Mitogen-Activated Protein Kinase Inhibitor-Induced Inflammatory Alopecia in Woman With Ovarian Cancer.

Inflammatory alopecia is an increasingly reported side effect of targeted cancer therapies. Here we report one case of inflammatory alopecia secondary to mitogen-activated protein kinase kinase (MEK) inhibitor agent Trametinib in a woman with ovarian cancer. Biopsies of the scalp were consistent with early scarring alopecia compatible with drug-induced alopecia. Significant improvement in hair loss occurred after treatment with intralesional Kenalog (ILK) injections and oral isotretinoin. Though acute alopecia has been described in patients using MEK inhibitors, this is the first reported case of inflammatory alopecia.  J Drugs Dermatol. 2024;23(4):7802.     doi:10.36849/JDD.7802e  .

Mesenchymal stem cells alleviate sepsis-induced acute lung injury by blocking neutrophil extracellular traps formation and inhibiting ferroptosis in rats.

Acute lung injury (ALI) is one of the most serious complications of sepsis, characterized by high morbidity and mortality rates. Ferroptosis has recently been reported to play an essential role in sepsis-induced ALI. Excessive neutrophil extracellular traps (NETs) formation induces exacerbated inflammation and is crucial to the development of ALI. In this study, we explored the effects of ferroptosis and NETs and observed the therapeutic function of mesenchymal stem cells (MSCs) on sepsis-induced ALI. First, we produced a cecal ligation and puncture (CLP) model of sepsis in rats. Ferrostain-1 and DNase-1 were used to inhibit ferroptosis and NETs formation separately, to confirm their effects on sepsis-induced ALI. Next, U0126 was applied to suppress the MEK/ERK signaling pathway, which is considered to be vital to NETs formation. Finally, the therapeutic effect of MSCs was observed on CLP models. The results demonstrated that both ferrostain-1 and DNase-1 application could improve sepsis-induced ALI. DNase-1 inhibited ferroptosis significantly in lung tissues, showing that ferroptosis could be regulated by NETs formation. With the inhibition of the MEK/ERK signaling pathway by U0126, NETs formation and ferroptosis in lung tissues were both reduced, and sepsis-induced ALI was improved. MSCs also had a similar protective effect against sepsis-induced ALI, not only inhibiting MEK/ERK signaling pathway-mediated NETs formation, but also alleviating ferroptosis in lung tissues. We concluded that MSCs could protect against sepsis-induced ALI by suppressing NETs formation and ferroptosis in lung tissues. In this study, we found that NETs formation and ferroptosis were both potential therapeutic targets for the treatment of sepsis-induced ALI, and provided new evidence supporting the clinical application of MSCs in sepsis-induced ALI treatment.

[Leptin-mediated ERK Signaling Pathway Promotes the Transformation 
of Rat Alveolar Type II Epithelial Cells Induced by Yunnan Tin Mine Dust].

