Tumor-targeted delivery of copper-manganese biomineralized oncolytic adenovirus for colorectal cancer immunotherapy.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Engineered Luminescent Oncolytic Vaccinia Virus Activation of Photodynamic-Immune Combination Therapy for Colorectal Cancer.

Oncolytic virus therapy is currently regarded as a promising approach in cancer immunotherapy. It has greater therapeutic advantages for colorectal cancer that is prone to distant metastasis. However, the therapeutic efficacy and clinical application of viral agents alone for colorectal cancer remain suboptimal. In this study, an engineered oncolytic vaccinia virus (OVV-Luc) that expresses the firefly luciferase gene is developed and loaded Chlorin e6 (Ce6) onto the virus surface through covalent coupling, resulting in OVV-Luc@Ce6 (OV@C). The OV@C infiltrates tumor tissue and induces endogenous luminescence through substrate catalysis, resulting in the production of reactive oxygen species. This unique system eliminates the need for an external light source, making it suitable for photodynamic therapy (PDT) in deep tissues. Moreover, this synergistic effect between PDT and viral immunotherapy enhances dendritic cell maturation, macrophage polarization, and reversal of the immunosuppressive microenvironment. This synergistic effect has the potential to convert a "cold" into a "hot" tumor, it offers valuable insights for clinical translation and application.

RETINAL VASCULAR OCCLUSION AND COVID-19 DIAGNOSIS: A Multicenter Population-Based Study.

BACKGROUND: Several ocular diseases have been reported in patients with coronavirus disease 2019 (COVID-19), especially retinal vascular occlusion. This study aimed to examine the risk of retinal vascular occlusion after COVID-19 diagnosis. METHODS: This retrospective cohort study was based on 46 health care organizations in the United States using the TriNetX network. Individuals who had laboratory confirmation of COVID-19 from January 1, 2020, to December 31, 2021, were included. Multivariate analysis was adjusted on age, sex, race, and comorbidities, and hazard ratio was calculated using the Cox proportional hazard regression model. RESULTS: A total of 1,460,634 paired individuals were enrolled for analysis. Patients with COVID-19 had a significantly higher risk of branch retinal vein occlusion (hazard ratio 1.27, 95% confidence interval [CI] 1.04-1.52) than those without COVID-19. The cumulative incidence rate of branch retinal vein occlusion was also significantly higher in patients with COVID-19 compared with those without COVID-19 (log-rank P = 0.014). Within 12 weeks after COVID-19 diagnosis, the transient effect of central retinal vein occlusion (hazard ratio 1.59, 95% confidence interval 1.15-2.17) and branch retinal vein occlusion (hazard ratio 2.11, 95% confidence interval 1.51-2.95) were observed. CONCLUSION: This large-scale multicenter study demonstrated that retinal vein occlusion may be associated with COVID-19.

Host plant-mediated effects on Buchnera symbiont: implications for biological characteristics and nutritional metabolism of pea aphids (Acyrthosiphon pisum).

Introduction: The pea aphid, Acyrthosiphon pisum, is a typical sap-feeding insect and an important worldwide pest. There is a primary symbiont-Buchnera aphidicola, which can synthesize and provide some essential nutrients for its host. At the same time, the hosts also can actively adjust the density of bacterial symbiosis to cope with the changes in environmental and physiological factors. However, it is still unclear how symbionts mediate the interaction between herbivorous insects' nutrient metabolism and host plants. Methods: The current study has studied the effects of different host plants on the biological characteristics, Buchnera titer, and nutritional metabolism of pea aphids. This study investigated the influence of different host plants on biological characteristics, Buchnera titer, and nutritional metabolism of pea aphids. Results and discussion: The titer of Buchnera was significantly higher on T. Pretense and M. officinalis, and the relative expression levels were 1.966±0.104 and 1.621±0.167, respectively. The content of soluble sugar (53.46±1.97µg/mg), glycogen (1.12±0.07µg/mg) and total energy (1341.51±39.37µg/mg) of the pea aphid on V. faba were significantly higher and showed high fecundity (143.86±11.31) and weight (10.46±0.77µg/mg). The content of total lipids was higher on P. sativum and T. pretense, which were 2.82±0.03µg/mg and 2.92±0.07µg/mg, respectively. Correlation analysis found that the difference in Buchnera titer was positively correlated with the protein content in M. officinalis and the content of total energy in T. pratense (P < 0.05). This study confirmed that host plants not only affected the biological characteristics and nutritional metabolism of pea aphids but also regulated the symbiotic density, thus interfering with the nutritional function of Buchnera. The results can provide a theoretical basis for further studies on the influence of different host plants on the development of pea aphids and other insects.

