Brown Adipocyte ADRB3 Mediates Cardioprotection via Suppressing Exosomal iNOS.

BACKGROUND: The ADRB3 (ß3-adrenergic receptors), which is predominantly expressed in brown adipose tissue (BAT), can activate BAT and improve metabolic health. Previous studies indicate that the endocrine function of BAT is associated with cardiac homeostasis and diseases. Here, we investigate the role of ADRB3 activation-mediated BAT function in cardiac remodeling. METHODS: BKO (brown adipocyte-specific ADRB3 knockout) and littermate control mice were subjected to Ang II (angiotensin II) for 28 days. Exosomes from ADRB3 antagonist SR59230A (SR-exo) or agonist mirabegron (MR-exo) treated brown adipocytes were intravenously injected to Ang II-infused mice. RESULTS: BKO markedly accelerated cardiac hypertrophy and fibrosis compared with control mice after Ang II infusion. In vitro, ADRB3 KO rather than control brown adipocytes aggravated expression of fibrotic genes in cardiac fibroblasts, and this difference was not detected after exosome inhibitor treatment. Consistently, BKO brown adipocyte-derived exosomes accelerated Ang II-induced cardiac fibroblast dysfunction compared with control exosomes. Furthermore, SR-exo significantly aggravated Ang II-induced cardiac remodeling, whereas MR-exo attenuated cardiac dysfunction. Mechanistically, ADRB3 KO or SR59230A treatment in brown adipocytes resulted an increase of iNOS (inducible nitric oxide synthase) in exosomes. Knockdown of iNOS in brown adipocytes reversed SR-exo-aggravated cardiac remodeling. CONCLUSIONS: Our data illustrated a new endocrine pattern of BAT in regulating cardiac remodeling, suggesting that activation of ADRB3 in brown adipocytes offers cardiac protection through suppressing exosomal iNOS.

The Role of Aryl Hydrocarbon Receptor in the Pathogenesis and Treatment of Psoriasis.

The pathogenesis of psoriasis is complex. Aryl hydrocarbon receptor (AhR) is a transcription factor that can be bound and activated by structurally diverse ligands and plays an important role in a range of biological processes and in the pathogenesis of different diseases. Recently, the role of AhR in psoriasis has attracted attention. AhR has toxicological functions and physiological functions. The overexpression and activation of AhR induced by the environmental pollutant and exogenous AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can drive the development of psoriasis. This TCDD-mediated toxicological response disrupts the physiological functions of AhR resulting in skin barrier disorders and the release of inflammatory cytokines, 2 of the pivotal factors of psoriasis. In addition, highly upregulated kynureninase in psoriasis decreases endogenous AhR agonists, thereby weakening the physiological functions of AhR. Activating AhR physiological signalling should be useful in the treatment of psoriasis. Studies have demonstrated that physiological activation of AhR can dampen the severity of psoriasis. The oldest and effective treatment for psoriasis coal tar works by activating AhR, and both new anti-psoriasis drugs tapinarof and benvitimod are formulations of AhR agonist, supporting that activation of AhR can be used as a new strategy for the treatment of psoriasis. Preclinical and preliminary clinical studies have revealed the anti-psoriasis effects of a number of AhR agonists, providing potential candidates for the development of new drugs for the treatment of psoriasis.

Factors associated with quality of life in Chinese people with psoriasis: a cross-sectional study.