BACKGROUND: Currently, a significant number of miners are involved in mining operations at the Gejiu tin mine in Yunnan. This occupational setting is associated with exposure to dust particles, heavy metals, polycyclic aromatic hydrocarbons, and radioactive radon, thereby significantly elevating the risk of lung cancer. This study aims to investigate the involvement of leptin-mediated extracellular regulated protein kinase (ERK) signaling pathway in the malignant transformation of rat alveolar type II epithelial cells induced by Yunnan tin mine dust. METHODS: Immortalized rat alveolar cells type II (RLE-6TN) cells were infected with Yunnan tin mine dust at a concentration of 200 µg/mL for nine consecutive generations to establish the infected cell model, which was named R200 cells. The cells were cultured normally, named as R cells. The expression of leptin receptor in both cell groups was detected using the Western blot method. The optimal concentration of leptin and mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) on R200 cells was determined using the MTT method. Starting from the 20th generation, the cells in the R group were co-cultured with leptin, while the cells in the R200 group were co-cultured with the MEK inhibitor U0126. The morphological alterations of the cells in each group were visualized utilizing hematoxylin-eosin staining. Additionally, concanavalin A (ConA) was utilized to detect any morphological differences, and an anchorage-independent growth assay was conducted to assess the malignant transformation of the cells. The changes in the ERK signaling pathway in epithelial cells after the action of leptin were detected using the Western blot method. RESULTS: Both the cells in the R group and R200 group express leptin receptor OB-R. Compared to the R200 group, the concentration of leptin at 100 ng/mL shows the most significant pro-proliferation effect. The proliferation of R200 cells infected with the virus is inhibited by 30 µmol/L U0126, and a statistically significant divergence was seen when compared to the control group (P<0.05). Starting from the 25th generation, the cell morphology of the leptin-induced R200 group (R200L group) underwent changes, leading to malignant transformation observed at the 30th generation. The characteristics of malignant transformation became evident by the 40th generation in the R200L group. In contrast, the other groups showed agglutination of P40 cells, and the speed of cell aggregation increased with an increase in ConA concentration. Notably, the R200L group exhibited faster cell aggregation compared to the U0126-induced R200 (R200LU) group. Additionally, the cells in the R200L group were capable of forming clones starting from P30, with a colony formation rate of 2.25‰±0.5‰. However, no clonal colonies were observed in the R200LU group and R200 group. The expression of phosphorylated extracellular signal-regulated kinase (pERK) was enhanced in cells of the R200L group. However, when the cells in the R200L group were treated with U0126, a blocking agent, the phosphorylation level of pERK decreased. CONCLUSIONS: Leptin can promote the malignant transformation of lung epithelial cells infected by mine dust, and the ERK signaling pathway may be necessary for the transformation of alveolar type II epithelial cells induced by Yunnan tin mine dust.

MEK inhibitor-induced paronychia in a paediatric population: A tertiary centre experience.

The cutaneous toxicity of MEK inhibitors may limit treatment adherence. The authors present a retrospective study of 41 paediatric patients with NF-1 undergoing therapy with selumetinib and propose a treatment algorithm.

Leptin-mediated ERK Signaling Pathway Promotes the Transformation of Rat Alveolar Type II Epithelial Cells Induced by Yunnan Tin Mine Dust / 中国肺癌杂志

BACKGROUND@#Currently, a significant number of miners are involved in mining operations at the Gejiu tin mine in Yunnan. This occupational setting is associated with exposure to dust particles, heavy metals, polycyclic aromatic hydrocarbons, and radioactive radon, thereby significantly elevating the risk of lung cancer. This study aims to investigate the involvement of leptin-mediated extracellular regulated protein kinase (ERK) signaling pathway in the malignant transformation of rat alveolar type II epithelial cells induced by Yunnan tin mine dust.@*METHODS@#Immortalized rat alveolar cells type II (RLE-6TN) cells were infected with Yunnan tin mine dust at a concentration of 200 μg/mL for nine consecutive generations to establish the infected cell model, which was named R₂₀₀ cells. The cells were cultured normally, named as R cells. The expression of leptin receptor in both cell groups was detected using the Western blot method. The optimal concentration of leptin and mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) on R₂₀₀ cells was determined using the MTT method. Starting from the 20th generation, the cells in the R group were co-cultured with leptin, while the cells in the R₂₀₀ group were co-cultured with the MEK inhibitor U0126. The morphological alterations of the cells in each group were visualized utilizing hematoxylin-eosin staining. Additionally, concanavalin A (ConA) was utilized to detect any morphological differences, and an anchorage-independent growth assay was conducted to assess the malignant transformation of the cells. The changes in the ERK signaling pathway in epithelial cells after the action of leptin were detected using the Western blot method.@*RESULTS@#Both the cells in the R group and R₂₀₀ group express leptin receptor OB-R. Compared to the R₂₀₀ group, the concentration of leptin at 100 ng/mL shows the most significant pro-proliferation effect. The proliferation of R₂₀₀ cells infected with the virus is inhibited by 30 μmol/L U0126, and a statistically significant divergence was seen when compared to the control group (P<0.05). Starting from the 25th generation, the cell morphology of the leptin-induced R₂₀₀ group (R₂₀₀L group) underwent changes, leading to malignant transformation observed at the 30th generation. The characteristics of malignant transformation became evident by the 40th generation in the R₂₀₀L group. In contrast, the other groups showed agglutination of P40 cells, and the speed of cell aggregation increased with an increase in ConA concentration. Notably, the R₂₀₀L group exhibited faster cell aggregation compared to the U0126-induced R₂₀₀ (R₂₀₀LU) group. Additionally, the cells in the R₂₀₀L group were capable of forming clones starting from P30, with a colony formation rate of 2.25‰±0.5‰. However, no clonal colonies were observed in the R₂₀₀LU group and R₂₀₀ group. The expression of phosphorylated extracellular signal-regulated kinase (pERK) was enhanced in cells of the R₂₀₀L group. However, when the cells in the R₂₀₀L group were treated with U0126, a blocking agent, the phosphorylation level of pERK decreased.@*CONCLUSIONS@#Leptin can promote the malignant transformation of lung epithelial cells infected by mine dust, and the ERK signaling pathway may be necessary for the transformation of alveolar type II epithelial cells induced by Yunnan tin mine dust.