Strong association of lumbar disk herniation with diabetes mellitus: a 12-year nationwide retrospective cohort study.

Background: Despite reports on the association between diabetes mellitus (DM) and lumbar disk herniation (LDH), large-scale, nationwide studies exploring this relationship are lacking. We aimed to examine the profiles of DM in individuals with LDH and explore the potential mechanisms underlying the development of these disorders. Methods: This retrospective, population-based study was conducted between 2008 and 2019 using data from the National Health Insurance (NHI) research database in Taiwan. The primary outcome was the date of initial LDH diagnosis, death, withdrawal from the NHI program, or end of the study period. Results: In total, 2,662,930 individuals with and 16,922,546 individuals without DM were included in this study; 719,068 matched pairs were established following propensity score matching (1:1 ratio) for sex, age, comorbidities, smoking, alcohol consumption, antihyperglycemic medications, and index year. The adjusted risk for developing LDH was 2.33-fold (95% confidence interval: 2.29-2.37; P<0.001), age-stratified analysis revealed a significantly greater risk of LDH in every age group, and both males and females were approximately twice as likely to develop LDH in the DM compared with non-DM cohort. Individuals with DM and comorbidities had a significantly higher risk of developing LDH than those without, and the serial models yielded consistent results. Treatment with metformin, sulfonylureas, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or alpha-glucosidase inhibitors was associated with a more than 4-fold increased risk of LDH in the DM cohort. DM was strongly associated with the long-term development of LDH; over the 12-year follow-up period, the cumulative risk of LDH was significantly higher in patients with than without DM (log-rank P<0.001). Conclusion: DM is associated with an increased risk of LDH, and advanced DM may indicate a higher risk of LDH.

Sodium-glucose co-transporter 2 inhibitor add-on therapy for metformin delays diabetic retinopathy progression in diabetes patients: a population-based cohort study.

To investigate how sodium-glucose co-transporter 2 inhibitors (SGLT2is) add-on therapy for metformin affects diabetic retinopathy (DR) progression in patients with type 2 diabetes mellitus (T2DM). This nationwide population-based study conducted from January 1, 2016, to December 31, 2018 involved 3,432,911 adults with T2DM in Taiwan. To adjust for potential confounders, data on sex, age, income, comorbidities, diabetes complication severity index score, staging of kidney disease, anti-diabetic medications, and index year were included. The outcome was DR progression, determined by procedure codes or the addition of ICD-9-CM or ICD-10-CM codes to the medical records of the patients during the study. Sensitivity analyses were performed to validate the findings. The adjusted hazard ratio (aHR) of DR progression was 0.89 for the SGLT2is add-on group, relative to the control group [95% confidence interval (CI) 0.81-0.99, P = 0.026]. The Kaplan-Meier curve of the cumulative incidence rate showed that the cumulative incidence of DR progression was considerably decreased in the SGLT2is cohort (log-rank P = 0.0261). The use of SGLT2is for less than 1 year and 1-2 years were associated with a significant increase in the risk of DR progression (aHR 1.56 and 1.88, respectively); however, the risk markedly reduced if the SGLT2is regimen was used for more than 2 years (aHR 0.41, 95% Cl 0.35-0.48; P < 0.001). The serial sensitivity analysis showed consistent findings. The aHR of DR progression was 0.82 for the SGLT2is cohort relative to the non-SGLT2is cohort based on the fundoscopy or indirect ophthalmoscopy findings within 1 year before the outcome date (95% Cl 0.71-0.95; P = 0.009). Co-administration of metformin and SGLT2is may reduce the risk of DR progression. Short-term use of SGLT2is may markedly increase the risk of DR, whereas prolonged use SGLT2is may significantly decrease it.

