Extracorporeal Photopheresis in Dermatological Diseases.

Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary's syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP's ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.

Ultraviolet Radiation Biological and Medical Implications.

Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength: UVA (315 to 400 nm), UVB (280 to 320 nm), and UVC (100 to 280 nm). UV radiation can cause direct DNA damage in the forms of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In addition, UV radiation can also cause DNA damage indirectly through photosensitization reactions caused by reactive oxygen species (ROS), which manifest as 8-hydroxy-2'-deoxyguanine (8-OHdG). Both direct and indirect DNA damage can lead to mutations in genes that promote the development of skin cancers. The development of melanoma is largely influenced by the signaling of the melanocortin one receptor (MC1R), which plays an essential role in the synthesis of melanin in the skin. UV-induced mutations in the BRAF and NRAS genes are also significant risk factors in melanoma development. UV radiation plays a significant role in basal cell carcinoma (BCC) development by causing mutations in the Hedgehog (Hh) pathway, which dysregulates cell proliferation and survival. UV radiation can also induce the development of squamous cell carcinoma via mutations in the TP53 gene and upregulation of MMPs in the stroma layer of the skin.

Interferon Lambda Signaling Restrains Experimental Autoimmune Encephalomyelitis.

IFN-λ is a type III interferon (IFN) with pleiotropic functions in modulating immune responses. To address its function in autoimmune neuroinflammation, we evaluated the development and progression of experimental autoimmune encephalitis (EAE) in IFNLR1KO (Ifnlr1-/-) and C57Bl/6 (WT) mice following immunization with MOG35-55 peptide. The results show that Ifnlr1-/-mice developed significantly more severe EAE than WT littermates with a similar day of onset, suggesting the potential of IFN-λ in reducing disease severity. We next interrogated whether IFN-λ differentially modulates EAE induced by encephalitogenic Th1 cells or Th17 cells. Encephalitogenic Th1 or Th17 generated from WT donors were transferred into WT or Ifnlr1-/-recipient mice. Whereas encephalitogenic Th1 cells induced more severe EAE in Ifnlr1-/- than WT recipients, the disease severity induced by encephalitogenic Th17 cells was similar. Additionally, in vitro experiments showed that Ifnlr1-/-macrophages promoted the expansion of myelin peptide-reactive Th17 cells but not Th1 cells. Early in the disease, the spinal cords of EAE mice displayed a significantly greater proportion of Ly6C-Ly6G+ cells with CXCR2+CD62Llo phenotype, indicating activated neutrophils. These findings suggest that IFN-λ signaling restrains activation and migration of neutrophils to the CNS, potentially attenuating neutrophil-mediated disease progression in autoimmune neuroinflammation. Recombinant IFN-λ can be used as a potential therapeutic target for treatment of patients with multiple sclerosis as it has fewer side effects due to the restricted expression of its receptor.

Nanozymes and carbon-dots based nanoplatforms for cancer imaging, diagnosis and therapeutics: Current trends and challenges.

Cancer patients face a significant clinical and socio-economic burden due to increased incidence, mortality, and poor survival. Factors like late diagnosis, recurrence, drug resistance, severe side effects, and poor bioavailability limit the scope of current therapies. There is a need for novel, cost-effective, and safe diagnostic methods, therapeutics to overcome recurrence and drug resistance, and drug delivery vehicles with enhanced bioavailability and less off-site toxicity. Advanced nanomaterial-based research is aiding cancer biologists by providing solutions for issues like hypoxia, tumor microenvironment, low stability, poor penetration, target non-specificity, and rapid drug clearance. Currently, nanozymes and carbon-dots are attractive due to their low cost, high catalytic activity, biocompatibility, and lower toxicity. Nanozymes and carbon-dots are increasingly used in imaging, biosensing, diagnosis, and targeted cancer therapy. Integrating these materials with advanced diagnostic tools like CT scans and MRIs can aid in clinical decision-making and enhance the effectiveness of chemotherapy, photothermal, photodynamic, and sonodynamic therapies, with minimal invasion and reduced collateral effects.

K-Homology Type Splicing Regulatory Protein: Mechanism of Action in Cancer and Immune Disorders.

