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25 pages, 1139 KiB  
Review
Lamotrigine Therapy: Relation Between Treatment of Bipolar Affective Disorder and Incidence of Stevens–Johnson Syndrome—A Narrative Review of the Existing Literature
by Kacper Żełabowski, Kacper Wojtysiak, Zuzanna Ratka, Kamil Biedka and Agnieszka Chłopaś-Konowałek
J. Clin. Med. 2025, 14(12), 4103; https://doi.org/10.3390/jcm14124103 - 10 Jun 2025
Cited by 1 | Viewed by 1287
Abstract
Lamotrigine is the drug of choice for the treatment of depressive episodes in bipolar disorder (BD). Despite its generally favorable tolerability profile, lamotrigine use is associated with a risk of Cutaneous Adverse Drug Reactions (cADRs), including Stevens–Johnson Syndrome (SJS) and Lyell’s syndrome, also [...] Read more.
Lamotrigine is the drug of choice for the treatment of depressive episodes in bipolar disorder (BD). Despite its generally favorable tolerability profile, lamotrigine use is associated with a risk of Cutaneous Adverse Drug Reactions (cADRs), including Stevens–Johnson Syndrome (SJS) and Lyell’s syndrome, also known as toxic epidermal necrolysis (TEN). Genetic markers HLA and, in particular, HLA-B 15:02 and HLA-A 31:01 are crucial in predicting individuals’ susceptibility to developing the symptoms. The symptoms are triggered by type IV hypersensitivity developing because of CTL and NK cell activation, leading to keratinocyte apoptosis, epidermal necrosis and skin detachment. The exact pharmacotherapy that should be widely utilized in treating affected patients has not yet been established. New therapies including JAK inhibitors or cyclosporine show potential in improving outcomes by reducing mortality and enhancing the period of recovery. Key factors in preventing cADRs may include adequate patient observation, gradual titration of the patient’s dose, and reduction of risk factors through screening for HLA polymorphisms. When the initial symptoms of cADR are identified, it is imperative to make an immediate decision to discontinue treatment, as this can significantly reduce the risk of progression to SJS/TEN and systemic complications. The purpose of this review is to identify a significant correlation between lamotrigine use in BD and the occurrence of SJS by showing the risk factors, neuropharmacological mechanisms, immune response and correctness of pharmacotherapy. Full article
(This article belongs to the Special Issue Clinical Pharmacology: Adverse Drug Reactions)
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16 pages, 5022 KiB  
Article
Sericin-Based Poly(Vinyl) Alcohol Relieves Plaque and Epidermal Lesions in Psoriasis; a Chance for Dressing Development in a Specific Area
by Khwanchanok Tuentam, Pornanong Aramwit, Onrapak Reamtong, Suangsuda Supasai, Urai Chaisri, Kamonpan Fongsodsri, Rungnapha Yamdech, Napatara Tirawanchai, Passanesh Sukphopetch and Sumate Ampawong
Int. J. Mol. Sci. 2023, 24(1), 145; https://doi.org/10.3390/ijms24010145 - 21 Dec 2022
Cited by 9 | Viewed by 2698
Abstract
The noncontagious immune-mediated skin disease known as psoriasis is regarded as a chronic skin condition with a 0.09–11.4% global prevalence. The main obstacle to the eradication of the disease continues to be insufficient treatment options. Sericin, a natural biopolymer from Bombyx mori cocoons, [...] Read more.