The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study.

Reports on uveitis after COVID-19 have been limited. Our objective was to examine the risk of uveitis among COVID-19 patients. This was a retrospective cohort study based on the TriNetX platform. The exposure group was patients with positive laboratory test result for SARS-CoV-2 and the comparison group was those tested negative for COVID-19 throughout the study period. The endpoint is the new diagnoses of uveitis. This study composed of 2 105 424 patients diagnosed with COVID-19 (55.4% female; 62.5% white; mean age at index 40.7 years) and 2 105 424 patients (55.4% female; 62.4% white; mean age at index 40.7 years) who never had COVID-19. There was significantly increased risk of new diagnosis of uveitis since the first month after diagnosis of COVID-19 compared with matched controls (HR: 1.18, 95% CI: 1.03-1.34) up to 24 months (HR: 1.16, 95% CI: 1.09-1.22). Our findings strengthen those previously raised by case series with a larger and multicenter study. We found that uveitis was significantly associated with COVID-19 infection. Our findings reiterate the need for careful investigation as well as increased awareness from ophthalmologists in considering the possibility of COVID-19 in vulnerable patients with new presentation of uveitis.

A chronological review of COVID-19 case fatality rate and its secular trend and investigation of all-cause mortality and hospitalization during the Delta and Omicron waves in the United States: a retrospective cohort study.

Introduction: Coronavirus disease 2019 (COVID-19) has caused more than 690 million deaths worldwide. Different results concerning the death rates of the Delta and Omicron variants have been recorded. We aimed to assess the secular trend of case fatality rate (CFR), identify risk factors associated with mortality following COVID-19 diagnosis, and investigate the risks of mortality and hospitalization during Delta and Omicron waves in the United States. Methods: This study assessed 2,857,925 individuals diagnosed with COVID-19 in the United States from January 2020, to June 2022. The inclusion criterion was the presence of COVID-19 diagnostic codes in electronic medical record or a positive laboratory test of the SARS-CoV-2. Statistical analysis was bifurcated into two components, longitudinal analysis and comparative analysis. To assess the discrepancies in hospitalization and mortality rates for COVID-19, we identified the prevailing periods for the Delta and Omicron variants. Results: Longitudinal analysis demonstrated four sharp surges in the number of deaths and CFR. The CFR was persistently higher in males and older age. The CFR of Black and White remained higher than Asians since January 2022. In comparative analysis, the adjusted hazard ratios for all-cause mortality and hospitalization were higher in Delta wave compared to the Omicron wave. Risk of all-cause mortality was found to be greater 14-30 days after a COVID-19 diagnosis, while the likelihood of hospitalization was higher in the first 14 days following a COVID-19 diagnosis in Delta wave compared with Omicron wave. Kaplan-Meier analysis revealed the cumulative probability of mortality was approximately 2-fold on day 30 in Delta than in Omicron cases (log-rank p < 0.001). The mortality risk ratio between the Delta and Omicron variants was 1.671 (95% Cl 1.615-1.729, log-rank p < 0.001). Delta also had a significantly increased mortality risk over Omicron in all age groups. The CFR of people aged above 80 years was extremely high as 17.33%. Conclusion: Male sex and age seemed to be strong and independent risk factors of mortality in COVID-19. The Delta variant appears to cause more hospitalization and death than the Omicron variant.

Non-Negative Low-Rank Representation With Similarity Correction for Cell Type Identification in scRNA-Seq Data.