K homology-type splicing regulatory protein (KSRP) is emerging as a key player in cancer biology, and immunology. As a single-strand nucleic acid binding protein it functions in both transcriptional and post-transcriptional regulation, while facilitating multiple stages of RNA metabolism to affect proliferation and control cell fate. However, it must interact with other proteins to determine the fate of its bound substrate. Here we provide an minireview of this important regulatory protein and describe its complex subcellular functions to affect RNA metabolism, stability, miRNA biogenesis and maturation, stress granule function, metastasis, and inflammatory processes.

An update on clinical trials for chemoprevention of human skin cancer.

The pathophysiology of skin cancer is complex, with multiple factors contributing to its development. The proactive treatment of skin cancer has been investigated in the form of chemoprevention of cutaneous malignancies in clinical trials. Chemoprevention is the use of natural or pharmacologic agents that prevent or reverse skin cancer development. Multiple trials have arisen over the past decades to explore the efficacy of specific agents to halt the progression of UV radiation damage. This comprehensive review article aims to assess clinical trials performed with chemopreventive agents for melanoma and nonmelanoma skin cancers. The following compounds were most often used in these trials: nicotinamide, retinoids, polyphenolic antioxidants, COX-2 selective inhibitors, non-steroidal anti-inflammatory drugs, difluoromethylornithine, and 5-fluorouracil. Many agents show promise in their ability to prevent nonmelanoma skin cancer formation, with few melanoma trials demonstrating efficacy. The chemoprevention efforts aimed at skin cancer are complex; current and future trials will be instrumental in identifying therapeutic agents that pose efficacy in halting cancer development and assessing whether long-term administration is tolerable.

Modulation of Skin Cancer by the Stimulator of Interferon Genes.

Morbidity and mortality from skin cancer continue to rise domestically and globally, and melanoma and non-melanoma skin cancers are a topic of interest in the dermatology and oncology communities. In this review, we summarize the stimulator of interferon genes (STING) pathway, its specific role in the pathogenesis of DNA damage and skin cancer, and STING-specific therapies that may fight both melanoma and non-melanoma skin (NMSC) cancers. Furthermore, we discuss specific portions of the STING pathway that may be used in addition to previously used therapies to provide a synergistic effect in future oncology treatments and discuss the limitations of current STING-based therapies.

Bacterial Metabolites and Inflammatory Skin Diseases.

The microbiome and gut-skin axis are popular areas of interest in recent years concerning inflammatory skin diseases. While many bacterial species have been associated with commensalism of both the skin and gastrointestinal tract in certain disease states, less is known about specific bacterial metabolites that regulate host pathways and contribute to inflammation. Some of these metabolites include short chain fatty acids, amine, and tryptophan derivatives, and more that when dysregulated, have deleterious effects on cutaneous disease burden. This review aims to summarize the knowledge of wealth surrounding bacterial metabolites of the skin and gut and their role in immune homeostasis in inflammatory skin diseases such as atopic dermatitis, psoriasis, and hidradenitis suppurativa.

Immunomodulation of Skin Cancer.

Skin cancer represents a major public health issue with a tremendous cost to healthcare systems in the United States and worldwide [...].

The Immunotherapeutic Role of Type I and III Interferons in Melanoma and Non-Melanoma Skin Cancers.

Interferons (IFNs) have demonstrated therapeutic potential in various skin cancers, specifically squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. The precise mechanism through which type I IFNs exert their antitumor effects in skin cancers is still being studied. However, intralesional type I IFN can be used as an alternative to surgery for select patient populations, and high-dose systemic IFN therapy has been shown to be promising in patients with operable high-risk or metastatic melanoma. Despite the therapeutic potential of IFNs in skin cancer treatment, the toxicity profile often prevents the completion of treatment and further expansion of its clinical application. Type I and III IFNs use the same Janus Kinases (JAKs) for signal transduction, which are pathways initiated at a cell surface receptor that mediates the activation of target genes in the nucleus, based on this shared signaling pathway. Due to selective tumor targeting and the ability to generate both innate and adaptive immune responses, we concluded that type III IFNs have minimal side effects compared with established treatments due to selective tumor targeting. While IFN-λ, a type III IFN, shows therapeutic potential as stand-alone or in combination with another IFN, further studies need to be conducted to explore the therapeutic potential of IFN-λ in skin cancer and the underlying physiological roles and mechanisms of action. In this review, we evaluate whether treatment of skin cancer with type III IFN will have minimal side effects compared with established treatments.

