Overexpression of NLRP12 enhances antiviral immunity and alleviates herpes simplex keratitis via pyroptosis/IL-18/IFN-γ signaling.

Herpes simplex keratitis (HSK) is a blinding disease caused by herpes simplex virus type 1 (HSV-1) infection, and rapid eradication of the virus from the affected cornea is imperative. Nod-like receptors (NLRs) are intracellular innate immune sensors closely associated with cell death, inflammation and immune responses. In this study, we investigated the role of NLRP12 in the antiviral immunology in HSK and the underlying mechanisms. We found that NLRP12 expression was significantly decreased in HSV-1-infected human corneal epithelial cells (HCE-Ts) and HSK mouse corneas. Overexpression of NLRP12 significantly reduced viral replication in infected HCE-Ts and functioned through inflammasome-mediated pyroptosis and downstream IL-18-IFN-γ axis. In HSK mouse models, overexpression of NLRP12 reduced viral replication in the cornea and alleviated HSK symptoms. This resulted from enhanced antiviral immune responses including the activation of specific immune cells in both the cornea and the draining lymph nodes. Specifically, the NLRP12-IL-18-IFN-γ axis regulated the interaction between infected corneal epithelial cells and macrophages. In conclusion, our study identified a role of NLRP12 in mediating pyroptosis and regulating antiviral immune responses. This novel finding opens the possibilities of NLRP12 as a viable target in the therapeutic strategies for HSV-1 infection.

CRISPR-Cas9-mediated deletion of carbonic anhydrase 2 in the ciliary body to treat glaucoma.

The carbonic anhydrase 2 (Car2) gene encodes the primary isoenzyme responsible for aqueous humor (AH) production and plays a major role in the regulation of intraocular pressure (IOP). The CRISPR-Cas9 system, based on the ShH10 adenovirus-associated virus, can efficiently disrupt the Car2 gene in the ciliary body. With a single intravitreal injection, Car2 knockout can significantly and sustainably reduce IOP in both normal mice and glaucoma models by inhibiting AH production. Furthermore, it effectively delays and even halts glaucomatous damage induced by prolonged high IOP in a chronic ocular hypertension model, surpassing the efficacy of clinically available carbonic anhydrase inhibitors such as brinzolamide. The clinical application of CRISPR-Cas9 based disruption of Car2 is an attractive therapeutic strategy that could bring additional benefits to patients with glaucoma.

Neurotoxicity Profiling of Aluminum Salt-Based Nanoparticles as Adjuvants for Therapeutic Cancer Vaccine.

Therapeutic vaccines containing aluminum adjuvants have been widely used in the treatment of tumors due to their powerful immune-enhancing effects. However, the neurotoxicity of aluminum adjuvants with different physicochemical properties has not been completely elucidated. In this study, a library of engineered aluminum oxyhydroxide (EAO) and aluminum hydroxyphosphate (EAHP) nanoparticles was synthesized to determine their neurotoxicity in vitro. It was demonstrated that the surface charge of EAHPs and size of EAOs did not affect the cytotoxicity in N9, bEnd.3, and HT22 cells; however, soluble aluminum ions trigger the cytotoxicity in three different cell lines. Moreover, soluble aluminum ions induce apoptosis in N9 cells, and further mechanistic studies demonstrated that this apoptosis was mediated by mitochondrial reactive oxygen species generation and mitochondrial membrane potential loss. This study identifies the safety profile of aluminum-containing salts adjuvants in the nervous system during therapeutic vaccine use, and provides novel design strategies for their safer applications. SIGNIFICANCE STATEMENT: In this study, it was demonstrated that engineered aluminum oxyhydroxide and aluminum hydroxyphosphate nanoparticles did not induce cytotoxicity in N9, bEnd.3, and HT22 cells. In comparation, soluble aluminum ions triggered significant cytotoxicity in three different cell lines, indicating that the form in which aluminum is presenting may play a crucial role in its safety. Moreover, apoptosis induced by soluble aluminum ions was dependent on mitochondrial damage. This study confirms the safety of engineered aluminum adjuvants in vaccine formulations.

Targeted delivery of herpes simplex virus glycoprotein D to CD169+ macrophages using ganglioside liposomes alleviates herpes simplex keratitis in mice.

