Salidroside induces mitochondrial dysfunction and ferroptosis to inhibit melanoma progression through reactive oxygen species production.

Reactive oxygen species (ROS) induces necroptotic and ferroptosis in melanoma cells. Salidroside (SAL) regulates ROS in normal cells and inhibits melanoma cell proliferation. This study used human malignant melanoma cells treated with SAL either alone or in combination with ROS scavenger (NAC) or ferroptosis inducer (Erastin). Through cell viability, wound healing assays, and a Seahorse analyze found that SAL inhibited cell proliferation, migration, extracellular acidification rate, and oxygen consumption rate. Metabolic flux analysis, complexes I, II, III, and IV activity of the mitochondrial respiratory chain assays, mitochondrial membrane potential assay, mitochondrial ROS, and transmission electron microscope revealed that SAL induced mitochondrial dysfunction and ultrastructural damage. Assessment of malondialdehyde, lipid ROS, iron content measurement, and Western blot analysis showed that SAL activated lipid peroxidation and promoted ferroptosis in A-375 cells. These effects were abolished after NAC treatment. Additionally, SAL and Erastin both inhibited cell proliferation and promoted cell death; SAL increased the Erastin sensitivity of cells while NAC antagonized it. In xenograft mice, SAL inhibited melanoma growth and promoted ROS-dependent ferroptosis. SAL induced mitochondrial dysfunction and ferroptosis to block melanoma progression through ROS production, which offers a scientific foundation for conducting SAL pharmacological research in the management of melanoma.

Progressive Facial Ulcer: A Case Report of Pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by rapidly developing and painful skin ulcers with distinctive features. As far as we are concerned, there is no previous case report on facial PG in East-Asia. In this case, we describe a case of a 79-year-old man with a 3-month history of progressive painful ulcers on his cheek and upper lip. Initial suspicion of atypical mycobacterium infection led to an ineffective treatment regimen. Comprehensive infectious testing yielded negative results, and a positive pathergy test indicated a potential diagnosis of PG. A skin biopsy confirmed the diagnosis, and the patient showed significant improvement with intravenous methylprednisolone and oral cyclosporine treatment. After three months, complete resolution of the lesions was achieved without recurrence. The case highlights the diagnostic challenges associated with PG, which is often misdiagnosed due to its resemblance to other conditions. Thorough evaluation is crucial to exclude alternative diagnoses, particularly cutaneous infections. Clinical morphology, tissue biopsy, and culture are essential for accurate diagnosis. The presence of pathergy, the development of new lesions following minor trauma, can also be a diagnostic clue.

Orthogonal threading-through-ß-sheet design of lung cancer EGFR extracellular domain-derived peptidic mimotopes binding to anti-EGFR antibody.

Human epidermal growth factor receptor (EGFR) has been established as a therapeutic target of lung cancer and other diverse tumors. The antibody drug Cetuximab has been developed to target the third subdomain III (TSDIII) of EGFR extracellular domain (ECD) by competitively inhibiting epidermal growth factor binding. In this study, we performed systematic investigation on the crystal complex structure of EGFR ECD domain with Cetuximab to create a residue importance profile for the TSDIII subdomain, based on which a number of U-shaped, double-stranded linear peptides were derived and cyclized to orthogonally thread through most hotspot residues and many responsible residues within the TSDIII ß-sheet plane; they represent mimotopes of the key antibody-recognition site of TSDIII subdomain. Computational analyses revealed that these linear peptides cannot spontaneously fold to the desired conformation in free state due to their intrinsic flexibility. Cell-free assays confirmed that the stapling can considerably improve the binding affinity of linear peptides to Cetuximab by up to 18-fold. The cOrt1 [3-18] cyclic peptide was measured to have the highest affinity in all designed linear and cyclic peptides.

Multi-spectral radiation thermometry based on an Alpha spectrum-LM algorithm under the background of high temperature and intense reflection.

