Therapeutic effects and mechanism of human amnion-derived mesenchymal stem cells on hypercoagulability in a uremic calciphylaxis patient.

Calciphylaxis is a rare cutaneous vascular disease that manifests with intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and microvessel thrombosis. Currently, there are no standardized guidelines for this disease. Recent studies have recognized a high prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategy with intravenous and local hAMSC application. In order to investigate the therapeutic mechanism of hAMSCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status, quality of life and skin biopsy were followed up. Polymerase chain reaction (PCR) was performed to determine the distribution of hAMSCs in multiple tissues including lung, kidney and muscle after infusion of hAMSCs for 24 h, 1 week and 1 month in mice aiming to investigate whether hAMSCs retain locally active roles after intravenous administration. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration over one-year period. Skin biopsy pathology suggested regenerative tissues after 1 month hAMSC application and full epidermal regeneration after 20 months hAMSC treatment. PCR analysis indicated that hAMSCs were homing in lung, kidney and muscle tissues of mice even until tail vein injection of hAMSCs for 1 month. We propose that hypercoagulability is a promising therapeutic target of calciphylaxis patients, which can be effectively improved by hAMSC treatment.

Comparative transcriptomic analysis of THP-1-derived macrophages infected with Mycobacterium tuberculosis H37Rv, H37Ra and BCG.

Tuberculosis (TB) remains a worldwide healthcare concern, and the exploration of the host-pathogen interaction is essential to develop therapeutic modalities and strategies to control Mycobacterium tuberculosis (M.tb). In this study, RNA sequencing (transcriptome sequencing) was employed to investigate the global transcriptome changes in the macrophages during the different strains of M.tb infection. THP-1 cells derived from macrophages were exposed to the virulent M.tb strain H37Rv (Rv) or the avirulent M.tb strain H37Ra (Ra), and the M.tb BCG vaccine strain was used as a control. The cDNA libraries were prepared from M.tb-infected macrophages and then sequenced. To assess the transcriptional differences between the expressed genes, the bioinformatics analysis was performed using a standard pipeline of quality control, reference mapping, differential expression analysis, protein-protein interaction (PPI) networks, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Q-PCR and Western blot assays were also performed to validate the data. Our findings indicated that, when compared to BCG or M.tb H37Ra infection, the transcriptome analysis identified 66 differentially expressed genes in the M.tb H37Rv-infected macrophages, out of which 36 genes were up-regulated, and 30 genes were down-regulated. The up-regulated genes were associated with immune response regulation, chemokine secretion, and leucocyte chemotaxis. In contrast, the down-regulated genes were associated with amino acid biosynthetic and energy metabolism, connective tissue development and extracellular matrix organization. The Q-PCR and Western blot assays confirmed increased expression of pro-inflammatory factors, altered energy metabolic processes, enhanced activation of pro-inflammatory signalling pathways and increased pyroptosis in H37Rv-infected macrophage. Overall, our RNA sequencing-based transcriptome study successfully identified a comprehensive, in-depth gene expression/regulation profile in M.tb-infected macrophages. The results demonstrated that virulent M.tb strain H37Rv infection triggers a more severe inflammatory immune response associated with increased tissue damage, which helps in understanding the host-pathogen interaction dynamics and pathogenesis features in different strains of M.tb infection.

Serum metabolomics analysis of mice that received repeated airway exposure to a water-soluble PM2.5 extract.

