of different strategies for designing nanomedicines, which are of great significance for exploring novel nanomedicines or translating current nanomedicines into clinical practice. We will discuss the challenges and prospects of preparing nanomedicines to utilize or alter the TME for achieving effective, safe anticancer treatment.

Eye pain and blurred vision as main complaints in a new case with MDPL syndrome.

INTRODUCTION: We report a novel phenotype of mandibular hypoplasia, deafness, and progeroid features with lipodystrophy (MDPL) syndrome with POLD1 mutation in a Chinese girl. CASE DESCRIPTION: Diabetic retinopathy was detected as the primary manifestation in a Chinese girl with MDPL syndrome carrying a known POLD1 mutation (c.1812_1814delCTC, p.Ser605del). Typical characteristics of the syndrome including mandibular hypoplasia, deafness, progeroid features, and diabetes were detected after comprehensive examinations. The patient suffered from blurred vision and eye pain due to the neovascularization of the retina (vitreous hemorrhage and retinal detachment) and iris (neovascular glaucoma). The literature review revealed that the prevalence of hepatomegaly and abnormal triglyceride levels were significantly higher in female than in male with MDPL syndrome carrying POLD1 mutations. CONCLUSION: These results expand our knowledge regarding the clinical phenotypes of MDPL syndrome with POLD1 mutations. Diabetic retinopathy is a non-negligible complication of MDPL syndrome. The phenotype varies among female and male patients with the syndrome. Hepatomegaly and abnormal triglyceride levels are more common in female patients with MDPL syndrome.

Effect of Preeclampsia on Ultrastructure of Thyroid Gland, Hepatic Type 1 Iodothyronine Deiodinase, and Thyroid Hormone Levels in Rats.

BACKGROUND: Although hypothyroidism during pregnancy may develop grave outcomes for both mothers and offspring, management of which is still a challenge due to the insufficient understanding of this disease. The close correlation between hypothyroidism and preeclampsia is well documented, suggesting that preeclampsia is a potential risk factor for the development of maternal hypothyroidism. However, the exact role of preeclampsia in gestational hypothyroidism is still obscure. OBJECTIVE: In this study, we explored the possible mechanisms of the effect of preeclampsia on thyroid function of maternal rats. METHODS: Thirty pregnant rats were randomly divided into normal pregnancy control (NOP), preeclampsia (PE), and preeclampsia supplemented with amlodipine besylate (PEAml). NG-Nitro-L-arginine-methyl ester was used to induce preeclamptic symptoms. On gestational day 21, rats were sacrificed, and then, the ultrastructure of the thyroid gland, type 1 iodothyronine deiodinase (Dio1) expression, and serum-free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulation hormones (TSH) were assessed. RESULTS: Compared to NOP rats, results of PE rats showed that thyroid follicular cells' ultrastructure was damaged; both hepatic Dio1 mRNA and protein levels were decreased. Interestingly, these changes were ameliorated in PEAml rats. Additionally, FT4, FT3, and TSH levels have no significant differences among groups. CONCLUSION: These findings indicated that preeclampsia could disrupt synthesis, secretion, and metabolism function of thyroid hormones by damaging thyroid follicular cells and interfering Dio1 expression.

Endogenous Endophthalmitis Caused by Klebsiella pneumoniae: A Ten-Year Retrospective Study in Western China.

OBJECTIVES: The aim of this study was to analyse the clinical features, microbiology results, management and outcomes of patients with endogenous endophthalmitis caused by Klebsiella pneumoniae in western China. METHODS: A retrospective review of medical records of 10 eyes in 10 subjects diagnosed with endogenous K. pneumoniae endophthalmitis from January 2008 to December 2018 was undertaken. RESULTS: The top 3 predisposing medical conditions included diabetes mellitus (50%), malignancy (20%) and cardiac stent implantation (10%). Extraocular infective foci were mainly found in the liver (40%), lungs (20%) and kidneys (10%). The positive culture rate was 85.71% (6/7) in vitreous samples, 83.33% (5/6) in blood samples and 100% (4/4) in body fluid samples. Only 20% of the patients, who had good initial visual acuity (VA) better than hand movement (HM), achieved a final VA better than 1.0 (log MAR). The mortality rate was 10%. CONCLUSIONS: Though the prognosis of endogenous K. pneumoniae endophthalmitis is often poor, patients with an initial VA better than HM may have a good prognosis under comprehensive treatments, including vitrectomy, systemic sensitive antibiotic injection and drainage of the primary infection loci.