Herpes simplex keratitis (HSK) is a common blinding corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. Antiviral drugs and corticosteroids haven't shown adequate therapeutic efficacy. During the early stage of HSV-1 infection, macrophages serve as the first line of defense. In particular, CD169+ macrophages play an important role in phagocytosis and antigen presentation. Therefore, we constructed GM-gD-lip, a ganglioside GM1 liposome vaccine encapsulating HSV-1 glycoprotein D and targeting CD169+ macrophages. After subconjunctival injection of the vaccine, we evaluated the survival rate and ocular surface lesions of the HSK mice, as well as the virus levels in the tear fluid, corneas, and trigeminal ganglia. We discovered that GM-gD-lip reduced HSV-1 viral load and alleviated the clinical severity of HSK. The GM-gD-lip also increased the number of corneal infiltrating macrophages, especially CD169+ macrophages, and polarized them toward M1. Furthermore, the number of dendritic cells (DCs) and CD8+ T cells in the ocular draining lymph nodes was significantly increased. These findings demonstrated that GM-gD-lip polarized CD169+ macrophages toward M1 to eliminate the virus while cross-presenting antigens to CD8+ T cells via DCs to activate adaptive immunity, ultimately attenuating the severity of HSK. The use of GM-gD-lip as an immunotherapeutic method for the treatment of HSK has significant implications.

Diagnostic performance of wide-field optical coherence tomography angiography in detecting open-angle glaucoma in high myopia.

PURPOSE: To compare the diagnostic performance of the capillary density (CD) of the central 1-6 mm and peripheral 6-12 mm annular regions in detecting open-angle glaucoma in high myopia (HM) using 15 × 12 mm wide-field swept-source optical coherence tomography angiography (WF SS-OCTA). METHODS: The study enrolled 206 and 103 eyes with HM and highly myopic open-angle glaucoma (HM-OAG), respectively. WF SS-OCTA images centred on the fovea were obtained to analyse the changes in the CD in the 1-3 mm, 3-6 mm, 6-9 mm, and 9-12 mm annular regions. CD of the superficial capillary plexus (SCP) was measured with the built-in software. The area under the receiver operating characteristic curve (AUROC) of each region was compared. RESULTS: The diagnostic performance of the SCP CD in the central 1-6 mm annular region (AUROC = 0.849) was better than that in the peripheral 6-12 mm annular region (AUROC = 0.756, p = 0.001). The annular AUROCs of SCP CD peaked in the 3-6 mm annular region (AUROC = 0.858) and gradually decreased with increasing diameter and were lower than the corresponding AUROCs of the ganglion cell-inner plexiform layer thickness (p < 0.05 for all comparisons). SCP CD of the inferior quadrant in the 3-6 mm annular region had the best diagnostic performance (AUROC = 0.859). CONCLUSION: The SCP CD in the central 1-6 mm annular region exhibited better diagnostic performance for the detection of HM-OAG in HM. The assessment of more peripheral regions has no added value in detecting glaucoma in HM.

The effects of chalazion and the excision surgery on the ocular surface.

Purpose: To evaluate the effects of chalazion excision on the ocular surface, taking into account the subjective symptoms and the objective parameters of the tear film. Methods: This prospective, interventional clinical study included 52 eyes from 26 patients with eyelid chalazion who underwent excision of the lesions between March and August 2022. Chalazion excision was performed on the patient's chalazion eye, and the contralateral eye served as the control. The following parameters were investigated both preoperatively and 1 week, 1 month, and 3 months postoperatively: the Ocular Surface Disease Index (OSDI), Schirmer I test, corneal fluorescein stain (CFS), tear meniscus height (TMH), noninvasive first breakup time (NifBUT), noninvasive average breakup time (NiaBUT), bulbar conjunctival redness score, the thickness of the lipid layer, and meibomian gland loss. Results: Before surgery, the OSDI score of the chalazion eye was significantly higher than the contralateral eye. The bulbar conjunctival redness score (p = 0.043) and the OSDI score (p = 0.004) improved significantly in the first month after surgery. In the third month after surgery, the objective parameters showed significant improvements, including TMH (p = 0.032), NiaBUT (p = 0.028), bulbar conjunctival redness score (p < 0.001), the thickness of the lipid layer (p = 0.021), and meibomian gland loss (p = 0.005). Conclusions: Our study revealed that chalazion excision can significantly improve the subjective symptoms and the objective tear film parameters of the ocular surface.

Integrated Transcriptome Analysis of Long Noncoding RNA and mRNA in Developing and Aging Mouse Retina.