BACKGROUND: Air pollutant exposure negatively affects human health; however, the molecular mechanisms causing disease remain largely unclear. OBJECTIVES: To explore the effects of respiratory particulate matter (PM2.5) exposure on the serum metabolome and to identify biomarkers for risk assessment of PM2.5 exposure. METHODS: PM2.5 from Nanjing, China, was collected, and its water-soluble extract was subjected to component analysis. BALB/c mice received acute or prolonged exposure to insoluble PM2.5 particles or its water-soluble extract, and lung tissue was submitted to histopathological analyses. Serum samples were collected pre- and post-PM2.5 exposure and analyzed by liquid chromatography/mass spectrometry. RESULTS: Component analysis revealed that metals and inorganic ions were the most abundant components in the soluble PM2.5 samples. Acute exposure to insoluble PM2.5 particles and prolonged exposure to the water-soluble PM2.5 extract both induced severe lung injury, and the lung histopathological scores were significantly associated with PM2.5 exposure. Metabolomics analysis showed that prolonged exposure to the water-soluble PM2.5 extract was associated with statistically significant metabolite changes; the serum concentrations of 30 known metabolites, including metabolites of phospholipids, amino acids and sphingolipids, differed significantly between the control and PM2.5 exposure group. Pathway analysis identified an association of the tricarboxylic acid cycle (TCA) and the phospholipase metabolism pathway with PM2.5 exposure. The most influential metabolites for discriminating between the PM2.5-exposure group serum and the control serum were LysoPE, LysoPC, LGPC, citric acid, PAF C-18, NeuAcalpha2-3Galbeta-Cer, Lyso-PAF C-16, ganglioside GA2, 1-sn-glycero-3-phosphocholine, PC and L-tryptophan. CONCLUSIONS: Respiratory exposure to water-soluble PM2.5 extract has developmental consequences affecting not only the respiratory system but also metabolism.

Clinicopathological Characteristics and Outcome of Cytophagic Histiocytic Panniculitis: A Single-Center, Retrospective Study.

Background: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Purpose: To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge. Material and Methods: Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022. Results: All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal. Conclusion: The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.

Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, also may be present in hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma. The presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders and streptococcal infections. In addition, EBV-negative CHP has a better prognosis than previously thought and provides knowledge of its prognosis in the Chinese population. With changes in the disease pedigree supported by the development of medical technology, CHP may present as a reactive process of a combined primary disease.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-SIN1 association mediates ultraviolet B (UVB)-induced Akt Ser-473 phosphorylation and skin cell survival.

BACKGROUND: The exposure of skin keratinocytes to Ultraviolet (UV) irradiation leads to Akt phosphorylation at Ser-473, which is important for the carcinogenic effects of excessive sun exposure. The present study investigated the underlying mechanism of Akt Ser-473 phosphorylation by UVB radiation. RESULTS: We found that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and mammalian target of rapamycin (mTOR) complex 2 (mTORC2) were both required for UVB-induced Akt Ser-473 phosphorylation in keratinocytes. Inhibition of DNA-PKcs activity via its inhibitor NU7026, a dominant-negative kinase-dead mutation, RNA interference (RNAi) or gene depletion led to the attenuation of UVB-induced Akt Ser-473 phosphorylation. Meanwhile, siRNA silencing or gene depletion of SIN1, a key component of mTORC2, abolished Akt Ser-473 phosphorylation by UVB. Significantly, we discovered that DNA-PKcs was associated with SIN1 in cytosol upon UVB radiation, and this complexation appeared required for Akt Ser-473 phosphorylation. Meanwhile, this DNA-PKcs-SIN1 complexation by UVB was dependent on epidermal growth factor receptor (EGFR) activation, and was disrupted by an EGFR inhibitor (AG1478) or by EGFR depletion. UVB-induced complexation between DNA-PKcs and mTORC2 components was also abolished by NU7026 and DNA-PKcs mutation. Finally, we found that both DNA-PKcs and SIN1 were associated with apoptosis resistance of UVB radiation, and inhibition of them by NU7026 or genetic depletion significantly enhanced UVB-induced cell death and apoptosis. CONCLUSION: Taken together, these results strongly suggest that DNA-PKcs-mTORC2 association is required for UVB-induced Akt Ser-473 phosphorylation and cell survival, and might be important for tumor cell transformation.

[Epithelioid hemangioma: a clinicopathologic analysis of 7 cases].