FLUOROFENIDONE ATTENUATES PULMONARY INFLAMMATION AND FIBROSIS BY INHIBITING THE IL-11/MEK/ERK SIGNALING PATHWAY.

ABSTRACT: Idiopathic pulmonary fibrosis is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. Interleukin (IL)-11 plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. In this study, we explore whether a potential antifibrotic agent fluorofenidone (FD) exerts its anti-inflammatory and antifibrotic effects through suppressing activation of the IL-11/MEK/ERK signaling pathway in vivo and in vitro. Male C57BL/6 J mice were intratracheally injected with bleomycin or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with hemotoxylin and eosin, and Masson trichrome. Cytokines were measured using the enzyme-linked immunosorbent assay. The α-smooth muscle actin (α-SMA), fibronectin, and collagen I were measured using immunohistochemistry, and the phosphorylated extracellular signal-regulated kinase, phosphorylated mitogen-activated protein kinase, IL-11RA, and gp130 were measured using Western blot. The RAW264.7 cells and the normal human lung fibroblasts were treated with IL-11 and/or FD, IL-11RA-siRNA, or MEK inhibitor. The expressions of phosphorylated extracellular signal-regulated kinase, phosphorylated mitogen-activated protein kinase, IL-11RA, gp130, α-SMA, fibronectin, and collagen I were measured using Western blot and/or real-time polymerase chain reaction, and the cytokines were measured using enzyme-linked immunosorbent assay. Results showed that FD markedly reduced the expressions of IL-8, IL-18, IL-11, monocyte chemotactic protein-1, α-SMA, fibronectin, and collagen I in mice lung tissues. In addition, FD attenuated IL-11-induced expressions of α-SMA, fibronectin, and collagen I and inhibited IL-11RA, gp130, and phosphorylation of the ERK and MEK protein expression, as well as reduced the expressions of IL-8, IL-18, and monocyte chemotactic protein-1 in vitro. This study demonstrated that FD attenuated bleomycin-induced pulmonary inflammation and fibrosis in mice by inhibiting the IL-11/MEK/ERK signaling pathway.

Sirt1 overexpression improves senescence-associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL-11 transcription.