The noncontagious immune-mediated skin disease known as psoriasis is regarded as a chronic skin condition with a 0.09–11.4% global prevalence. The main obstacle to the eradication of the disease continues to be insufficient treatment options. Sericin, a natural biopolymer from Bombyx mori cocoons, can improve skin conditions via its immunomodulatory effect. Many external therapeutic methods are currently used to treat psoriasis, but sericin-based hydrogel is not yet used to treat plaques of eczema. Through the use of an imiquimod rat model, this study sought to identify the physical and chemical characteristics of a silk sericin-based poly(vinyl) alcohol (SS/PVA) hydrogel and assess both its therapeutic and toxic effects on psoriasis. The cytokines, chemokines, and genes involved in the pathogenesis of psoriasis were investigated, focusing on the immuno-pathological relationships. We discovered that the SS/PVA had a stable fabrication and proper release. Additionally, the anti-inflammatory, antioxidant, and anti-apoptotic properties of SS/PVA reduced the severity of psoriasis in both gross and microscopic skin lesions. This was demonstrated by a decrease in the epidermal histopathology score, upregulation of nuclear factor erythroid 2-related factor 2 and interleukin (IL)-10, and a decrease in the expression of tumor necrosis factor (TNF)-α and IL-20. Moreover, the genes S100a7a and S100a14 were downregulated. Additionally, in rats given the SS/PVA treatment, blood urea nitrogen, creatinine, and serum glutamic oxaloacetic transaminase levels were within normal limits. Our findings indicate that SS/PVA is safe and may be potentiated to treat psoriasis in a variety of forms and locations of plaque because of its physical, chemical, and biological characteristics. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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18 pages, 400 KiB  
Review
Toxic Epidermal Necrolysis: A Clinical and Therapeutic Review
by Gonçalo Canhão, Susana Pinheiro and Luís Cabral
Eur. Burn J. 2022, 3(3), 407-424; https://doi.org/10.3390/ebj3030036 - 8 Aug 2022
Cited by 1 | Viewed by 3600
Abstract
Toxic Epidermal Necrolysis is a rare dermatological condition with high mortality and serious consequences on its survivors. Despite having been first described in 1956, its pathophysiology remains uncertain, mainly regarding its mechanisms, although it seems that certain apoptosis pathways are pivotal in starting [...] Read more.
Toxic Epidermal Necrolysis is a rare dermatological condition with high mortality and serious consequences on its survivors. Despite having been first described in 1956, its pathophysiology remains uncertain, mainly regarding its mechanisms, although it seems that certain apoptosis pathways are pivotal in starting keratinocytes’ apoptosis and in activating T cells, especially those mediated by tumour necrosis factor, Fas-FasL and granulysin. In general, its aetiology and presentation are consensual, being defined as a generalized necrolysis of the epidermis that occurs as an uncontrolled immune response to a specific drug or one of its metabolites, highlighting cotrimoxazole and allopurinol as the most important. This necrolysis leads to a massive shedding of the epidermal layer of the skin, with stronger incidences in the torso, upper limbs and face. Its complications tend to be severe, noting that septic ones are responsible for over half of the disease’s mortality. Nearly all survivors develop long-term sequelae, namely hypertrophic scarring and skin pigmentation anomalies. Regarding treatment, many different opinions arise, including contradictory ones, regarding more importantly immunomodulation therapies that have been the focus of several studies through the years. It is safe to state that supportive therapy is the only modality that has significantly strong evidence backing its efficacy in reducing mortality and improving prognosis, which have improved in the past years as general health care quality increased. In conclusion, it is imperative to say that more research is needed for new potential therapies with large study populations and more scientific rigor. Likewise, investigation towards its basic pathophysiology should also be promoted, mainly at a biomolecular level, allowing for an improved prevention of this illness. Full article
15 pages, 1566 KiB  
Review
Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: A Review of Diagnosis and Management
by Robert Frantz, Simo Huang, Abhirup Are and Kiran Motaparthi
Medicina 2021, 57(9), 895; https://doi.org/10.3390/medicina57090895 - 28 Aug 2021
Cited by 122 | Viewed by 38519
Abstract
Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare diseases that are characterized by widespread epidermal necrosis and sloughing of skin. They are associated with significant morbidity and mortality, and early diagnosis and treatment is critical in achieving favorable outcomes for patients. [...] Read more.
Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare diseases that are characterized by widespread epidermal necrosis and sloughing of skin. They are associated with significant morbidity and mortality, and early diagnosis and treatment is critical in achieving favorable outcomes for patients. In this scoping review, Excerpta Medica dataBASE and PubMed were searched for publications that addressed recent advances in the diagnosis and management of the disease. Multiple proteins (galectin 7 and RIP3) were identified that are promising potential biomarkers for SJS/TEN, although both are still in early phases of research. Regarding treatment, cyclosporine is the most effective therapy for the treatment of SJS, and a combination of intravenous immunoglobulin (IVIg) and corticosteroids is most effective for SJS/TEN overlap and TEN. Due to the rare nature of the disease, there is a lack of prospective, randomized controlled trials and conducting these in the future would provide valuable insights into the management of this disease. Full article
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5 pages, 3979 KiB  
Case Report
A Case of Stevens–Johnson Syndrome in Recurrent Late-Stage Ovarian Cancer Patient after Management of Chronic Pain with Elastomeric Pump
by Andrej Cokan, Vida Gavrić Lovrec and Iztok Takač
Curr. Oncol. 2021, 28(4), 2928-2932; https://doi.org/10.3390/curroncol28040256 - 3 Aug 2021
Cited by 3 | Viewed by 6627
Abstract
(1) Background. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, characterized by extensive necrosis and detachment of the epidermis. (2) Case presentation. We present a case of a 46-year-old patient with late-stage high-grade serous ovarian cancer who was primarily [...] Read more.
(1) Background. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, characterized by extensive necrosis and detachment of the epidermis. (2) Case presentation. We present a case of a 46-year-old patient with late-stage high-grade serous ovarian cancer who was primarily treated with neoadjuvant chemotherapy and interval debulking, which was followed by adjuvant chemotherapy. At first recurrence, she was again treated with chemotherapy, and due to severe abdominal pain, an elastomeric pump containing analgesics, anti-inflammatories, and ondansetron was administered. In the same month, she was admitted to the hospital due to severe dysphagia, and in the following days she developed haemorrhagic vesiculobullous lesions on the facial skin and trunk. Stevens–Johnson syndrome was confirmed and ondansetron as a plausible leading cause was discontinued. Despite multimodal treatment, her condition deteriorated, and she died. (3) Discussion and conclusion. Although gynaecologists rarely encounter Stevens–Johnson syndrome, high mortality of the disease should ensure a low threshold for diagnosing and treating this disease. Full article
(This article belongs to the Section Gynecologic Oncology)
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16 pages, 2242 KiB  
Article
Association of HLA-B*51:01, HLA-B*55:01, CYP2C9*3, and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population
by Shobana John, Karuppiah Balakrishnan, Chonlaphat Sukasem, Tharmarajan Chinnathambi Vijay Anand, Bhutorn Canyuk and Sutthiporn Pattharachayakul
J. Pers. Med. 2021, 11(8), 737; https://doi.org/10.3390/jpm11080737 - 28 Jul 2021
Cited by 13 | Viewed by 3766
Abstract
Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen (HLA)-B*15:02 is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, [...] Read more.
Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen (HLA)-B*15:02 is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, the association is much weaker than it is reported for carbamazepine (CBZ). In this study, we investigated the association of pharmacogenetic variants of the HLA B gene and CYP2C9*3 with PHT-CADRs in South Indian epileptic patients. This prospective case-controlled study included 25 PHT-induced CADRs, 30 phenytoin-tolerant patients, and 463 (HLA-B) and 82 (CYP2C9*3) normal-controls from previous studies included for the case and normal-control comparison. Six SCARs cases and 19 mild-moderate reactions were observed among the 25 cases. Pooled data analysis was performed for the HLA B*51:01 and PHT-CADRs associations. The Fisher exact test and multivariate binary logistic regression analysis were used to identify the susceptible alleles associated with PHT-CADRs. Multivariate analysis showed that CYP2C9*3 was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759–84.87, p = 003). In subgroup analysis, CYP2C9*3 and HLA