Mice have emerged as a widely employed model for investigating various retinal diseases. However, the availability of comprehensive datasets capturing the entire developmental and aging stages of the mouse retina, particularly during the elderly period, encompassing integrated lncRNA and mRNA expression profiles, is limited. In this study, we assembled a total of 18 retina samples from mice across 6 distinct stages of development and aging (5 days, 3 weeks, 6 weeks, 10 weeks, 6 months, and 15 months) to conduct integrated lncRNA and mRNA sequencing analysis. This invaluable dataset offers a comprehensive transcriptomic resource of mRNA and lncRNA expression profiles during the natural progression of retinal development and aging. The discoveries stemming from this investigation will significantly contribute to the elucidation of the underlying molecular mechanisms associated with various retinal diseases, such as congenital retinal dysplasia and retinal degenerative diseases.

Therapeutic Potential of Biochanin A in Herpes Simplex Keratitis.

Herpes simplex keratitis (HSK) is a blinding eye disease that is initiated by the herpes simplex virus type 1 (HSV-1). Resistance to acyclovir (ACV) and the side effects of corticosteroid drugs have become concerning issues, so it is crucial to develop new antivirals for treating HSK. In this study, we report that biochanin A (BCA), a naturally occurring flavonoid compound, provides multifaceted protective effects with anti-viral, anti-inflammatory, anti-oxidative stress and anti-apoptotic activities to alleviate HSK. The results show that BCA significantly inhibited HSV-1 replication in vitro and further proved that BCA principally influenced the early stage of virus infection. We reveal that BCA downregulated the expression of pro-inflammatory factors triggered by HSV-1, including TNF-α, RANTES, IL-1ß and IL-6. Furthermore, BCA treatment alleviated oxidative stress and apoptotic arising from HSV-1 infection. Lastly, we induced HSK in male C57BL/6 mice and treated them with either BCA or phosphate buffer solution (PBS) eye drops. We observed the ocular surface lesions; determined the virus load in the tear fluid, corneas as well as trigeminal ganglions (TGs); and detected the levels of inflammation and apoptosis in the corneas simultaneously. These results show that BCA inhibits HSV-1 and alleviates the corneal lesion degree. Our study illustrates that BCA is a promising therapeutic approach for application in treating HSK.

Comparison on cognitive outcomes of antidiabetic agents for type 2 diabetes: A systematic review and network meta-analysis.

We aimed to summarise current evidence on different antidiabetic drugs to delay cognitive impairment, including mild cognitive impairment, dementia, Alzheimer's disease (AD) and vascular dementia, among subjects with type 2 diabetes mellitus (T2DM). Medline, Cochrane and Embase databases were searched from inception to 31 July 2022. Two investigators independently reviewed and screened trials comparing antidiabetic drugs with no antidiabetic drugs, placebo, or other active antidiabetic drugs on cognitive outcomes in T2DM. Data were analysed using meta-analysis and network meta-analysis. Twenty-seven studies met the inclusion criteria, including 3 randomised controlled trials, 19 cohort studies and 5 case-control studies. Compared with non-user, SGLT-2i (OR 0.41 [95% CI 0.22-0.76]), GLP-1RA (OR 0.34 [95% CI 0.14-0.85]), thiazolidinedione (OR 0.60 [95% CI 0.51-0.69]), and DPP-4i (OR 0.78 [95% CI 0.61-0.99]) users had a decreased risk of dementia, whereas sulfonylurea (OR 1.43 [95% CI 1.11-1.82]) increased dementia risk. Network meta-analysis showed that SGLT-2i was most likely to rank best (SUCRA = 94.4%), GLP-1 RA second best (SUCRA = 92.7%), thiazolidinedione third best (SUCRA = 74.7%) and DPP-4i fourth best (SUCRA = 54.9%), while sulfonylurea second worst (SUCRA = 20.0%) for decreasing dementia outcomes, by synthesising evidence from direct and indirect comparisons of multiple intervention. Evidence suggests the effects of SGLT-2i ≈ GLP-1 RAs > thiazolidinedione > DPP-4i for delaying cognitive impairment, dementia and AD outcomes, whereas sulfonylurea was associated with the highest risk. These findings provide evidence for evaluating the optional treatment for clinical practice. PROSPERO REGISTRATION: Registration no. CRD42022347280.

Salidroside alleviates oxidative stress in dry eye disease by activating autophagy through AMPK-Sirt1 pathway.