BACKGROUND: The ultimate goal of medical care is to eradicate disease and restore normality to a person's life. Quality of life (QOL) is a concern as dermatologists and researchers strive to find better drug treatments. However, there have been few reports on the factors associated with QOL among Chinese people with psoriasis. METHODS: A total of 185 people with psoriasis were surveyed to assess their sociodemographic status, disease-related information, psychosocial status, and QOL. The questionnaires included a sociodemographic questionnaire, the Athens Insomnia Scale, the Hospital Anxiety and Depression Scale, the Perceived Social Support Scale, the Psychosocial Adaptation Questionnaire of Chronic Skin Disease and the Dermatology Life Quality Index. Multiple stepwise regression and path analysis were used to study the factors associated with QOL among Chinese people with psoriasis and to analyse the relationship between them. RESULTS: The results showed that the presence of anxiety/depression, lesion area, sleep disorders, psychosocial adaptation, and sex could jointly predict 62.1% of the variance in QOL among Chinese people with psoriasis. According to previous theories and the literature, a path model was established for five variables. Four internal variables could be effectively explained. The values of the explanatory variables were 62.1% (F(1056) = 61.020, p = 0.000) for QOL, 71.8% (F(2433) = 117.370, p = 0.000) for anxiety/depression, 44.0% (F(660) = 36.935, p = 0.000) for sleep disorders, and 66.9% (F(6886) = 93.556, p = 0.000) for psychosocial adaptation. The path analysis confirmed that 9 paths were consistent with the predicted path, and 3 paths were not confirmed. CONCLUSION: To improve QOL among Chinese people with psoriasis, attention should be given to the presence of anxiety/depression, lesion area, sleep disorders, psychosocial adaptation and sex differences. Therefore, health care programs for psoriasis should include physical, psychological and social aspects.

The possible role of Wnt/ß-catenin signalling in vitiligo treatment.

Vitiligo is a common chronic skin disease which has an adverse impact on patients' life. Its pathogenesis is complex, involving autoimmunity and oxidative stress (OS). Autoimmunity leads to the loss of epidermal melanocytes and the formation of the depigmented patches of the disease. Treatment of vitiligo should control the exaggerated immune response to arrest the progress of active disease, and then promote melanocytes to repigmentation. Wnt/ß-catenin signalling pathway has been of recent interest in vitiligo. Wnt/ß-catenin signalling pathway is downregulated in vitiligo. Upregulation of Wnt/ß-catenin signalling possibly control vitiligo autoimmune response by protecting melanocyte from OS damage, inhibiting CD8+ T cell effector cell differentiation and enhancing Treg. Wnt/ß-catenin signalling plays a critical role in the melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes. Promoting Wnt/ß-catenin signalling can not only arrest the progress of active disease of vitiligo but also promote repigmentation. Some of the main effective therapies for vitiligo are likely to work by activating Wnt/ß-catenin signalling. Agents that can enhance the effect of Wnt/ß-catenin signalling may become potential candidates for the development of new drugs for vitiligo treatment.

Peroxisome proliferator-activator receptor γ and psoriasis, molecular and cellular biochemistry.

The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results.

Nuclear factor erythroid 2-related factor 2 (Nrf2) as a potential therapeutic target for vitiligo.

Vitiligo is an autoimmune disease of the skin which causes loss of melanocytes from the epidermis. Recently, it is demonstrated that oxidative stress (OS) plays a significant role in the immuno-pathogenesis of vitiligo. A major mechanism in the cellular defense against OS is activation of the nuclear factor erythroid2-related factor (Nrf2)-Kelch-like ECH-associated protein 1(Keap1)-antioxidant responsive element (ARE) signaling pathway. Recently it has been shown that vitiligo melanocytes have impaired Nrf2-ARE signaling. A number of drugs including those known as Nrf2 activators and those known to possess effects to activate Nrf2, have been used in treating vitiligo with certain therapeutic effects. Also, studies have shown that a number of compounds can protect melanocytes against OS via activating Nrf2. These compounds may be considered as candidates for developing new drugs for vitiligo in the future. Nrf2 can be considered as a potential therapeutic target for vitiligo.

Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II-Induced Hypertension via Regulatory T Cells.

RATIONALE: Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear. OBJECTIVE: We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs). METHODS AND RESULTS: We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR-deficient (C3aR-/-), or C5aR-deficient (C5aR-/-) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals. CONCLUSIONS: C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.

Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells.