B*55:01 were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138–136.2, p = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125–15.67, p = 0.035), respectively. Pooled data analysis has confirmed the association between HLA B*51:01/PHT-SCARs (OR = 6.273, 95% CI 2.24–16.69, p = <0.001) and HLA B*51:01/PHT-overall CADRs (OR = 2.323, 95% CI 1.22–5.899, p = 0.037). In this study, neither the case nor the control groups had any patients with HLA B*15:02. The risk variables for PHT-SCARs, PHT-overall CADRs, and PHT-MPE were found to be HLA B*51:01, CYP2C9*3, and HLA B*55:01, respectively. These alleles were identified as the risk factors for the first time in the South Indian Tamil population for PHT-CADRs. Further investigation is warranted to establish the clinical relevance of these alleles in this population with larger sample size. Full article
(This article belongs to the Special Issue Pharmacogenetics to Avoid Adverse Drug Reactions)
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40 pages, 1483 KiB  
Review
Potential Role of Curcumin and Its Nanoformulations to Treat Various Types of Cancers
by Md. Tanvir Kabir, Md. Habibur Rahman, Rokeya Akter, Tapan Behl, Deepak Kaushik, Vineet Mittal, Parijat Pandey, Muhammad Furqan Akhtar, Ammara Saleem, Ghadeer M. Albadrani, Mohamed Kamel, Shaden A.M. Khalifa, Hesham R. El-Seedi and Mohamed M. Abdel-Daim
Biomolecules 2021, 11(3), 392; https://doi.org/10.3390/biom11030392 - 7 Mar 2021
Cited by 174 | Viewed by 12974
Abstract
Cancer is a major burden of disease globally. Each year, tens of millions of people are diagnosed with cancer worldwide, and more than half of the patients eventually die from it. Significant advances have been noticed in cancer treatment, but the mortality and [...] Read more.
Cancer is a major burden of disease globally. Each year, tens of millions of people are diagnosed with cancer worldwide, and more than half of the patients eventually die from it. Significant advances have been noticed in cancer treatment, but the mortality and incidence rates of cancers are still high. Thus, there is a growing research interest in developing more effective and less toxic cancer treatment approaches. Curcumin (CUR), the major active component of turmeric (Curcuma longa L.), has gained great research interest as an antioxidant, anticancer, and anti-inflammatory agent. This natural compound shows its anticancer effect through several pathways including interfering with multiple cellular mechanisms and inhibiting/inducing the generation of multiple cytokines, enzymes, or growth factors including IκB kinase β (IκKβ), tumor necrosis factor-alpha (TNF-α), signal transducer, and activator of transcription 3 (STAT3), cyclooxygenase II (COX-2), protein kinase D1 (PKD1), nuclear factor-kappa B (NF-κB), epidermal growth factor, and mitogen-activated protein kinase (MAPK). Interestingly, the anticancer activity of CUR has been limited primarily due to its poor water solubility, which can lead to low chemical stability, low oral bioavailability, and low cellular uptake. Delivering drugs at a controlled rate, slow delivery, and targeted delivery are other very attractive methods and have been pursued vigorously. Multiple CUR nanoformulations have also been developed so far to ameliorate solubility and bioavailability of CUR and to provide protection to CUR against hydrolysis inactivation. In this review, we have summarized the anticancer activity of CUR against several cancers, for example, gastrointestinal, head and neck, brain, pancreatic, colorectal, breast, and prostate cancers. In addition, we have also focused on the findings obtained from multiple experimental and clinical studies regarding the anticancer effect of CUR in animal models, human subjects, and cancer cell lines. Full article
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38 pages, 1470 KiB  
Review
Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways
by Saleh A. Almatroodi, Mohammed A. Alsahli, Ahmad Almatroudi, Amit Kumar Verma, Abdulaziz Aloliqi, Khaled S. Allemailem, Amjad Ali Khan and Arshad Husain Rahmani
Molecules 2021, 26(5), 1315; https://doi.org/10.3390/molecules26051315 - 1 Mar 2021
Cited by 129 | Viewed by 9849
Abstract
Polyphenolic flavonoids are considered natural, non-toxic chemopreventers, which are most commonly derived from plants, fruits, and vegetables. Most of these polyphenolics exhibit remarkable antioxidant, anti-inflammatory, and anticancer properties. Quercetin (Qu) is a chief representative of these polyphenolic compounds, which exhibits excellent antioxidant and [...] Read more.
