USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.

Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.

Interactions between antifungals and everolimus against Cryptococcus neoformans.

Cryptococcus is the causal agent of cryptococcosis, a disease with high mortality mainly related to HIV immunosuppression and usually manifests with pneumonia and/or meningoencephalitis. There are very few therapeutic options; thus, innovative approaches are required. Herein, We examined the interaction of everolimus (EVL) with amphotericin B (AmB) and azoles [fluconazole (FLU), posaconazole (POS), voriconazole (VOR), itraconazole (ITR)] against Cryptococcus. Eighteen Cryptococcus neoforman clinical isolates were analyzed. Following the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M27-A4, we conducted a broth microdilution experiment to determine the minimum inhibitory concentrations (MICs) of azoles, EVL, and AmB for assessing antifungal susceptibility. A fractional inhibitory concentration index (FICI) of less than and equal to 0.5 indicated synergy, with a range of 0.5 to 4.0 indicated indifference and a value more than 4.0 indicated antagonism. These experiments revealed that EVL had antifungal activity against C. neoforman. Moreover, EVL, POS, AmB, FLU, ITR, and VOR exhibited MIC values ranging from 0.5-2 µg/mL, 0.03125-2 µg/mL, 0.25-4 µg/mL, 0.5-32µg/mL, 0.0625-4µg/mL and 0.03125-2µg/mL, respectively. The combination of EVL with AmB and azoles (POS, FLU, ITR, and VOR) exhibited synergistic antifungal effects against 16 (88.9%), 9 (50%), 11 (61.1%), 10 (55.6%) or 6 (33.3%) of analyzed Cryptococcus strains. In the presence of EVL, the MIC values of AmB and azoles were significantly lowered. No antagonism was observed. Subsequently, in vivo analyses conducted using the G. mellonella model further confirmed that combination EVL+ POS, EVL+ FLU, and EVL+ITR treatment were associated with significantly improved larval survival following Cryptococcus spp. infection. These findings provide the first published evidence suggesting that a combination of EVL and AmB or azoles exhibit a synergistic effect and may be an effective antifungal disease treatment strategy for infections caused by Cryptococcus spp.

RNA-seq reveal RNA binding protein GNL3 as a key mediator in the development of psoriasis vulgaris by regulating the IL23/IL17 axis.

BACKGROUND: Psoriasis is a systemic chronic inflammatory skin disorder that was prone to recurrence. The RNA binding protein GNL3 has an important function in maintaining the proliferative ability of stem cells, and its overexpression leads to apoptosis. GNL3 is expressed in the epidermis, however, its regulatory mechanism in psoriasis vulgaris is still poorly understood. OBJECTIVE: To identify the role of GNL3 in the pathogenesis of psoriasis vulgaris. MATERIALS AND METHODS: RNA-seq was performed to obtain the data of genes' expression and splicing events in Hela cells after shGNL3 and shCtrl was transferred. High quality results of differentially expressed genes (DEGs) and alternative splicing events (ASEs) were further attained by quality control and analysis. Through the functional enrichment analysis of DEGs and ASEs, the regulating effect of GNL3 was discussed, and the hypothesis was further confirmed in HaCat cells and psoriasis lesions. RESULTS: The mRNA expression of IL23A in Hela cells was upregulated in GNL3 knockdown, and the ratio of ASE occurred in TNFAIP3 was increased. However, in HaCaT cells, the mRNA expression level of IL23A was downregulated in GNL3 knockdown, and the ratio of ASE of TNFAIP3 was decreased. Additionally, the results obtained in HaCaT cells was further validated in the lesional psoriatic skin. CONCLUSION: GNL3 takes an important part in the development of psoriasis vulgaris by regulating the IL23/IL17 axis, which may serve as the basis of effective targeted treatment in future.

Interaction Between Amorolfine and Voriconazole Against Fusarium species.

Fusarium species represent a range of fungal pathogens capable of causing diverse mycotic diseases. Relative to antibacterial drugs, few effective antifungal agents have been developed to date, and all are subject to significant limitations. As such, there is an urgent need to design novel antifungal treatments for infections caused by Fusarium spp. Herein, 15 clinical isolates, including 5 Fusarium oxysporum and 10 Fusarium solani strains, were analyzed to explore the relative inhibitory effects of different combinations of amorolfine (AMO) and voriconazole (VOR) on the growth of these fungal pathogens. These analyses were conducted by measuring minimal inhibitory concentration (MIC) values for these antifungal agents in a broth microdilution assay and by using an in vivo model of Fusarium-infected Galleria mellonella. These experiments revealed that in isolation, AMO and VOR exhibited MIC values ranging from 4 to 16 µg/mL and 2 to 8 µg/mL, respectively. However, these effective MIC values fell to 1-2 µg/mL and 0.5-2 µg/mL, respectively, when AMO and VOR were administered in combination with one another, exhibiting synergistic activity against 73.3% of analyzed Fusarium strains. Subsequent in vivo analyses conducted using the G. mellonella model further confirmed that combination VOR + AMO treatment was associated with significantly improved larval survival following Fusarium spp. infection. Together, these results serve as the first published evidence demonstrating that VOR and AMO exhibit synergistic activity against infections caused by Fusarium spp., indicating that they may represent an effective approach to antifungal disease treatment.