OBJECTIVE: To study the clinicopathologic features, diagnosis and differential diagnosis of epithelioid hemangioma. METHODS: The morphologic features of 7 cases of epithelioid hemangioma of skin, bone and venous vessels were studied. RESULTS: There were altogether 4 male and 3 female patients (median age = 34 years; age range from 14 to 54 years). The 3 skin cases presented as single or multiple erythematous to bluish nodules or papules, with or without itchiness. The 2 bone cases appeared as osteolytic expansile lesions on radiologic examination. The remaining 2 cases involved medium-sized venous structures and presented as small isolated nodules in soft tissue. Histologically, the lesions were characterized by the presence of exuberant endothelial proliferations with various degree of inflammatory reaction. The neoplastic endothelial cells were plump, eosinophilic and polygonal, forming vascular channels. Occasional solid sheet-like arrangement was demonstrated. Intracytoplasmic vacuoles were commonly identified, indicating formation of primary lumen. The surrounding stroma contained various number of eosinophils and lymphoplasmacytic cells. Immunohistochemical study showed that the tumor cells were positive for endothelial markers (CD31 and CD34) and negative for epithelial marker (cytokeratin). Follow-up information was available in 6 cases. The duration of follow-up ranged from 5 to 36 months (median = 14 months). There was no evidence of recurrence or distant metastasis. CONCLUSIONS: Epithelioid hemangioma is a rare benign curable lesion which can be multifocal, involving skin, soft tissue and bone. It needs to be distinguished from Kimura's disease and epithelioid hemangioendothelioma.

A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome.

Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients' hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

Vitamin D attenuates DNCB-induced atopic dermatitis-like skin lesions by inhibiting immune response and restoring skin barrier function.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease causing erythema and itching. The etiology of AD is complex and not yet clear. Vitamin D is a fat-soluble vitamin that promotes skin cell growth and differentiation and regulates immune function. This study aimed to explore the therapeutic effect of calcifediol, the active metabolite of vitamin D, on experimental AD and the possible mechanism of action. We found that the levels of vitamin D binding protein (VDBP) and vitamin D receptor (VDR) in biopsy skin samples from AD patients decreased compared with controls. We used 2,4-dinitrochlorobenzene (DNCB) to induce an AD mouse model on the ear and back of BALB/c mice. A total of five groups were used: the control group, the AD group, the AD + calcifediol group, the AD + dexamethasone group, and the calcifediol alone group. Under calcifediol treatment, mice exhibited reduced spinous layer thickening, reduced inflammatory cell infiltration, downregulated aquaporin 3 (AQP3) expression, and restored the barrier function of the skin. Simultaneous calcifediol treatment decreased STAT3 phosphorylation, inhibited inflammation and chemokine release, decreased AKT1 and mTOR phosphorylation, and suppressed epidermal cell proliferation and abnormal differentiation. In conclusion, our study demonstrated that calcifediol significantly protected mice against DNCB-induced AD. In a mouse model of AD, calcifediol may reduce inflammatory cell infiltration and chemokines by inhibiting the phosphorylation of STAT3 and may restore skin barrier function through the downregulation of AQP3 protein expression and inhibition of cell proliferation.

Curcumin treatment suppresses cachexia-associated adipose wasting in mice by blocking the cAMP/PKA/CREB signaling pathway.

BACKGROUND: Cachexia is a multifactorial debilitating syndrome that is responsible for 22% of mortality among cancer patients, and there are no effective therapeutic agents available. Curcumin, a polyphenolic compound derived from the plant turmeric, has been shown to have anti-inflammatory, antioxidant, anti-autophagic, and antitumor activities. However, its function in cancer cachexia remains largely unexplored. PURPOSE: This study aimed to elucidate the mechanisms by which curcumin improves adipose atrophy in cancer cachexia. METHODS: C26 tumor-bearing BALB/c mice and ß3-adrenoceptor agonist CL316243 stimulated BALB/c mice were used to observe the therapeutic effects of curcumin on the lipid degradation of cancer cachexia in vivo. The effects of curcumin in vitro were examined using mature 3T3-L1 adipocytes treated with a conditioned medium of C26 tumor cells or CL316243. RESULTS: Mice with C26 tumors and cachexia were protected from weight loss and adipose atrophy by curcumin (50 mg/kg, i.g.). Curcumin significantly reduced serum levels of free fatty acids and increased triglyceride levels. In addition, curcumin significantly inhibited PKA and CREB activation in the adipose tissue of cancer cachectic mice. Curcumin also ameliorated CL316243-induced adipose atrophy and inhibited hormone-mediated PKA and CREB activation in mice. Moreover, the lipid droplet degradation induced by C26 tumor cell conditioned medium in mature 3T3-L1 adipocytes was ameliorated by curcumin (20 µM) treatment. Curcumin also improved the lipid droplet degradation of mature 3T3-L1 adipocytes induced by CL316243. CONCLUSION: Curcumin might be expected to be a therapeutic supplement for cancer cachexia patients, primarily through inhibiting adipose tissue loss via the cAMP/PKA/CREB signaling pathway.

Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling.

Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. Sulforaphane (SFN) has been shown to have anti-inflammatory and antioxidant properties. In this study, we investigated the effects of SFN on a mouse model of psoriasis induced by imiquimod (IMQ) and its underlying molecular mechanism. Mice treated with SFN showed significant improvement in psoriatic symptoms, including reduced erythema, scales, and cutaneous thickness. Histopathological analysis and immunohistochemical staining revealed decreased expression of K16, K17, and Ki67 in SFN-treated mice, indicating reduced abnormal differentiation of keratinocytes and cutaneous inflammation. SFN treatment also reduced the activation of STAT3 and NF-κB pathways and downregulated pro-inflammatory cytokines IL-1ß, IL-6, and CCL2. In vitro experiments using HaCaT cells demonstrated that SFN inhibited IL-22 and TNF-α-induced activation of inflammatory pathways and keratinocyte proliferation. Network pharmacology analysis suggested that the KEAP1-NRF2 pathway might be involved in the protective effects of SFN on psoriasis. We observed reduced NRF2 expression in human psoriatic lesions, and subsequent experiments showed that SFN activated KEAP1-NRF2 pathway in vivo and in vitro. Importantly, NRF2-deficient mice exhibited aggravated psoriasis-like symptoms and reduced response to SFN treatment. Our findings indicate that SFN ameliorates psoriasis symptoms and inflammation through the KEAP1-NRF2 pathway, suggesting a potential therapeutic role for SFN in the treatment of psoriasis.

Increasing ceramides sensitizes genistein-induced melanoma cell apoptosis and growth inhibition.

The aim of the current study is to investigate the effect of ceramides on genistein-induced anti-melanoma effects in vitro. We found that exogenously added cell-permeable short-chain ceramides (C6) dramatically enhanced genistein-induced growth inhibition and apoptosis in cultured melanoma cells. Genistein treatment only induced a moderate intracellular ceramides accumulation in B16 melanoma cells. Two different agents including 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a ceramide glucosylation inhibitor, and the sphingosine kinase-1 (SphK1) inhibitor II (SKI-II), a sphingosine (ceramides precursor) phosphorylation inhibitor, both facilitated genistein-induced ceramides accumulation and melanoma cell apoptosis. Co-administration of ceramide (C6) and genistein induced a significant Akt inhibition and c-jun-NH(2)-kinase (JNK) activation, caspase-3 cleavage and cytochrome c release. Caspase-3 inhibitor z-DVED-fmk, JNK inhibitor SP 600125, or to restore Akt activation by introducing a constitutively active form of Akt (CA-Akt) diminished ceramide (C6) and genistein co-administration-induced in vitro anti-melanoma effect. Our study suggests that increasing cellular level of ceramides may sensitize genistein-induced anti-melanoma effects.

2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle.

Cachexia is characterized by progressive weight loss accompanied by the loss of specific skeletal muscle and adipose tissue. Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic-lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid ß-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle.

Respiratory exposure to PM2.5 soluble extract induced chronic lung injury by disturbing the phagocytosis function of macrophage.

Exposure to airborne urban particles is a contributing factor for the development of multiple types of respiratory diseases; its pathological role as a cause of lung injury is still unclear. In this study, PM2.5 soluble extract was collected, and its toxicological effect on lung pathological changes was examined. To assess its pathological mechanism, Human Monocyte-Like Cell Line, THP-1, and mouse macrophage, RAW264.7, were used to determine the effects of PM2.5 soluble extract on cell toxicity, phagocytosis, and transcriptome. We found that PM2.5 soluble extract exposure activated NF-κB and MAPK signaling pathways, then induces the production of pro-inflammatory cytokines. RNA-seq results showed that the transcription profiles, including 1213 genes, have been changed in responses to PM2.5 exposure. Additionally, PM2.5 led to phagocytic dysfunction, which may exacerbate the cause of lung injury. Exposure to PM2.5 soluble extract triggers the death of respiratory macrophages, impairs its phagocytosis capacity, thus delaying the inflammatory cell clearance in the lung, which results in chronic lung injury.