Single-cell RNA sequencing (scRNA-Seq) technology has emerged as a powerful tool to investigate cellular heterogeneity within tissues, organs, and organisms. One fundamental question pertaining to single-cell gene expression data analysis revolves around the identification of cell types, which constitutes a critical step within the data processing workflow. However, existing methods for cell type identification through learning low-dimensional latent embeddings often overlook the intercellular structural relationships. In this paper, we present a novel non-negative low-rank similarity correction model (NLRSIM) that leverages subspace clustering to preserve the global structure among cells. This model introduces a novel manifold learning process to address the issue of imbalanced neighbourhood spatial density in cells, thereby effectively preserving local geometric structures. This procedure utilizes a position-sensitive hashing algorithm to construct the graph structure of the data. The experimental results demonstrate that the NLRSIM surpasses other advanced models in terms of clustering effects and visualization experiments. The validated effectiveness of gene expression information after calibration by the NLRSIM model has been duly ascertained in the realm of relevant biological studies. The NLRSIM model offers unprecedented insights into gene expression, states, and structures at the individual cellular level, thereby contributing novel perspectives to the field.

Prognostic utility of 99mTc-MIBI single photon emission computerized tomography myocardial perfusion imaging in patients with ischemia and non-obstructive coronary artery disease.

Objective: The aim of our study was to evaluate the prognostic value of gated SPECT MPI in non-obstructed coronary arteries (INOCA) patients, sought to stratify patients more accurately and thus derive more reliable prognostic information. Materials and methods: In total, 167 patients with INOCA were enrolled. The patients were divided into two groups according to their SSS. Patients were followed-up regularly in terms of major adverse cardiovascular event (MACE), including cardiac death, nonfatal myocardial infarction, stroke, re-hospitalization with angina pectoris, and recurrent angina pectoris. Kaplan-Meier curves and Cox's proportional hazards models were used to analyze survival and identify predictive factors. Results: Adverse cardiac events occurred in 33 cases (19.8%). The rate of MACE was higher in the summed stress score (SSS) ≥4 group than in the SSS 0-3 group (30.1% vs. 9.5%, respectively, P = 0.001) and MACE-free survival was lower (annual MACE-free rates of 87.5% vs. 96.2%, respectively, P = 0.003). Event-free survival was consistently higher in patients with normal arteries than in those with non-obstructive coronary artery disease (annual MACE-free rates of 96.1% and 88.4%, P = 0.035). When the SSS and the CAG results were combined, patients with normal coronary arteries (SSS 0-3) had the best prognosis and those with non-obstructive coronary artery stenosis (SSS ≥ 4) had the worst. However, the early prognosis of patients with non-obstructive coronary artery disease and SSS of 0-3 was comparable to that of patients with normal coronary arteries and SSS ≥ 4 (annual MACE-free rates of 100%, 94.6%, 93.1%, and 78.2%, respectively). Multivariate Cox's regression indicated that the SSS [hazard ratio (HR) = 1.126, 95% confidence interval (CI) 1.042-1.217, P = 0.003] and non-obstructive coronary artery disease (HR = 2.559, 95% CI 1.249-5.246, P = 0.01) were predictors of adverse cardiac events. Conclusion: SPECT MPI data were prognostic for INOCA patients, thus identifying groups at high risk. The long-term predictive efficacy of such data exceeded that of CAG data. A combination of the two measures more accurately stratified INOCA patients in terms of risk.

Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug.