Dry eye disease (DED) is a multifactorial disease, and oxidative stress plays a crucial role in its pathogenesis. Recently, multiple studies have shown that upregulation of autophagy can protect the cornea from oxidative stress damage. The present study investigated the therapeutic effects of salidroside, the main component of Rhodiola crenulata, in both in vivo and in vitro dry eye models. The results showed that topical eye drop treatment with salidroside restored corneal epithelium damage, increased tear secretion, and reduced cornea inflammation in the DED mice. Salidroside activated autophagy through AMP-activated protein kinase (AMPK)-sirtuin-1 (Sirt1) signaling pathway, which promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). This process restored antioxidant enzyme activity, reduced reactive oxygen species (ROS) accumulation, and alleviated oxidative stress. The application of autophagy inhibitor chloroquine and AMPK inhibitor Compound C reversed the therapeutic efficacy of salidroside, validating the above findings. In conclusion, our data suggest that salidroside is a promising candidate for DED treatment.

Evaluation of corneal dendritic cell density and subbasal nerve density in contact lens wearers using IVCM: A systematic review and meta-analysis.

Purpose: To evaluate the subclinical changes in corneal dendritic cell density (CDCD) and corneal subbasal nerve density (CSND) in asymptomatic contact lens (CL) wearers. Methods: Databases including PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for trials and studies reporting the changes of corneal CDCD and CSND in contact lens wearers published until 25 June 2022. PRISMA guidelines as well as recommended meta-analysis practices were followed. Meta-analysis was conducted using RevMan V.5.3 software. Results: After the screening, 10 studies with 587 eyes of 459 participants were included. Seven studies reported the data of CDCD. Compared with the control group, CDCD in the CL wearers was higher (18.19, 95% CI 18.8-27.57, p = 0.0001). Type of in vivo confocal microscopy (IVCM), wear duration, and frequency of lens change were sources of heterogeneity. The difference in CSND between CL wearers and the control group was insignificant, and subgroup analysis did not reveal a source of heterogeneity. Conclusion: Overall, CDCD increased in CL wears, while CSND did not show significant differences. IVCM is a feasible tool to assess subclinical changes in CL wearers.

p53 mutation and deletion contribute to tumor immune evasion.

TP53 (or p53) is widely accepted to be a tumor suppressor. Upon various cellular stresses, p53 mediates cell cycle arrest and apoptosis to maintain genomic stability. p53 is also discovered to suppress tumor growth through regulating metabolism and ferroptosis. However, p53 is always lost or mutated in human and the loss or mutation of p53 is related to a high risk of tumors. Although the link between p53 and cancer has been well established, how the different p53 status of tumor cells help themselves evade immune response remains largely elusive. Understanding the molecular mechanisms of different status of p53 and tumor immune evasion can help optimize the currently used therapies. In this context, we discussed the how the antigen presentation and tumor antigen expression mode altered and described how the tumor cells shape a suppressive tumor immune microenvironment to facilitate its proliferation and metastasis.

A carbon dot-based nanoscale covalent organic framework as a new emitter combined with a CRISPR/Cas12a-mediated electrochemiluminescence biosensor for ultrasensitive detection of bisphenol A.

Exploring new highly efficient electrochemiluminescence (ECL) luminophores is a necessary condition for developing ultrasensitive ECL biosensors. Therefore, a luminescent carbon dot-based covalent organic framework (CD-COF) was prepared using aldehyde-based carbon dots (CDs) and 1,3,5-tris (4-aminophenyl) benzene (TPB). Because the CD-COF made the regular arrangement of CDs conducive to improving the ECL response, CD-COF had a higher ECL intensity and efficiency than CDs. What's more, the ECL intensity of the CD-COF/S2O82-/Bu4N+ system was about 2.98, 7.50, and 28.08 times higher than those of the CD-COF/S2O82-, CDs/S2O82- and S2O82- systems, respectively. Considering the remarkable ECL performance, the CD-COF/S2O82-/Bu4N+ system was employed combined with the CRISPR/Cas12a trans-cutting strategy to construct an "off-on" ECL biosensor for BPA detection. The proposed ECL biosensor exhibited excellent performance with a wide linear range from 1.0 × 10-14 mol L-1 to 1.0 × 10-5 mol L-1 with a low detection limit of 2.21 fM (S/N = 3) under the optimized conditions. The biosensor demonstrated that CD-COF can be used as an efficient ECL emitter, thus expanding the application field of COFs. In addition, the good stability and specificity of the biosensor enabled the rapid detection of BPA, which will provide valuable insights into promising ultrasensitive ECL biosensors.

PKHB1 peptide induces antiviral effects through induction of immunogenic cell death in herpes simplex keratitis.