In order to meet the needs of multi-spectral radiation temperature measurement under high temperature background, this paper studies the problems of reflected radiation interference and spectral emissivity difficult to obtain in high temperature and intense reflection environment. First, using discrete triangular surface elements and radiation angle coefficients, an analysis model of high temperature background reflected radiation is constructed to describe the variation characteristics of high temperature background reflected radiation. Secondly, the least squares support vector machine (LSSVM) is optimized by particle swarm optimization (PSO) algorithm, and an emissivity model identification algorithm based on Alpha spectrum-Levenberg Marquarelt (LM) algorithm is proposed, which has stronger applicability and accuracy than existing emissivity model identification methods. Finally, the high temperature background radiation and the emissivity model are combined to construct and solve the multi-spectral target equation, so as to realize the reflected radiation error correction and radiation temperature measurement under the high temperature and intense reflection background. The simulation and experimental comparison with the existing methods show that the temperature measurement error of the radiation temperature measurement method proposed in this paper is below 9.5K, which can effectively correct the reflected radiation error and further improve the temperature measurement accuracy.

The renaissance of human skin organ culture: A critical reappraisal.

Human skin organ culture (hSOC) is a simple but highly instructive and clinically relevant skin research method. It has been used for decades to study the development, differentiation, and function as well as the response to wounding or test agents of intact human skin in the presence of its appendages and all resident cell populations. hSOC has also proven useful in toxicological and oncological studies and studies of skin aging (both chronological aging and photoaging), skin energy metabolism, skin immunology, pigmentation biology, and cutaneous (neuro-)endocrinology and neurobiology. The pathobiology and treatment of various dermatoses can also be assessed ex vivo by organ-culturing intact lesional human skin. In addition to morphological analyses by routine histochemistry, quantitative (immuno)histomorphometry has proven to be an excellent tool for quantitating and localizing protein expression patterns in defined skin compartments and distinct cell populations using a relatively small amount of precious human tissue. Finally, more recent technological advances, such as siRNA-mediated gene silencing and sensory reinnervation of hSOCs, have further extended the range of methodological applications for the ex vivo study of human skin; it has emerged as the ultimate preclinical assay system for investigative dermatology, including the testing of drugs, cosmeceuticals and nutraceuticals and more, and is just one step below human skin xenotransplant in vivo mouse models and clinical trials. Here, we critically review the renaissance and variety of hSOC assays, their applications and limitations, and we critically compare them with 3D skin "equivalent" assays. The review closes with perspectives on how this ancient but highly informative and physiologically relevant ex vivo skin research method may be further developed in the future.

The Preciseness in Diagnosing Thyroid Malignant Nodules Using Shear-Wave Elastography.

Our study aimed to identify more accurate results about the diagnostic role of shear-wave elastography (SWE) for thyroid malignant nodules through a meta-analysis. Potential articles were searched in PubMed, Embase, and the Cochrane Library databases. Overall sensitivity and specificity with 95% confidence intervals (CIs) was used to represent the diagnostic accuracy of SWE. Summary receiver operating characteristic (ROC) curve was constructed to illustrate the results. In addition, χ² and I² tests were performed to assess heterogeneity. A value of p≤0.05 indicated significant heterogeneity. All the analysis was conducted in Meta-DiSc version 1.4 software. Twenty studies were included in the analysis. There were a total of 2,907 patients and 3,397 thyroid nodules included in the meta-analysis. Overall sensitivity and specificity were 0.68 (95% CI: 0.66-0.70) and 0.85 (95% CI: 0.84-0.87), respectively. The results showed the area under curve (AUC) was 0.9041, suggesting high accuracy of SWE for differentiating benign and malignant thyroid nodules. SWE showed high accuracy in identifying thyroid malignant nodules, suggesting it could serve as a diagnostic biomarker in thyroid nodules.

TLR4/ROS/miRNA-21 pathway underlies lipopolysaccharide instructed primary tumor outgrowth in lung cancer patients.