Polyphenolic flavonoids are considered natural, non-toxic chemopreventers, which are most commonly derived from plants, fruits, and vegetables. Most of these polyphenolics exhibit remarkable antioxidant, anti-inflammatory, and anticancer properties. Quercetin (Qu) is a chief representative of these polyphenolic compounds, which exhibits excellent antioxidant and anticancer potential, and has attracted the attention of researchers working in the area of cancer biology. Qu can regulate numerous tumor-related activities, such as oxidative stress, angiogenesis, cell cycle, tumor necrosis factor, proliferation, apoptosis, and metastasis. The anticancer properties of Qu mainly occur through the modulation of vascular endothelial growth factor (VEGF), apoptosis, phosphatidyl inositol-3-kinase (P13K)/Akt (proteinase-kinase B)/mTOR (mammalian target of rapamycin), MAPK (mitogen activated protein kinase)/ERK1/2 (extracellular signal-regulated kinase 1/2), and Wnt/β-catenin signaling pathways. The anticancer potential of Qu is documented in numerous in vivo and in vitro studies, involving several animal models and cell lines. Remarkably, this phytochemical possesses toxic activities against cancerous cells only, with limited toxic effects on normal cells. In this review, we present extensive research investigations aimed to discuss the therapeutic potential of Qu in the management of different types of cancers. The anticancer potential of Qu is specifically discussed by focusing its ability to target specific molecular signaling, such as p53, epidermal growth factor receptor (EGFR), VEGF, signal transducer and activator of transcription (STAT), PI3K/Akt, and nuclear factor kappa B (NF-κB) pathways. The anticancer potential of Qu has gained remarkable interest, but the exact mechanism of its action remains unclear. However, this natural compound has great pharmacological potential; it is now believed to be a complementary—or alternative—medicine for the prevention and treatment of different cancers. Full article
(This article belongs to the Special Issue Natural Products: Therapeutic Properties and Beyond)
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17 pages, 2331 KiB  
Article
The Effects of Ozone on Atlantic Salmon Post-Smolt in Brackish Water—Establishing Welfare Indicators and Thresholds
by Kevin T. Stiller, Jelena Kolarevic, Carlo C. Lazado, Jascha Gerwins, Christopher Good, Steven T. Summerfelt, Vasco C. Mota and Åsa M. O. Espmark
Int. J. Mol. Sci. 2020, 21(14), 5109; https://doi.org/10.3390/ijms21145109 - 20 Jul 2020
Cited by 31 | Viewed by 7828
Abstract
Ozone is a strong oxidant, and its use in aquaculture has been shown to improve water quality and fish health. At present, it is predominantly used in freshwater systems due to the high risk of toxic residual oxidant exposure in brackish water and [...] Read more.
Ozone is a strong oxidant, and its use in aquaculture has been shown to improve water quality and fish health. At present, it is predominantly used in freshwater systems due to the high risk of toxic residual oxidant exposure in brackish water and seawater. Here, we report the effects of ozone on Atlantic salmon (Salmo salar) post-smolts (~100 g), in a brackish water (12 ppt) flow-through system. Salmon were exposed to oxidation reduction potential concentrations of 250 mV (control), 280 mV (low), 350 mV (medium), 425 mV (high) and 500 mV (very high). The physiological impacts of ozone were characterized by blood biochemical profiling, histopathologic examination and gene expression analysis in skin and gills. Fish exposed to 425 mV and higher showed ≥33% cumulative mortality in less than 10 days. No significant mortalities were recorded in the remaining groups. The skin surface quality and the thickness of the dermal and epidermal layers were not significantly affected by the treatments. On the other hand, gill histopathology showed the adverse effects of increasing ozone doses and the changes were more pronounced in the group exposed to 350 mV and higher. Cases of gill damages such as necrosis, lamellar fusion and hypertrophy were prevalent in the high and very high groups. Expression profiling of key biomarkers for mucosal health