OBJECTIVE: Recent studies have shown that altered mitochondrial dynamics impairs the function in senescent endothelial cells (ECs). However, the underlying molecular mechanism remains to be elucidated. Herein, we investigated the role and underlying mechanism of mitochondrial fission protein dynamin-related protein 1 (DRP1) in vascular aging. APPROACH AND RESULTS: We found that DRP1 expression is decreased in senescent ECs, accompanied with long interconnected mitochondria and impaired angiogenic function. In addition, there was marked increase of autophagosomes but not of autolysosomes (assessed as punctate dual fluorescent mCherry-GFP (green fluorescent protein) tandem-tagged light chain 3 expression) in senescent ECs, indicating impaired autophagic flux. DRP1 knockdown or pharmacological inhibition in young ECs resulted in elongated mitochondria, suppressed autophagic flux, premature senescence, and impaired angiogenic function. In contrast, adenoviral-mediated overexpression of DRP1 in senescent ECs restored autophagic flux and improved angiogenic function. EC senescence was associated with the increase of mitochondrial reactive oxygen species and antioxidant N-acetyl-cysteine restored autophagosome clearance and improved angiogenic function. Consistently, en face staining of old rat thoracic aorta revealed a decrease of DRP1 expression and increase of autophagosomes accumulation. Furthermore, in vivo knockdown of Drp1 in common carotid arteries significantly impaired the autophagosome clearance. Importantly, downregulation of Drp1 directly abrogated microvessels outgrowth from ex vivo aortic rings. CONCLUSIONS: These results suggest that loss of DRP1 during senescence exacerbates ECs dysfunction by increasing mitochondrial reactive oxygen species and subsequently inhibiting autophagic flux.

Mitochondrial division inhibitor Mdivi-1 ameliorates angiotensin II-induced endothelial dysfunction.

Mitochondrial fission can occur via activation of dynamin-related protein 1 (Drp1), which participates in the mitochondrial membrane scission process. The present study was designed to investigate the effect of angiotensin II (AngII) on mitochondrial fission and fusion in human umbilical vascular endothelial cells (HUVECs). And we further inquire into whether Mdivi-1, a newly identified pharmacological inhibitor of Drp1, can prevent endothelial dysfunction induced by AngII. The HUVECs were treated with AngII alone or in combination with Mdivi-1. Western blot was used to detect protein expressions of Drp1, endothelial nitric oxide synthase (eNOS) and apoptosis-related enzymes. MitoTracker Red and JC-1 dye were used to detect mitochondrial morphology and membrane potential, respectively. DCFH-DA probe was used to access intracellular reactive oxygen species (ROS) generation. Transwell assay was used to evaluate cell migration. Annexin V/PI staining was used to assess cellular apoptosis. The results showed that, in cultured HUVECs, AngII (1 × 10-7 mol/L, 12 h) treatment significantly upregulated the expression of Drp1 followed by increased apoptosis and decreased eNOS expression. The treatment of AngII resulted in a change in mitochondrial morphology from elongated to uniformly punctate organelles, which was accompanied by decreased mitochondrial membrane potential. Furthermore, Mdivi-1 significantly protected against AngII-induced endothelial dysfunction, as shown by increased mitochondrial membrane potential and eNOS expression, reduced ROS level, decreased apoptosis and migration ability. Taking together, our data suggest that inhibition of Drp1 with Mdivi-1 can restore AngII-induced endothelial dysfunction.

KLF4 suppresses anticancer effects of brusatol via transcriptional upregulating NCK2 expression in melanoma.

Brusatol (Bru), a main extract from traditional Chinese medicine Brucea javanica, has been reported to exist antitumor effect in many tumors including melanoma. However, the underlying mechanism in its anti-melanoma effect still need further exploration. Here, we reported that the protein expression of KLF4 in melanoma cells were significantly downregulated in response to brusatol treatment. Overexpression of KLF4 suppressed brusatol-induced melanoma cell apoptosis; while knockdown of KLF4 enhanced antitumor effects of brusatol on melanoma cells not only in vitro but also in vivo. Further studies on the mechanism revealed that KLF4 bound to the promoter of NCK2 directly and facilitated NCK2 transcription, which suppressed the antitumor effect of brusatol on melanoma. Furthermore, our findings showed that miR-150-3p was dramatically upregulated under brusatol treatment which resulted in the downregulation of KLF4. Our results suggested that the miR-150-3p/KLF4/NCK2 axis might play an important role in the antitumour effects of brusatol in melanoma.