Neutrophil Extracellular Traps Serve as Key Effector Molecules in the Protection Against Phialophora verrucosa.

Phialophora verrucosa (P. verrucosa) is a pathogen that can cause chromoblastomycosis and phaeohyphomycosis. Recent evidence suggests that neutrophils can produce neutrophil extracellular traps (NETs) that can protect against invasive pathogens. As such, we herein explored the in vitro functional importance of P. verrucosa-induced NET formation. By assessing the co-localization of neutrophil elastase and DNA, we were able to confirm the formation of classical NETs entrapping P. verrucosa specimens. Sytox Green was then used to stain these NETs following neutrophil infection with P. verrucosa in order to quantify the formation of these extracellular structures. NET formation was induced upon neutrophil exposure to both live, UV-inactivated, and dead P. verrucosa fungi. The ability of these NETs to kill fungal hyphae and conidia was demonstrated through MTT and pouring plate assays, respectively. Overall, our results confirmed that P. verrucosa was able to trigger the production of NETs, suggesting that these extracellular structures may represent an important innate immune effector mechanism controlling physiological responses to P. verrucosa infection, thereby aiding in pathogen control during the acute phases of infection.

Tazarotene/Betamethasone Dipropionate Cream in Patients with Plaque Psoriasis: Results of a Prospective, Multicenter, Observational Study.

BACKGROUND: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment. OBJECTIVES: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment. METHODS: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment. RESULTS: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment. CONCLUSION: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.

PM2.5 promotes apoptosis of human epidermal melanocytes through promoting oxidative damage and autophagy.

Pollutants such as PM2.5 are polluting the environment seriously, causing numerous health problems. However, the skin toxicity caused by PM2.5 has been little reported so far. CCK-8 was used to test the effects of PM2.5 on melanin cell proliferation. The effect of PM2.5 on melanocyte apoptosis was detected by flow cytometry. ELISA was used to detect the expression of oxidative stress-related factors, including reactive oxygen species (ROS). The expression of autophagosomes was detected by MDC immunohistochemical staining, and Western blot was used to detect the expression of autophagy marker LC3II/I. With the increasing concentrations of PM2.5, the proliferation rate and apoptosis rate of melanocytes decreased significantly, meanwhile the expression of oxidative stress-related factors ROS, was obviously increased. The expression of LC3II/I induced by PM2.5 venom was higher than that of the control group in a concentration-dependent manner. However, there was no statistically significant difference between the water-soluble components of PM2.5 and the water-insoluble ones. PM2.5 can inhibit the proliferation of melanocytes and induce their apoptosis, which may be related to the oxidative damage of PM2.5. PM2.5 also induced autophagy in melanocytes, which is obviously correlated with its concentration. The mechanism may be a self-protective response of cells to oxidative stress injury and apoptosis.

Consensus of Chinese experts on protection of skin and mucous membrane barrier for health-care workers fighting against coronavirus disease 2019.

Health professions preventing and controlling Coronavirus Disease 2019 are prone to skin and mucous membrane injury, which may cause acute and chronic dermatitis, secondary infection and aggravation of underlying skin diseases. This is a consensus of Chinese experts on protective measures and advice on hand-cleaning- and medical-glove-related hand protection, mask- and goggles-related face protection, UV-related protection, eye protection, nasal and oral mucosa protection, outer ear, and hair protection. It is necessary to strictly follow standards of wearing protective equipment and specification of sterilizing and cleaning. Insufficient and excessive protection will have adverse effects on the skin and mucous membrane barrier. At the same time, using moisturizing products is highly recommended to achieve better protection.

Co-existence of Juvenile dermatomyositis and psoriasis vulgaris with fungal infection: A case report and literature review.