Head and neck cancer is a major cancer type, with high motility rates that reduce the quality of life of patients. Herein, we investigated the effectiveness and mechanism of a combination therapy involving TLR9 activator (CpG-2722) and phosphatidylserine (PS)-targeting prodrug of SN38 (BPRDP056) in a syngeneic orthotopic head and neck cancer animal model. The results showed a cooperative antitumor effect of CpG-2722 and BPRDP056 owing to their distinct and complementary antitumor functions. CpG-2722 induced antitumor immune responses, including dendritic cell maturation, cytokine production, and immune cell accumulation in tumors, whereas BPRDP056 directly exerted cytotoxicity toward cancer cells. We also discovered a novel function and mechanism of TLR9 activation, which increased PS exposure on cancer cells, thereby attracting more BPRDP056 to the tumor site for cancer cell killing. Killed cells expose more PS in tumor for BPRDP056 targeting. Tumor antigens released from the dead cells were taken up by antigen-presenting cells, which enhanced the CpG-272-promoted T cell-mediated tumor-killing effect. These form a positive feed-forward antitumor effect between the actions of CpG-2722 and BPRDP056. Thus, the study findings suggest a novel strategy of utilizing the PS-inducing function of TLR9 agonists to develop combinational cancer treatments using PS-targeting drugs.

TLR9 and STING agonists cooperatively boost the immune response to SARS-CoV-2 RBD vaccine through an increased germinal center B cell response and reshaped T helper responses.

Vaccines are a powerful medical intervention for preventing epidemic diseases. Efficient inactivated or protein vaccines typically rely on an effective adjuvant to elicit an immune response and boost vaccine activity. In this study, we investigated the adjuvant activities of combinations of Toll-like receptor 9 (TLR9) and stimulator of interferon genes (STING) agonists in a SARS-CoV-2 receptor binding domain protein vaccine. Adjuvants formulated with a TLR9 agonist, CpG-2722, with various cyclic dinucleotides (CDNs) that are STING agonists increased germinal center B cell response and elicited humoral immune responses in immunized mice. An adjuvant containing CpG-2722 and 2'3'-c-di-AM(PS)2 effectively boosted the immune response to both intramuscularly and intranasally administrated vaccines. Vaccines adjuvanted with CpG-2722 or 2'3'-c-di-AM(PS)2 alone were capable of inducing an immune response, but a cooperative adjuvant effect was observed when both were combined. CpG-2722 induced antigen-dependent T helper (Th)1 and Th17 responses, while 2'3'-c-di-AM(PS)2 induced a Th2 response. The combination of CpG-2722 and 2'3'-c-di-AM(PS)2 generated a distinct antigen-dependent Th response profile characterized by higher Th1 and Th17, but lower Th2 responses. In dendritic cells, CpG-2722 and 2'3'-c-di-AM(PS)2 showed a cooperative effect on inducing expression of molecules critical for T cell activation. CpG-2722 and 2'3'-c-di-AM(PS)2 have distinct cytokine inducing profiles in different cell populations. The combination of these two agonists enhanced the expression of cytokines for Th1 and Th17 responses and suppressed the expression of cytokines for Th2 response in these cells. Thus, the antigen-dependent Th responses observed in the animals immunized with different vaccines were shaped by the antigen-independent cytokine-inducing profiles of their adjuvant. The expanded targeting cell populations, the increased germinal center B cell response, and reshaped T helper responses are the molecular bases for the cooperative adjuvant effect of the combination of TLR9 and STING agonists.

Risk assessment of retinal vascular occlusion after COVID-19 vaccination.

Coronavirus disease 2019 (COVID-19) vaccines are associated with several ocular manifestations. Emerging evidence has been reported; however, the causality between the two is debatable. We aimed to investigate the risk of retinal vascular occlusion after COVID-19 vaccination. This retrospective cohort study used the TriNetX global network and included individuals vaccinated with COVID-19 vaccines between January 2020 and December 2022. We excluded individuals with a history of retinal vascular occlusion or those who used any systemic medication that could potentially affect blood coagulation prior to vaccination. To compare the risk of retinal vascular occlusion, we employed multivariable-adjusted Cox proportional hazards models after performing a 1:1 propensity score matching between the vaccinated and unvaccinated cohorts. Individuals with COVID-19 vaccination had a higher risk of all forms of retinal vascular occlusion in 2 years after vaccination, with an overall hazard ratio of 2.19 (95% confidence interval 2.00-2.39). The cumulative incidence of retinal vascular occlusion was significantly higher in the vaccinated cohort compared to the unvaccinated cohort, 2 years and 12 weeks after vaccination. The risk of retinal vascular occlusion significantly increased during the first 2 weeks after vaccination and persisted for 12 weeks. Additionally, individuals with first and second dose of BNT162b2 and mRNA-1273 had significantly increased risk of retinal vascular occlusion 2 years following vaccination, while no disparity was detected between brand and dose of vaccines. This large multicenter study strengthens the findings of previous cases. Retinal vascular occlusion may not be a coincidental finding after COVID-19 vaccination.

