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• In this study,we modified chlorin e6 by adding a hydrogen chain with a six-carbon ring to the benzene ring and named this new photosensitizer as STBF. • Our results suggest that STBF-PDT inhibits CSCC cell proliferation by inhibition of Akt/mTOR signaling pathway. • Our findings provide theoretical and experiment basis to support STBF-PDT in the treatment of cSCC. Although most cutaneous squamous cell carcinoma (cSCC) cases are generally nonlethal and manageable with surgical excision, there ares till significant hazards for patients who are ineligible for surgical resection. We sought to find a suitable and effective treatment for cSCC. We modified chlorin e6 by adding a hydrogen chain with a six-carbon ring to the benzene ring and named this new photosensitizer as STBF. We first investigated the fluorescence characteristics, cellular uptake of STBF and subcellular localization. Next, cell viability was detected by CCK-8 assay and the TUNEL staining was performed. Akt/mTOR‐related proteins were examined by western blot. STBF‐ photodynamic therapy (PDT) inhibits cSCC cells viability in a light dose dependent manner. The antitumor mechanism of STBF-PDT might be due to the suppression of the Akt/mTOR signaling pathway. Further animal investigation determined that STBF-PDT led to a marked reduction in tumor growth. Our results suggest that STBF‐PDT exerts significant therapeutic effects in cSCC. Thus, STBF‐PDT is expected to be a promising method for the treatment of cSCC and the photosensitizer STBF may be destined for a wider range of applications in photodynamic therapy. [ABSTRACT FROM AUTHOR]

Rosacea is a common chronic facial inflammatory disease that affects millions of people worldwide. Due to the unclear etiology of rosacea, effective treatments are limited. Celastrol, a plant-derived triterpene, has been reported to alleviate inflammation in various diseases. However, whether celastrol exerts protective effects in rosacea remains to be elucidated. In this study, weighted gene co-expression network analyses (WGCNA) were performed. Hub modules closely related to rosacea clinical characteristics were identified and found to be involved in inflammation- and angiogenesis-related signaling pathways. Then, the pharmacological targets of celastrol were predicted using the TargetNet and Swiss Target Prediction databases. A GO analysis indicated that the biological process regulated by celastrol highly overlapped with the pathogenic biological processes in rosacea. Next, we showed that celastrol ameliorated erythema, skin thickness and inflammatory cell infiltration in the dermis of LL37-treated mice. Celastrol suppressed the expression of rosacea-related inflammatory cytokines and inhibited the Th17 immune response and cutaneous angiogenesis in LL37-induced rosacea-like mice. We further demonstrated that celastrol attenuated LL37-induced inflammation by inhibiting intracellular-free calcium ([Ca2+] i)-mediated mTOR signaling in keratinocytes. Chelating intracellular Ca2+ with BAPTA/AM potentiated celastrol-induced repression of LL37-induced p-S6 elevation. The mTOR agonist MHY1485 dramatically reinforced LL37-induced rosacea-like characteristics, while celastrol attenuated these outcomes. Moreover, celastrol inhibited LL37-activated NF-κB in a mTOR signaling-dependent manner. In conclusion, our findings underscore that celastrol may be a rosacea protective agent by inhibiting the LL37-activated Ca2+/CaMKII-mTOR-NF-κB pathway associated with skin inflammation disorders. [Display omitted] • Celastrol is a potential drug of regulating inflammation and angiogenesis. • Celastrol ameliorates rosacea-like features in LL37-treated mice. • Celastrol inhibits LL37-induced rosacea by inhibiting Ca2+-CaMKII-mTOR signaling. • Celastrol inhibits LL37-induced rosacea by inhibiting Ca2+-CaMKII-dependent mTOR-NF-κB signaling. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) is a noninvasive therapeutic method which gradually being used in clinic including cancers. Exosomes mediate intercellular communication functions in disease development and the potential clinical applications in diagnosis and therapy. However, few studies have discussed the relationship between LIPUS and exosomes. Herein, we show that low intensity (0.6–2.1 W/cm2 or 0.6–3.4 W/cm2) LIPUS promoted exosomes secretion whereas higher intensity (3.4–5.0 W/cm2 or 5.0 W/cm2) LIPUS inhibited exosomes secretion, and this phenomenon is associated with autophagy. Pretreatment with 3-MA or down-regulation of LC3 potentiated low intensity LIPUS's promotion of exosomes secretion and conferred resistance to higher intensity LIPUS's effects on exosomes secretion. Furthermore, pretreatment with PP242 attenuated LIPUS-influenced exosomes secretion while expression of constitutively active Akt (Ad-myr-Akt) elevated LIPUS-influenced exosomes secretion, implying mTOR-dependent mechanism involved. The findings indicate that LIPUS influences exosomes secretion by targeting mTOR-mediated LC3 signaling in SPC-A1 and SPC-A1-BM cells. Our data provided initial evidence to connect LIPUS and secretion of exosomes, and highlight that LIPUS may be exploited in exosome-related diseases. [ABSTRACT FROM AUTHOR]

Highlights: [•] hsBAFF-induced extracellular Ca2+ influx and ER Ca2+ release elevates [Ca2+]i. [•] hsBAFF-elevated [Ca2+]i activates mTOR signaling in B lymphocytes. [•] hsBAFF-elevated [Ca2+]i elicits CaMKII phosphorylation in B lymphocytes. [•] hsBAFF-increased CaMKII phosphorylation activates mTOR signaling in B lymphocytes. [•] hsBAFF promotes B cell growth and survival via Ca2+/CaMKII/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract B cell activating factor from the TNF family (BAFF) is implicated in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Autophagy plays a crucial role in balancing the beneficial and detrimental effects of immunity and inflammation. However, little is known about whether and how excessive BAFF mediates autophagy contributing to B-cell proliferation and survival. Here, we show that excessive human soluble BAFF (hsBAFF) inhibited autophagy with a concomitant reduction of LC3-II in normal and B-lymphoid (Raji) cells. Knockdown of LC3 not only potentiated hsBAFF inhibition of autophagy, but also attenuated hsBAFF activation of Akt/mTOR pathway, thereby diminishing hsBAFF-induced B-cell proliferation/viability. Further, we found that hsBAFF inhibition of autophagy was Akt/mTOR-dependent. This is supported by the findings that hsBAFF increased mTORC1-mediated phosphorylation of ULK1 (Ser757); Akt inhibitor X, mTORC1 inhibitor rapamycin, mTORC1/2 inhibitor PP242, expression of dominant negative Akt, or knockdown of mTOR attenuated hsBAFF-induced phosphorylation of ULK1, decrease of LC3-II level, and increase of cell proliferation/viability. Chelating intracellular free Ca2+ ([Ca2+] i) with BAPTA/AM or preventing [Ca2+] i elevation using EGTA or 2-APB profoundly blocked hsBAFF-induced activation of Akt/mTOR, phosphorylation of ULK1 and decrease of LC3-II, as well as increase of cell proliferation/viability. Similar effects were observed in the cells where CaMKII was inhibited by KN93 or knocked down by CaMKII shRNA. Collectively, these results indicate that hsBAFF inhibits autophagy promoting cell proliferation and survival through activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in normal and neoplastic B-lymphoid cells. Our findings suggest that manipulation of intracellular Ca2+ level or CaMKII, Akt, or mTOR activity to promote autophagy may be exploited for prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases. Graphical abstract Unlabelled Image Highlights • hsBAFF promotes B-cell proliferation and survival by inhibiting autophagy. • Downregulation of LC3 protein level is critical for hsBAFF inhibition in B cells. • hsBAFF-activated Akt/mTOR signaling represses autophagy via phosphorylating ULK1 (Ser757) in B cells. • hsBAFF inhibits autophagy by activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in B cells. [ABSTRACT FROM AUTHOR]