Determining the mechanism of senescence-associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence-associated pulmonary fibrosis by activating TGF-ß1/IL-11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF-ß1/IL-11/MEK/ERK signaling-mediated senescence-associated pulmonary fibrosis in vitamin D-deficient (Cyp27b1-/- ) mice, and whether Sirt1 downregulated IL-11 expression transcribed by TGF-ß1/Smad2 signaling through deacetylating histone at the IL-11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild-type (WT) mice were examined for cell senescence, fibrosis markers, and TGF-ß1/IL-11/MEK/ERK signaling proteins, and 1,25(OH)2 D3 and IL-11 levels were detected in serum. Nine-week-old WT, Sirt1 mesenchymal transgene (Sirt1Tg ), Cyp27b1-/- , and Sirt1Tg Cyp27b1-/- mice were observed the pulmonary function, aging, and senescence-associated secretory phenotype and TGF-ß1/IL-11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF-ß1/IL-11/MEK/ERK signaling, and promoting senescence-associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence-associated secretory phenotype, and fibrosis through downregulating TGF-ß1/IL-11/MEK/ERK signaling in Cyp27b1-/- mice. Sirt1 negatively regulated IL-11 expression through deacetylating H3K9/14ac mainly at the region from -871 to -724 of IL-11 promoter, also the major binding region of Smad2 which regulated IL-11 expression at the transcriptional level, and subsequently inhibiting TGF-ß1/IL-11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence-associated pulmonary fibrosis induced by vitamin D deficiency.

HAIR DYE-INDUCED RETINOPATHY MIMICKING MEK-INHIBITOR RETINOPATHY.

PURPOSE: To report a new toxic retinopathy related to the use of hair dye. METHODS: Case reports of three patients with follow-up after exposure and until resolution. RESULTS: There were three middle-aged women (32-66 year old) all of whom had bilateral moderate to severe vision loss and normal slit-lamp examination at presentation. Fundus examination showed bilateral multiple serous retinal detachments predominantly located in the posterior pole, with some pigment epithelial hypertrophy in chronic cases. Optical coherence tomography showed similar features as in MEK-inhibitor retinopathy. Electrooculogram performed in one patient showed abnormal Arden ratio. During follow-up, visual acuity improved with regression of the serous retinal detachments. The speed of resolution was proportional to the acuteness of the exposure to aromatic amines. CONCLUSION: Hair dyes containing aromatic amines can be responsible for bilateral toxic retinopathy mimicking MEK-inhibitor retinopathy.

Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care.

OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. METHODS: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. RESULTS: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. CONCLUSION: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

Rasopatías: trastornos del desarrollo con predisposición al cáncer y manifestaciones cutáneas / Rasopathies: Developmental Disorders That Predispose to Cancer and Skin Manifestations

Las proteínas de la vía RAS/MAPK (mitogen activated protein kinase pathway) desempeñan un papel fundamental en la proliferación, diferenciación, supervivencia y muerte celular. Desde hace más de 30 años se sabe que el 30% de los cánceres humanos presentan una mutación somática en alguno de los genes que codifican estas proteínas. En contraste con el elevado potencial de malignidad de las mutaciones somáticas, las mutaciones en la línea germinal provocan anomalías en el desarrollo del individuo que, si bien dependen específicamente del gen afectado, a menudo se superponen clínicamente. Así, todos los pacientes comparten un grado variable de retraso mental o dificultades de aprendizaje, trastornos cardiacos, dismorfismo facial, anomalías cutáneas y, en algunas instancias, predisposición al cáncer. Entre estos síndromes, conocidos como rasopatías, se incluyen el síndrome de Noonan, el síndrome de Costello, la neurofibromatosis 1, el síndrome LEOPARD, el síndrome cardio-facio-cutáneo y el síndrome de Legius. Es interesante conocer las manifestaciones cutáneas de las rasopatías, ya que estas pueden ayudar a esclarecer el diagnóstico de la enfermedad (AU)

Proteins belonging to the RAS/mitogen activated protein kinase (MAPK) pathway play key roles in cell proliferation, differentiation, survival, and death. For more than 30years now we have known that 30% of human cancers carry somatic mutations in genes encoding proteins from this pathway. Whereas somatic mutations have a high malignant potential, germline mutations are linked to developmental abnormalities that are often poorly clinically differentiated, although each is dependent upon the specific gene affected. Thus, all patients share varying degrees of mental retardation or learning difficulties, heart disease, facial dysmorphism, skin anomalies, and, in some cases, predisposition to cancer. These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. Recognizing the skin manifestations of rasopathies can facilitate diagnosis of these syndromes (AU)

Rotenone-induced apoptosis is mediated by p38 and JNK MAP kinases in human dopaminergic SH-SY5Y cells.

Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.