Dermoscopy-based Radiomics Help Distinguish Basal Cell Carcinoma and Actinic Keratosis: A Large-scale Real-world Study Based on a 207-combination Machine Learning Computational Framework.

This study has used machine learning algorithms to develop a predictive model for differentiating between dermoscopic images of basal cell carcinoma (BCC) and actinic keratosis (AK). We compiled a total of 904 dermoscopic images from two sources - the public dataset (HAM10000) and our proprietary dataset from the First Affiliated Hospital of Dalian Medical University (DAYISET 1) - and subsequently categorised these images into four distinct cohorts. The study developed a deep learning model for quantitative analysis of image features and integrated 15 machine learning algorithms, generating 207 algorithmic combinations through random combinations and cross-validation. The final predictive model, formed by integrating XGBoost with Lasso regression, exhibited effective performance in the differential diagnosis of BCC and AK. The model demonstrated high sensitivity in the training set and maintained stable performance in three validation sets. The area under the curve (AUC) value reached 1.000 in the training set and an average of 0.695 in the validation sets. The study concludes that the constructed discriminative diagnostic model based on machine learning algorithms has excellent predictive capabilities that could enhance clinical decision-making efficiency, reduce unnecessary biopsies, and provide valuable guidance for further treatment.

Activation of ß3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue.

AIMS: ß3-AR (ß3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate ß3-AR activation-mediated PVAT function in AD/AA. METHODS AND RESULTS: Aortas from patients with thoracic aortic dissection (TAD) were collected to detect ß3-AR expression in PVAT. ApoE-/- and ß-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a ß3-AR agonist. The results demonstrated an up-regulation of ß3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of ß3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. CONCLUSIONS: Our findings illustrated the therapeutic potential of ß3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.

[Retrospective study of complication of interspinous implants for degenerative lumbar disease].

OBJECTIVE: To summarize and analyze the complications of interspinous implants for degenerative lumbar disease. METHODS: From September 2007 to September 2011, 177 cases with degenerative lumbar diseases were treated with interspinous implants. There were 99 male patients and 78 female patients, the average age was 44.5 years (26 - 71 years). According to the application interspinous dynamic stabilization system type were divided into the Wallis group (136 cases) and Coflex group (41 cases). The clinical results were assessed by visual analog scale (VAS) of pain on lumbar and lower limbers, lumbar Japanese Orthopedic Association (JOA) score and Prolo functional score. The radiological results including segmental lodosis and segement movement degree were assessed by lumbar X ray and dynamic X ray. Summarize and analyze the complications both during operation and post operation. Quantitative datas were compared by paried-samples t test and complication rate was compared by χ(2) test. RESULTS: There were 168 cases had completed follow-up and the average time was 34.7 months (3 - 50 months). In the final follow-up, lumbar pain VAS, lower limber pain VAS, lumbar JOA score and Prolo functional score were better than pre-operation (t = 10.7, 7.9, 13.4 and 8.8, P < 0.01). Segment lodosis angles was 14° ± 4° which was less than pre-operation 19° ± 4° (t = 9.4, P < 0.01).Segment movement degree was larger in Coflex group (12.6° ± 3.1°) than in Wallis group (9.7° ± 2.7°) (t = 8.6, P < 0.05). Complication rate was 10.7% (18/168), which of Wallis group was 6.2% (8/130) and Coflex group was 26.3% (10/38) (χ(2) = 12.5, P < 0.01). In Wallis group, there were 3 cases with dura tear and cerebrospinal fluid leakage, 1 case with nerve root injury and foot drop, 2 cases with spacer breakage when implantation and change the implants and 2 cases with recurrence of lumbar disc herniation. In Coflex group, there was 1 case with dura tear and cerebrospinal fluid leakage, 2 cases with mild displacement post operation, 1 case with debridement for aseptic wound exudates, 1 case with implant removal for breakage 1 week post operation, 4 cases with recurrence of lumbar disc herniation and 1 case with lumbar disc herniation 6 months post operation of lumbar stenosis. CONCLUSIONS: The application of interspinous implants for degenerative lumbar diseases is effective and relative safe, but would suffer from the risk of complications.