The risk of ischemic stroke significantly increases in individuals with blepharitis: A population-based study involving 424,161 patients.

INTRODUCTION: To investigate the association of blepharitis and ischemic stroke. METHODS: This nationwide retrospective cohort study used population-based data in Taiwan. Individuals aged 20 and above with diagnosis of blepharitis was included based on electrical medical records. After exclusion of ineligible cases, 424,161 patients were identified between 2008 and 2018. The blepharitis and non-blepharitis cohorts were matched based on sex, age, and comorbidities. Multivariable-adjusted Cox proportional hazards model was adopted to calculate the hazard ratio and 95% confidence interval (CI) between blepharitis and non-blepharitis cohorts. The incidence of ischemic stroke was estimated by Kaplan-Meier analysis. RESULTS: 424,161 pairs of blepharitis cohort and non-blepharitis cohort were 1:1 propensity score matched for statistical analysis. Patients with blepharitis had significantly increased risk of ischemic stroke compared with the individuals without blepharitis (adjusted hazard ratio 1.32, 95% CI 1.29-1.34, P < 0.001). A significantly higher risk of ischemic stroke was observed in blepharitis cohort with a previous diagnosis of cancer than in those without cancer (P for interaction < 0.0001). Kaplan-Meier survival analysis revealed the cumulative incidence of ischemic stroke increased in the blepharitis cohort compared with that in the non-blepharitis cohort in 10 years (log-rank P < 0.001). The follow-up period analysis further indicated 1.41-fold adjusted hazard (95% CI 1.35-1.46, P < 0.001) of ischemic stroke within a year after blepharitis diagnosis. CONCLUSIONS: Patients with blepharitis had an elevated risk of developing ischemic stroke. Early treatment and active surveillance are suggested for patients with chronic blepharitis. Further research is required to determine the casual relationship between blepharitis and ischemic stroke, as well as the underlying mechanism.

Role of L-Arginine on the Expression of Coagulation Factor VIII Gene.

Objective: To explore the key sites in which L-arginine affects the expression of human coagulation factor VIII gene, and to create new drug targets for the treatment of hemophilia. Methods: A total of 5 human FVIII genes (A1, A2, A3, C1 and C2) with B domain deletion were transfected into human umbilical vein endothelial cells (HUVECs) as promoters. Run-on assay and ELISA analysis were performed to observe the driving effect of each domain gene on chloramphenicol acetyl transferase (CAT) gene transcription and expression, and the effect of L-arginine on each promoter. Results: In co-culture with L-arginine, transcriptional expression of the CAT gene was not detected in the PCAT3-Basic group (negative control without promoters), PA3-CAT3-Enhancer group or PC1-CAT3-Enhancer group. The transcriptional expression of CAT gene in the PCAT3-Control group (positive control with promoters) and PA1-CAT3-Enhancer group was unchanged compared with the non-L-arginine intervention, while the transcriptional expression of CAT gene in the PA2-CAT3-Enhancer group was significantly enhanced. Conclusions: A1 and A2 domain genes had promoter function and could initiate the transcription and expression of CAT gene, but A3, C1 and C2 domain genes could not. Moreover, L-arginine can significantly enhance transcription and expression of human coagulation factor VIII via A2 domain.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration.