Herpes simplex keratitis (HSK) is a severe, infectious corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. The increasing prevalence of acyclovir resistance, the side effects of hormonal drugs, and the ease of recurrence after surgery have made it crucial to develop new methods of treating HSK. HSV-1 evades the host immune response through various mechanisms. Therefore, we explored the role of the immunogenic cell death inducer PKHB1 peptide in HSK. After subconjunctival injection of PKHB1 peptide, we observed the ocular surface lesions and survival of HSK mice and detected the virus levels in tear fluid, corneas, and trigeminal ganglions. We found that PKHB1 peptide reduced HSV-1 levels in the eye and alleviated the severity of HSK. Moreover, it increased the number of corneal infiltrating antigen-presenting cells (APCs), such as macrophages and dendritic cells, and CD8+ T cells in ocular draining lymph nodes. We further observed that PKHB1 peptide promoted the exposure of calreticulin, as well as the release of ATP and high-mobility group box 1 in HSV-1-infected cells in vitro. Our findings suggested that PKHB1 peptide promoted the recruitment and maturation of APCs by inducing the release of large amounts of damage-associated molecular patterns from infected cells. APCs then phagocytized antigenic materials and translocated to the lymph nodes, triggering a cytotoxic T lymphocyte-dependent immune response that ultimately alleviated HSK.

Probiotics from Dairy Products on Intestinal Barrier Function Using Caco-2 Cells under Microscope.

With the continuous improvement of human living standards, people's demand for health has become an important international research hotspot. In recent years, 41.3% of the total incidence of multiple organ failure (MOF) caused by dysfunction of the intestinal screen was found every year. The mortality rate is 62%, which is more than twice that of developed countries. This paper is aimed at observing the microscopic effects of probiotics derived from dairy products using Caco-2 cells on intestinal barrier function. Based on the above background, the purpose of this study was to construct a Caco-2 cell model under microscope to study the effect of probiotics on intestinal barrier function. This study first describes the background knowledge of the integration of modern microscope technology and medical field and the correlation between them. The results showed that the relative adhesion rates of Lactobacillus bulgaricus, Lactobacillus acidophilus, and Streptococcus thermophilus were 4.67 ± 0.07%, 11.53 ± 0.06%, and 18.31 ± 0.08%, respectively, which were lower than those in the normal group. The production of antibacterial substances can inhibit intestinal pathogens and adjust the balance of intestinal flora.

Hydroxychloroquine induces apoptosis of myeloid-derived suppressor cells via up-regulation of CD81 contributing to alleviate lupus symptoms.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that results from widespread immune complex deposition and secondary tissue injury. Hydroxychloroquine (HCQ) has been used clinically to treat SLE, while its exact mechanism has still remained elusive. Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of SLE. In this study, we aimed to explore the effects of HCQ on the apoptosis of MDSCs in lupus mice and its possible molecular regulatory mechanism. METHODS: We constructed the imiquimod (IMQ)-induced lupus model in mice. The proportion and apoptosis of MDSCs were measured by flow cytometry. CD81-overexpressed adeno-associated virus was intraperitoneally injected into the lupus mice. We also transfected the CD81 siRNA into bone marrow-derived MDSCs, and employed qRT-PCR and Western blotting to quantify the level of CD81. RESULTS: The results showed that HCQ ameliorated IMQ-induced lupus symptoms, and simultaneously inhibited the expansion of MDSCs. In particular, HCQ induced the apoptosis of MDSCs, and also up-regulated the expression level of CD81 in MDSCs, which might indicate the relationship between the expression level of CD81 and the apoptosis of MDSCs. CD81 was further confirmed to participate in the apoptosis of MDSCs and lupus disease progression by overexpressing CD81 in vivo. Molecular docking experiment further proved the targeting effect of HCQ on CD81. And then we interfered CD81 in bone marrow derived MDSCs in vitro, and it was revealed that HCQ rescued the decreased expression level of CD81 and relieved the immune imbalance of Th17/Treg cells. CONCLUSION: In summary, HCQ promoted the apoptosis of MDSCs by up-regulating the expression level of CD81 in MDSCs, and ultimately alleviated lupus symptoms. Our results may assist scholars to develop further effective therapies for SLE.

Nectin-1 and Non-muscle Myosin Heavy Chain-IIB: Major Mediators of Herpes Simplex Virus-1 Entry Into Corneal Nerves.