Two Cases of Treatment of Moderate to Severe Acne with an Acupuncture-Debridement Microsurgical Technique and Review of the Literature.

Acne is a chronic inflammatory disease of pilosebaceous glands. Microsurgical acupuncture and debridement technique is one of the most precise and effective external treatment for acne. We introduce successful treatment of two cases of moderate to severe acne with this technique and describe the characteristics and mechanism of the technique in detail. We innovatively put forward a series of technical schemes including minimally invasive debridement, key points in operation and combined medication in the microsurgical therapeutic technique of acupuncture and debridement. It provides a practical reference for the simple and effective therapeutic technique to be applied to the clinical treatment of acne.

Non-pharmacological interventions for patients with psoriasis: a scoping review.

OBJECTIVES: Healthcare ultimately aims to eradicate diseases and restore normality to people's lives. However, until this is achieved for every person, there is a need to support and assist patients with psoriasis using non-pharmacological interventions. These 'adjuvant' approaches have received little attention, whereas dermatologists and researchers strive for better pharmacological therapy. Here, we aimed to perform a scoping review to identify and catalogue non-pharmacological interventions for patients with psoriasis. DESIGN: A scoping review. SETTING: All healthcare settings. SEARCH STRATEGY: EMBASE, PubMed, CINAHL, PsycINFO and Scopus databases were searched from their inception to June 2022. Irrespective of the study type, the studies included non-pharmacological interventions for patients with psoriasis. This theme was extracted from the included articles. Two reviewers independently screened and analysed the data. RESULTS: From 1322 initial records, 71 studies were identified and analysed. Non-pharmacological interventions for patients with psoriasis include two levels: organisational and individual. The organisational non-pharmacological interventions included the nationwide healthcare model (PsPSP, ProvenCare, German PsoHealth and Psoriasis Network, IMPROVE model and PsoWell clinic), innovative teledermatology models (mHealth app, electronic Targeted Intervention for Psoriasis study and therapist-guided internet-based cognitive and behavioural treatments) and multidisciplinary interventions. The individual non-pharmacological interventions included educational interventions (therapeutic patient education, psychoeducational intervention and self-management education), psychosocial interventions (cognitive and behavioural treatments, self-help and peer-to-peer support programmes) and others (happify and motivational interviewing-based training). CONCLUSIONS: Based on previous literature, a nationwide healthcare model protocol was constructed for patients with psoriasis. This provided the direction for developing a new psoriasis healthcare model and a basis for summarising the non-pharmacological interventions for patients with psoriasis, which helps them adjust to changes in the skin disease.

Molecular characteristics and therapeutic implications of Toll-like receptor signaling pathway in melanoma.

Melanoma is a malignant tumor of melanocytes and is often considered immunogenic cancer. Toll-like receptor-related genes are expressed differently in most types of cancer, depending on the immune microenvironment inside cancer, and the key function of Toll-like receptors (TLRs) for melanoma has not been fully elucidated. Based on multi-omics data from TCGA and GEO databases, we first performed pan-cancer analysis on TLR, including CNV, SNV, and mRNA changes in TLR-related genes in multiple human cancers, as well as patient prognosis characterization. Then, we divided melanoma patients into three subgroups (clusters 1, 2, and 3) according to the expression of the TLR pathway, and explored the correlation between TLR pathway and melanoma prognosis, immune infiltration, metabolic reprogramming, and oncogene expression characteristics. Finally, through univariate Cox regression analysis and LASSO algorithm, we selected six TLR-related genes to construct a survival prognostic model, divided melanoma patients into the training set, internal validation set 1, internal validation set 2, and external validation set for multiple validations, and discussed the correlation between model genes and clinical features of melanoma patients. In conclusion, we constructed a prognostic survival model based on TLR-related genes that precisely and independently demonstrated the potential to assess the prognosis and immune traits of melanoma patients, which is critical for patients' survival.

HOXB9 a miR-122-5p regulated gene, suppressed the anticancer effects of brusatol by upregulating SCD1 expression in melanoma.