BACKGROUND: The excessive activation of the microglia leads to the release of inflammatory factors that contribute to neuronal cell loss and neurodegeneration in Parkinson's Disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) that belongs to a newly found neurotrophic factors (NTFs) family has been reported to promote neuronal survival in the PD models. However, the effects of the MANF on neuroinflammation in PD remain unclear. METHODS: AAV8-MANF virus was constructed to determine whether the high expression of MANF can protect the neuroinflammation-induced dopaminergic neurodegeneration in rats with 6-OHDA-induced PD. Rotarod performance test, immunofluorescent staining and western bolt were employed to evaluate the behavioral dysfunction, dopaminergic neurodegeneration, microglia activation, and signal activation. 6-OHDA treated SH-SY5Y cells and LPS treated BV-2 cells were used as the in vitro model for MANF neuroprotective and neuroinflammation mechanisms. Cell vitality and apoptosis were evaluated with MTT, CCK-8 and flow cytometric analysis. The AKT/GSK3ß-Nrf2 signaling and the TNF-α/IL6 expression were measured by Western Blot. RESULTS: Our findings indicated that the elevated MANF expression by the AAV8-MANF administration ameliorated the motor dysfunction and protected the dopaminergic neurons in the 6-OHDA treated rats. The upregulated CD11b in the rat SN caused by the 6-OHDA administration was significantly attenuated by the pretreatment of the AAV8-MANF. Furthermore, the levels of p-AKT, p-GSK3ß, BCL-2, and Nrf-2 were upregulated by the high expression of the MANF. Under the oxidative stress of the 6-OHDA, the MANF significantly reduced the apoptotic effect of the TNF-α on the SH-SY5Y cells. In the LPS treated BV-2 cells, the MANF reduced the production of the TNF-α and IL-6, via enhancing the Nrf-2, p-Akt, p-GSK3ß, and p-NF-κß level. CONCLUSIONS: These results suggested that the MANF prevented the dopaminergic neurodegeneration caused by the microglia activation in PD via activation of the AKT/GSK3ß-Nrf-2 signaling axis.

Clinical Pharmacology of RNA Interference-Based Therapeutics: A Summary Based on Food and Drug Administration-Approved Small Interfering RNAs.

RNA-based oligonucleotide therapeutics are revolutionizing drug development for disease treatment. This class of therapeutics differs from small molecules and protein therapeutics in various ways, including both its mechanism of action and clinical pharmacology characteristics. These unique characteristics, along with evolving oligonucleotide-associated conjugates allowing specific tissue targeting, have fueled interest in the evaluation of RNA-based oligonucleotide therapeutics in a rapidly increasing number of therapeutic areas. With these unique attributes as well as growing therapeutic potential, oligonucleotide therapeutics have generated significant interest from a clinical pharmacology perspective. The Food and Drug Administration (FDA) previously published results of a survey that summarized clinical pharmacology studies supporting oligonucleotide therapies approved and in development between 2012 and 2018. Since the first approval of a small interfering RNA (siRNA) therapeutic in 2018, this class of modalities has gained momentum in various therapeutic areas. Hence, a comprehensive examination of the clinical pharmacology of FDA-approved siRNA therapeutics would benefit the path forward for many stakeholders. Thus, in this current review, we thoroughly examine and summarize clinical pharmacology data of the FDA-approved siRNA therapeutics approved from 2018 (year of first approval) to 2022, aimed at facilitating future drug development and regulatory decision making. SIGNIFICANCE STATEMENT: This review systematically summarizes the clinical pharmacology information of Food and Drug Administration (FDA)-approved small interfering RNAs (siRNA) therapeutics. SiRNAs are revolutionizing the drug development field. Unique clinical pharmacology characteristics represent a differentiating factor for this class of therapeutics. The FDArecently published a draft guidance for clinical pharmacology considerations for developing oligonucleotide therapeutics. As clinical development of this class of therapeutics is fast growing, this review will inform discovery and clinical-stage evaluation of upcoming siRNA-associated drug candidates.

The novel HLA-B*55:130 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*55:130 differs from HLA-B*55:35 by two nucleotides in exon 2.