Long-term exposure to PM2.5 aggravates pulmonary fibrosis and acute lung injury by disrupting Nrf2-mediated antioxidant function.

Epidemiological studies have indicated that exposure to ambient air-borne fine particulate matter (PM2.5) is associated with many cardiopulmonary diseases; however, the underlying pathological mechanisms of PM2.5-induced lung injury remain unknown. In this study, we aimed to assess the impact of acute or prolonged exposure to water-insoluble fractions of PM2.5 (PM2.5 particulate) on lung injury and its molecular mechanisms. Balb/c mice were randomly exposed to PM2.5 once (acute exposure) or once every three days for a total of 6 times (prolonged exposure). Lung, BALF and blood samples were collected, and pulmonary pathophysiological alterations were analyzed. Nrf2 knockout mice were adapted to assess the involvement of Nrf2 in lung injury, and transcriptomic analysis was performed to delineate the mechanisms. Through transcriptomic analysis and validation of Nrf2 knockout mice, we found that acute exposure to PM2.5 insoluble particulates induced neutrophil infiltration-mediated airway inflammation, whereas prolonged exposure to PM2.5 insoluble particulate triggered lung fibrosis by decreasing the transcriptional activity of Nrf2, which resulted in the downregulated expression of antioxidant-related genes. In response to secondary LPS exposure, prolonged PM2.5 exposure induced more severe lung injury, indicating that prolonged PM2.5 exposure induced Nrf2 inhibition weakened its antioxidative defense capacity against oxidative stress injury, leading to the formation of pulmonary fibrosis and increasing its susceptibility to secondary bacterial infection.

Alpha-7 nicotinic acetylcholine receptor agonist alleviates psoriasis-like inflammation through inhibition of the STAT3 and NF-κB signaling pathway.

Psoriasis is a chronic inflammatory cutaneous disease; it has been discovered that stimulation of the nervous system increases susceptibility to psoriasis. Although the cholinergic anti-inflammatory pathway, which is mediated by the alpha-7 nicotinic acetylcholine receptor (α7nAChR), is critical for controlling multiple types of inflammation, its expression pattern and pathogenesis function in psoriatic lesioned skin tissue are unknown. We hereby analyzed the expression of α7nAchR in human and mouse psoriatic skin tissue. In vivo, PNU-282987 or Methyllycaconitine, a specific agonist or antagonist of α7nAchR, were administered to imiquimod (IMQ)-induced psoriatic mouse models. The macroscopic appearance and histopathological features of the psoriatic mice skin were evaluated. In addition, cell proliferation and differentiation markers were investigated. The level of pro-inflammatory cytokines released from the lesioned skin, as well as the activation of the relevant signaling pathways, were measured. Our findings indicated that psoriatic lesional skin expressed an increased level of α7nAChR, with its tissue distribution being primarily in skin keratinocytes and macrophages. In an IMQ-induced murine psoriasis model, α7nAChR agonist PNU-282987 treatment alleviated psoriasis-like inflammation by down-regulating the expression of multiple types of pro-inflammatory mediators and normalized keratinocyte proliferation and differentiation, whereas α7nAChR antagonist treatment exacerbated its effect. Mechanically, we observed that activation of the α7nAChR inhibited the activation of the STAT3 and NF-κB signaling pathways in in vitro cultured HaCaT cells induced by Th17-related cytokine IL-6/IL-22 or Th1-related cytokine TNF-α. Taken together, these findings demonstrate that attenuation of psoriatic inflammation via the cholinergic anti-inflammatory pathway is dependent on α7nAChR activation.

A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.

Photodynamic therapy with acitretin for treatment of penile verrucous carcinoma.

Penile verrucous carcinoma exhibits a high potential for recurrence. Traditional treatment for penile verrucous carcinoma is radical surgery. Extensive resection generally leads to the loss of the patient's sexual function and limits the tolerance for additional additional surgical resection. Herein, we present a case of penile verrucous carcinoma, who achieved complete remission after 3 sessions of PDT and 6 months Acitretin. There was no recurrence at 12 months of follow-up. This case suggests that photodynamic therapy combined with acitretin is a treatment option for penile verrucous carcinoma.