Herpes Simplex Virus 1 (HSV-1) invades corneal nerves upon its infection of the cornea and then establishes latency in the trigeminal ganglion (TG). The latent virus in TG is often reactivated and travels back to the cornea, causing recurrent herpes simplex keratitis (HSK). The entry of HSV-1 into the corneal nerve is considered the initial step of infection resulting in HSV-1 latency and HSK recurrence. Several gD and gB receptors have been identified, including nectin-1, herpes virus entry medium (HVEM) and 3-O-sulfated heparan sulfate (3-OS-HS) as gD receptors, and non-muscle myosin heavy chain IIA (NMHC-IIA), NMHC-IIB and myelin-associated glycoprotein (MAG) as gB receptors. However, which receptors contribute to the entry of HSV-1 into corneal nerves are yet to be determined. This study observed that receptors nectin-1, HVEM, 3-OS-HS, NMHC-IIA, and NMHC-IIB, not MAG, were expressed in healthy corneal nerves. Further, we cultured TG neurons extracted from mice in vitro to screen for functional gD/gB receptors. Both in vitro siRNA knockdown and in vivo antibody blocking of either nectin-1 or NMHC-IIB reduced the entry and the replication of HSV-1 as shown by qPCR analysis and immunofluorescence measure, respectively. Also, we observed that the re-localization and the upregulation expression of NMHC-IIB after HSV-1 exposure were inhibited when gD receptor nectin-1 was knocked down. These data suggest that nectin-1 was the main gD receptor and NMHC-IIB was the main gB receptor in mediating HSV-1 entry and hold promise as therapeutic targets for resolving HSV-1 latency and HSK recurrence.

Mesenchymal Stromal Cells-Derived Extracellular Vesicles Regulate Dendritic Cell Functions in Dry Eye Disease.

We explored the therapeutic efficacy of Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) and its inhibition of the functions of dendritic cells (DCs) in dry eye disease (DED). MSC-EVs were isolated from the culture supernatants of mesenchymal stromal cells (MSCs) and characterized. In vitro, human corneal epithelial cells (HCECs) were cultured in hyperosmotic medium to simulate the DED hyperosmotic environment and treated with MSC-EVs. Cell viability was assessed, and the expression of inflammatory cytokines was quantified. Next, we induced DED in female C57BL/6 mice and divided the mice into groups treated with either MSC-EVs or phosphate buffer solution (PBS) eye drops. Disease severity was assessed; mRNA expression of inflammatory cytokines was analyzed by RT-PCR; and Th17 cells were detected by flow cytometry. Lastly, we evaluated DCs by immunofluorescence and flow cytometric analysis to assess its amounts and maturation. MSC-EVs showed protective effects on HCECs under hyperosmotic stress in vitro, suppressing the expression of inflammatory cytokines. In vivo, mice topically treated with MSC-Evs presented reduced DED disease severity compared to PBS-treated mice. MSC-Evs downregulated the expression of inflammatory cytokines, including TNF-α, IL-6, and IL-1ß, as well as the frequency of Th17 cells. Further investigation showed that MSC-EVs suppressed the increase of amounts and the maturation of DCs in DED. Changes of morphological characters of DCs were also inhibited by MSC-EVs. Our study revealed that MSC-EVs suppressed ocular surface inflammation by inhibiting DCs activation-mediated Th17 immune responses, explicating the therapeutic potential of MSC-EVs in DED and other ocular surface diseases.

Research progress of the relationship between pyroptosis and disease.

Pyroptosis, characterized by proinflammation, has been defined as a new type of programmed cell death in recent years. Inflammasomes are activated by the corresponding pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS), followed up by the cleavage of pro-interleukin-1ß (pro-IL-1ß), pro-interleukin-18 (pro-IL-18) and gasdermin D. The N-terminal fragment of gasdermin D gives rise to the destruction of cell membrane, leading to cell rupture as well as the efflux of proinflammatory cytokines. Recent studies have shown that pyroptosis is associated with a variety of diseases due to its proinflammation effect and the dysfunction of related cells. The relationship between pyroptosis and associated diseases is described in this review.

Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints.

In recent years, the role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments, including surgery, chemotherapy and radiotherapy. Of note, the clinical successes of immune checkpoint blockade, such as PD-1 and CTLA-4, represent a landmark event in cancer immunotherapy development. Therefore, further exploration of how immune checkpoints are regulated in the tumor microenvironment will provide key insights into checkpoint blockade therapy. In this review, we discuss in details about the regulation of immune checkpoints mediated by immune cells, oncolytic viruses, epigenetics, and gut microbiota and mutual regulation by co-expressed checkpoints. Finally, predictions are made for future personalized cancer immunotherapy based on different checkpoint modulations.