Brusatol (Bru), a Chinese medicine Brucea javanica extract, has a variety of antitumour effects. However, its role and underlying mechanism in melanoma have not been fully elucidated. In this study, we found that brusatol inhibited melanoma cell proliferation and migration and promoted cell apoptosis in vitro, in addition to suppressing melanoma cell tumorigenesis in vivo. Further studies on the mechanism revealed that brusatol significantly downregulated the expression of stearoyl-CoA desaturase 1 (SCD1). Increased SCD1 expression could impair the antitumour effects of brusatol on melanoma cells. Subsequently, we found that HOXB9, an important transcription factor, was directly bound to the promoter of SCD1, facilitating its transcription. Overexpression of HOXB9 inhibited brusatol-induced SCD1 reduction and promoted cell survival. Furthermore, our results revealed that miR-122-5p was significantly increased in response to brusatol treatment and led to a decrease in HOXB9 in melanoma. Collectively, our data suggested that the miR-122-5p/HOXB9/SCD1 axis might play an important role in the antitumour effects of brusatol and that brusatol might have potential clinical implications in melanoma therapy.

Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.

Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.

Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy vs. Chemotherapy Alone as First-Line Treatment in Patients With Esophageal Squamous Cell Carcinoma and PD-L1 CPS of 10 or More.

Background: This study aimed to analyze the economics of pembrolizumab plus chemotherapy as first-line treatment in patients with esophageal squamous cell carcinoma (ESCC) and programmed cell death-Ligand 1 (PD-L1) combined positive score (CPS) of 10 or more in China. Methods: Based on the advanced ESCC of the KEYNOTE-590 clinical trial data, a Markov model was performed to simulate the clinical course and evaluate the patient's total lifetime, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) for pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil) vs. chemotherapy alone in first-line treatment of ESCC and PD-L1 CPS of 10 or more. Utility values and direct costs related to the treatments were gathered from the published literature data. One-way and probabilistic sensitivity analyses were conducted to check the stability of the model. Results: The baseline analysis indicated that the incremental effectiveness and cost of pembrolizumab plus chemotherapy vs. chemotherapy alone added 1.23 QALYs and resulted in an incremental cost of $51,320.22, which had an ICER of $41,805.12/QALY, higher than the willingness-to-pay (WTP) threshold of China ($37,663.26/QALY). The sensitivity analysis demonstrated that the ICERs were most sensitive to the cycle of pembrolizumab used and the cost of pembrolizumab. Conclusion: The result of our present analysis suggests that the addition of pembrolizumab plus chemotherapy as first-line treatment might not be cost-effective for patients with ESCC and PD-L1 CPS of 10 or more in China.

Identifying Molecular Subtypes and 6-Gene Prognostic Signature Based on Hypoxia for Optimizing Targeted Therapies in Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) accounts for a great number of all lung cancer cases. Hypoxia, one of the hallmarks in solid cancer, is closely involved in cancer cell progression and migration. This study aimed to develop a molecular subtyping system based on hypoxia-related genes and construct a prognostic model for NSCLC patients. Methods: Unsupervised consensus clustering was used to classify molecular subtypes. Mutation and immune analyses were conducted to compare differences among the molecular subtypes. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) analysis, and step Akaike information criterion (stepAIC) were performed to screen prognostic genes. Results: Two molecular subtypes (C1 and C2) were identified based on hypoxia-related genes and showed significant differences in survival, enriched pathways, tumor microenvironment (TME), and sensitivity to immunotherapy and chemotherapy. Interestingly, C1 subtype had better survival and response to targeted therapies. Oncogenic pathways, such as hypoxia, epithelial mesenchymal transition (EMT), NOTCH signaling, and p53 signaling pathways were more enriched in C2 subtype. A 6-gene prognostic model with robust ability was developed to classify NSCLC patients into high-risk and low-risk groups. Conclusion: The novel molecular subtypes could assist personalized therapies to select suitable patients. The six prognostic genes may be novel targets for further understanding mechanisms of NSCLC development associated with hypoxia and exploiting novel targeted therapies.