INTRODUCTION: The incidence rate of psoriasis vulgaris (PSV) coexisting with Juvenile dermatomyositis (JDM) is low. Through our thorough literature search, we found that PSV arising on JDM with superficial fungal infection of facial skin is rarely reported. So, we hereby, report a case of combination of the above three diseases. Meanwhile, we also reviewed the previous literatures aiming at the related basis, clinical manifestation, diagnosis, and treatment of the diseases. Interestingly, of all cases, this case is the only one in which the symptom of muscle weakness preceded the appearance of rash. CASE PRESENTATION: A 21-year-old man diagnosed with JDM 6 years ago came to our inpatient department due to the appearance of new rash. Skin examination showed some sharply demarcated scaly plaques over the head, neck, torso, and bilateral upper limbs with pruritus and scaling. Histological examination and typical clinical manifestation confirmed the diagnosis of PSV for his new rash. Family history was negative for JDM and PSV. The clear erythema located on his face revealed the existence of superficial fungal infection with the help of fungal fluorescence microscopy. He had marked improvement of his symptoms with the treatment given at our department. In the past 3 months, the patient has been on regular follow-up at our outpatient department, and his condition is stable at present. DISCUSSION: This paper presents a case of PSV arising on JDM coexisting with superficial fungal infection on the face hoping that this will help clinicians in the better diagnosis of the diseases during literature search.

Particulate matter 2.5 regulates lipid synthesis and inflammatory cytokine production in human SZ95 sebocytes.

A large body of evidence indicates that particulate matter (PM)2.5 is associated with various negative effects on human health. However, the impact and molecular mechanism of PM2.5 on the skin have not been elucidated. Therefore, the present study aimed to investigate the effects of two types of PM2.5 [water-soluble extracts (W-PM2.5) and non-water-soluble extracts (NW-PM2.5)] on cell proliferation, cell cycle progression, lipid synthesis, and inflammatory cytokine production of human SZ95 sebocytes. The results demonstrated that NW-PM2.5 and W-PM2.5 exposure dose-dependently inhibited SZ95 sebocyte proliferation by inducing G1 cell arrest. Furthermore, NW-PM2.5 and W-PM2.5 significantly reduced sebaceous lipid synthesis and markedly promoted the production of inflammatory cytokines, including interleukin-1α (IL-1α), IL-6 and IL-8 in SZ95 sebocytes. Additionally, the expression of aryl hydrocarbon (Ah) receptor (AhR), AhR nuclear translocator protein (ARNT), as well as cytochrome P450 1A1 were significantly increased following PM2.5 exposure. Thus, these findings indicate that PM2.5 exerts inhibitory effects on cell proliferation and lipid synthesis, and stimulatory effects on inflammatory cytokine production and AhR signaling activation in human SZ95 sebocytes.

ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation.

BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance. Here we showed that overexpression of HDAC6 confers resistance to vemurafenib in BRAF-mutant A375 cells. ACY-1215, a selective HDAC6 inhibitor, inhibits the proliferation and induces the apoptosis of A375 cells. Moreover, ACY-1215 sensitizes A375 cells to vemurafenib induced cell proliferation inhibition and apoptosis induction, which occur partly through induction of endoplasmic reticulum (ER) stress and inactivation of extracellular signal-regulated kinase (ERK). Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of melanoma and overcoming resistance to vemurafenib.

A novel truncating mutation of PTCH1 in a Chinese family with Gorlin syndrome.

Gorlin syndrome, a rare autosomal dominant disease, is characterized by numerous basal cell carcinomas, multiple jaw cysts, palmar and plantar pits and embryological deformities. Mutations in the PTCH1 gene are the most common molecular defects associated with Gorlin syndrome. We detected a duplication of thymine after nucleotide position 2927 in exon 18 of the PTCH1 gene (c.2927 dupT) in a fifty-year-old male proband with peri-anal basal cell carcinoma and his brother. The mutation creates a frameshift and leads to a premature stop codon (p.Tyr977 Leufs* 16) lacking 5 of the 12 transmembrane-spanning domains. However, the functional significance of truncation of the N terminal regions remains currently unknown and to be further investigated. The current findings indicate that genetic testing of PTCH1 gene mutational status may aid in the early diagnosis of Gorlin syndrome in which multiple complex abnormalities are present, hampering prompt diagnosis and treatment.

CTLA-4 gene polymorphism and the risk of systemic lupus erythematosus in the Chinese population.

Several variants of CTLA-4 have been reported to be associated with susceptibility systemic lupus erythematosus (SLE); however, findings have been inconsistent across different populations. Using a case-control study design, we have investigated the role of CTLA-4 polymorphism at positions -1661 and -1722 on SLE susceptibility in our Chinese SLE population in central China's Hubei province. Samples were collected from 148 SLE patients and 170 healthy controls. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotypes of the two sites. Statistically significant difference was observed in genotypes for -1722, but not for -1661. The frequency of the T allele on the -1722 SNP was significantly increased in SLE patients: 57.8% versus 40.6% in controls (P < 0.001, OR = 2.002). While the detected C allele frequency in the controls was significantly elevated in comparison to that in the SLE patients (59.4% versus 42.2%). On the contrary, no association was found between SLE and CTLA-4 polymorphism at position -1661.