Activation of Toll-like receptor 4 (TLR4) signaling in human lung cancer with lipopolysaccharide (LPS) enhances tumor progression. However, whether primary human lung cancer outgrowth could respond to LPS and underlying mechanisms are unclear. Here we determined that TLR4 activation with LPS promoted outgrowth of primary human lung cancer cells in vitro and in vivo. Mechanistically, LPS stimulation increased expression levels of microRNA-21 (miR-21) in primary human lung cancer cells. Inhibition of miR-21 blocked the enhanced lung cancer growth induced by LPS in vitro and in vivo. Up-regulation of miR-21 promoted outgrowth of primary human lung cancer. Down-regulation of miR-21 limited primary human lung cancer outgrowth. Further, TLR4 activation in primary human lung cancer cells increased their ROS levels. Scavenge of ROS abrogated the up-regulation of miR-21 in primary human lung cancer cells and attenuated LPS-induced outgrowth. For in vivo relevance, expression of TLR4 was correlated with miR-21 expression and ROS production in freshly isolated, untreated primary human lung cancer cells. These findings demonstrate an essential role of TLR4/ROS/miR-21 pathway in LPS-induced outgrowth of primary human lung cancer. Our study connected a framework of innate signaling, oxidative stress and microRNA in tumor immunity and provided clues for developing new therapeutics for lung cancer.

Tripartite motif-containing 29 as a novel biomarker in non-small cell lung cancer.

Tripartite motif-containing 29 (TRIM29) is a member of the tripartite motif (TRIM) protein family. TRIM29 has been reported to be deregulated in a number of cancer types, suggesting the oncogenic function of TRIM29. However, its clinical significance in non-small cell lung cancer (NSCLC) has not been fully elucidated. In the present study, the TRIM29 expression status was investigated by immunohistochemical analysis in paraffin-embedded specimens obtained from 320 patients with surgically resected NSCLC, treated between 2000 and 2007. High TRIM29 expression was significantly associated with smoking (P=0.012), T stage (P=0.015) and M stage (P=0.003). Furthermore, elevated TRIM29 expression level was correlated with reduced overall (OS) and disease-free survival. In addition, high TRIM29 expression was an independent prognostic factor for OS [P=0.003, hazard ratio (HR)=2.102, 95% confidence interval (CI), 1.069-3.193]. In conclusion, these results suggest that TRIM29 may be a useful prognostic marker in NSCLC patients and a potential molecular target for NSCLC treatment.

Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells.

Recently, salidroside (p-hydroxyphenethyl-beta-d-glucoside) has been identified as one of the most potent compounds isolated from plants of the Rhodiola genus used widely in traditional Chinese medicine, but pharmacokinetic data on the compound are unavailable. We were the first to report the cytotoxic effects of salidroside on cancer cell lines derived from different tissues, and we found that human breast cancer MDA-MB-231 cells (estrogen receptor negative) were sensitive to the inhibitory action of low-concentration salidroside. To further investigate the cytotoxic effects of salidroside on breast cancer cells and reveal possible ER-related differences in response to salidroside, we used MDA-MB-231 cells and MCF-7 cells (estrogen receptor-positive) as models to study possible molecular mechanisms; we evaluated the effects of salidroside on cell growth characteristics, such as proliferation, cell cycle duration, and apoptosis, and on the expression of apoptosis-related molecules. Our results demonstrated for the first time that salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells and may be a promising candidate for breast cancer treatment.

A preliminary study: the anti-proliferation effect of salidroside on different human cancer cell lines.

Salidroside (p-hydroxyphenethyl-beta-d-glucoside), which is present in all species of the genus Rhodiola, has been reported to have a broad spectrum of pharmacological properties. The present study, for the first time, focused on evaluating the effects of the purified salidroside on the proliferation of various human cancer cell lines derived from different tissues, and further investigating its possible molecular mechanisms. Cell viability assay and [(3)H] thymidine incorporation were used to evaluate the cytotoxic effects of salidroside on cancer cell lines, and flow cytometry analyzed the change of cell cycle distribution induced by salidroside. Western immunoblotting further studied the expression changes of cyclins (cyclin D1 and cyclin B1), cyclin-dependent kinases (CDK4 and Cdc2), and cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1)). The results showed that salidroside inhibited the growth of various human cancer cell lines in concentration- and time-dependent manners, and the sensitivity to salidroside was different in those cancer cell lines. Salidroside could cause G1-phase or G2-phase arrest in different cancer cell lines, meanwhile, salidroside resulted in a decrease of CDK4, cyclin D1, cyclin B1 and Cdc2, and upregulated the levels of p27(Kip1) and p21(Cip1). Taken together, salidroside could inhibit the growth of cancer cells by modulating CDK4-cyclin D1 pathway for G1-phase arrest and/or modulating the Cdc2-cyclin B1 pathway for G2-phase arrest.