supported the histology results, showing that gills were significantly more affected by higher ozone doses compared to the skin. Increasing ozone doses triggered anti-oxidative stress and inflammatory responses in the gills, where transcript levels of glutathione reductase, copper/zinc superoxide dismutase, interleukin 1β and interleukin were significantly elevated. Heat shock protein 70 was significantly upregulated in the skin of fish exposed to 350 mV and higher. Bcl-2 associated x protein was the only gene marker that was significantly upregulated by increasing ozone doses in both mucosal tissues. In conclusion, the study revealed that short-term exposure to ozone at concentrations higher than 350 mV in salmon in brackish water resulted in significant health and welfare consequences, including mortality and gill damages. The results of the study will be valuable in developing water treatment protocols for salmon farming. Full article
(This article belongs to the Special Issue Fish Mucosal Physiology and Immunology)
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19 pages, 5251 KiB  
Article
Statin Drugs Plus Th1 Cytokines Potentiate Apoptosis and Ras Delocalization in Human Breast Cancer Lines and Combine with Dendritic Cell-Based Immunotherapy to Suppress Tumor Growth in a Mouse Model of HER-2pos Disease
by Crystal M. Oechsle, Loral E. Showalter, Colleen M. Novak, Brain J. Czerniecki and Gary K. Koski
Vaccines 2020, 8(1), 72; https://doi.org/10.3390/vaccines8010072 - 6 Feb 2020
Cited by 17 | Viewed by 3812
Abstract
A dendritic cell-based, Type 1 Helper T cell (Th1)-polarizing anti-Human Epidermal Growth Factor Receptor-2 (HER-2) vaccine supplied in the neoadjuvant setting eliminates disease in up to 30% of recipients with HER-2-positive (HER-2pos) ductal carcinoma in situ (DCIS). We hypothesized that drugs [...] Read more.
A dendritic cell-based, Type 1 Helper T cell (Th1)-polarizing anti-Human Epidermal Growth Factor Receptor-2 (HER-2) vaccine supplied in the neoadjuvant setting eliminates disease in up to 30% of recipients with HER-2-positive (HER-2pos) ductal carcinoma in situ (DCIS). We hypothesized that drugs with low toxicity profiles that target signaling pathways critical for oncogenesis may work in conjunction with vaccine-induced immune effector mechanisms to improve efficacy while minimizing side effects. In this study, a panel of four phenotypically diverse human breast cancer lines were exposed in vitro to the combination of Th1 cytokines Interferon-gamma (IFN-γ) and Tumor Necrosis Factor-alpha (TNF-α) and lipophilic statins. This combination was shown to potentiate multiple markers of apoptotic cell death. The combination of statin drugs and Th1 cytokines minimized membrane K-Ras localization while maximizing levels in the cytoplasm, suggesting a possible means by which cytokines and statin drugs might cooperate to maximize cell death. A combined therapy was also tested in vivo through an orthotopic murine model using the neu-transgenic TUBO mammary carcinoma line. We showed that the combination of HER-2 peptide-pulsed dendritic cell (DC)-based immunotherapy and simvastatin, but not single agents, significantly suppressed tumor growth. Consistent with a Th1 cytokine-dependent mechanism, parenterally administered recombinant IFN-γ could substitute for DC-based immunotherapy, likewise inhibiting tumor growth when combined with simvastatin. These studies show that statin drugs can amplify a DC-induced effector mechanism to improve anti-tumor activity. Full article
(This article belongs to the Section Vaccination Against Cancer and Chronic Diseases)
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18 pages, 2928 KiB  
Article
Blockade of EGFR Activation Promotes TNF-Induced Lung Epithelial Cell Apoptosis and Pulmonary Injury
by Toshimitsu Yamaoka, Satoru Arata, Mayumi Homma, Tetsuya Homma, Sojiro Kusumoto, Koichi Ando, Ryou Manabe, Yasunari Kishino, Motoi Ohba, Junji Tsurutani, Masafumi Takimoto, Tohru Ohmori and Hironori Sagara
Int. J. Mol. Sci. 2019, 20(16), 4021; https://doi.org/10.3390/ijms20164021 - 17 Aug 2019
Cited by 31 | Viewed by 5571
Abstract
Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis [...] Read more.
Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment. Full article
(This article belongs to the Special Issue Kinase Signal Transduction 1.0)
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10 pages, 2318 KiB  
Article
Nile Tilapia Derived TP4 Shows Broad Cytotoxicity toward to Non-Small-Cell Lung Cancer Cells
by Chen-Hung Ting and Jyh-Yih Chen
Mar. Drugs 2018, 16(12), 506; https://doi.org/10.3390/md16120506 - 13 Dec 2018
Cited by 30 | Viewed by 4054
Abstract
Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality due to a lack of effective treatments. Conventional chemotherapies affect healthy cells and cause multidrug resistance, while tumors may eventually develop resistance to less-toxic targeted therapies. Thus, the need to [...] Read more.
Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality due to a lack of effective treatments. Conventional chemotherapies affect healthy cells and cause multidrug resistance, while tumors may eventually develop resistance to less-toxic targeted therapies. Thus, the need to develop novel therapies for NSCLC is urgent. Here, we show that Nile tilapia-derived Tilapia piscidin (TP) 4 is cytotoxic to a panel of NSCLC cells with different genetic profiles. We observed that TP4 triggers NSCLC cell death through the necrosis and combining TP4 with potent Epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKI)s, Erlotinib, and Gefitinib, improved drug responses in EGFR-mutated NSCLC cells, but not in EGFR-wild-type NSCLC cells. This work provides novel insights into potential NSCLC treatments, which may utilize antimicrobial peptide TP4 as monotherapy or in combination with EGFR-TKIs. Full article
(This article belongs to the Collection Marine Compounds and Cancer)
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11 pages, 1338 KiB  
Review
Review of Toxic Epidermal Necrolysis
by Victoria Harris, Christopher Jackson and Alan Cooper
Int. J. Mol. Sci. 2016, 17(12), 2135; https://doi.org/10.3390/ijms17122135 - 18 Dec 2016
Cited by 47 | Viewed by 24663
Abstract
Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of [...] Read more.
Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of TEN is incompletely understood. Historically, it has been regarded as a drug-induced immune reaction initiated by cytotoxic lymphocytes via a human leukocyte antigen (HLA)-restricted pathway. Several mediators have been identified as contributors to the cell death seen in TEN, including; granulysin, soluble Fas ligand, perforin/granzyme, tumour necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand. Currently, granulysin is accepted as the most important mediator of T cell proliferation. There is uncertainty around the accepted management of TEN. The lack of definitive management guidelines for TEN is explained in part by the rarity of the disease and its high mortality rate, which makes it difficult to conduct randomised control trials on emerging therapies. Developments have been made in pharmacogenomics, with numerous HLA alleles identified; however, these have largely been ethnically specific. These associations have translated into screening recommendations for Han Chinese. Full article
(This article belongs to the Special Issue Inflammatory Skin Conditions)
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17 pages, 456 KiB  
Review
Cytotoxic Proteins and Therapeutic Targets in Severe Cutaneous Adverse Reactions
by Shih-Chi Su and Wen-Hung Chung
Toxins 2014, 6(1), 194-210; https://doi.org/10.3390/toxins6010194 - 3 Jan 2014
Cited by 48 | Viewed by 12631
Abstract
Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are rare but life-threatening conditions induced mainly by a variety of drugs. Until now, an effective treatment for SJS/TEN still remains unavailable. Current studies have suggested that the [...] Read more.
Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are rare but life-threatening conditions induced mainly by a variety of drugs. Until now, an effective treatment for SJS/TEN still remains unavailable. Current studies have suggested that the pathobiology of drug-mediated SJS and TEN involves major histocompatibility class (MHC) I-restricted activation of cytotoxic T lymphocytes (CTLs) response. This CTLs response requires several cytotoxic signals or mediators, including granulysin, perforin/granzyme B, and Fas/Fas ligand, to trigger extensive keratinocyte death. In this article, we will discuss the cytotoxic mechanisms of severe cutaneous adverse reactions and their potential applications on therapeutics for this disease. Full article
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