Reviewing the Prospective Pharmacological Potential of Isothiocyanates in Fight against Female-Specific Cancers.

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers.

Transforming growth factor receptor III (Betaglycan) regulates the generation of pathogenic Th17 cells in EAE.

The transforming growth factor receptor III (TßRIII) is commonly recognized as a co-receptor that promotes the binding of TGFß family ligands to type I and type II receptors. Within the immune system, TßRIII regulates T cell development in the thymus and is differentially expressed through activation; however, its function in mature T cells is unclear. To begin addressing this question, we developed a conditional knock-out mouse with restricted TßRIII deletion in mature T cells, necessary because genomic deletion of TßRIII results in perinatal mortality. We determined that TßRIII null mice developed more severe autoimmune central nervous neuroinflammatory disease after immunization with myelin oligodendrocyte peptide (MOG35-55) than wild-type littermates. The increase in disease severity in TßRIII null mice was associated with expanded numbers of CNS infiltrating IFNγ+ CD4+ T cells and cells that co-express both IFNγ and IL-17 (IFNγ+/IL-17+), but not IL-17 alone expressing CD4 T cells compared to Tgfbr3fl/fl wild-type controls. This led us to speculate that TßRIII may be involved in regulating conversion of encephalitogenic Th17 to Th1. To directly address this, we generated encephalitogenic Th17 and Th1 cells from wild type and TßRIII null mice for passive transfer of EAE into naïve mice. Remarkably, Th17 encephalitogenic T cells from TßRIII null induced EAE of much greater severity and earlier in onset than those from wild-type mice. The severity of EAE induced by encephalitogenic wild-type and Tgfbr3fl/fl.dLcKCre Th1 cells were similar. Moreover, in vitro restimulation of in vivo primed Tgfbr3fl/fl.dLcKCre T cells, under Th17 but not Th1 polarizing conditions, resulted in a significant increase of IFNγ+ T cells. Altogether, our data indicate that TßRIII is a coreceptor that functions as a key checkpoint in controlling the pathogenicity of autoreactive T cells in neuroinflammation probably through regulating plasticity of Th17 T cells into pathogenic Th1 cells. Importantly, this is the first demonstration that TßRIII has an intrinsic role in T cells.

Role of the Microbiome in Immunotherapy of Melanoma.

ABSTRACT: Novel immunotherapeutics for advanced melanoma have drastically changed survival rates and management strategies in recent years. Immune checkpoint inhibitors have emerged as efficacious agents for some patients but have not been proven to be as beneficial in other patient cohorts. Recent investigation into this observation has implicated the gut microbiome as a potential immunomodulator in regulating patient response to therapy. Numerous studies have provided evidence for this link. Bacterial colonization patterns have been associated with therapeutic outcomes, under the notion that favorable commensal organisms improve host immune response. This review aims to report the most recent and pertinent findings related to the relationship between gut microbial communities and melanoma therapy efficacy. This article also highlights the emerging frontier of artificial intelligence in its application regarding patient microbial composition evaluation, predictive models for therapy response, and recommendations for the future of probiotics and dietary interventions to optimize melanoma survival and outcomes.

Plant-Derived Bioactive Compounds in the Management of Neurodegenerative Disorders: Challenges, Future Directions and Molecular Mechanisms Involved in Neuroprotection.

Neurodegenerative disorders encompass a wide range of pathological conditions caused by progressive damage to the neuronal cells and nervous-system connections, which primarily target neuronal dysfunction and result in problems with mobility, cognition, coordination, sensation, and strength. Molecular insights have revealed that stress-related biochemical alterations such as abnormal protein aggregation, extensive generation of reactive oxygen and nitrogen species, mitochondrial dysfunction, and neuroinflammation may lead to damage to neuronal cells. Currently, no neurodegenerative disease is curable, and the available standard therapies can only provide symptomatic treatment and delay the progression of the disease. Interestingly, plant-derived bioactive compounds have drawn considerable attention due to their well-established medicinal properties, including anti-apoptotic, antioxidant, anti-inflammatory, anticancer, and antimicrobial properties, as well as neuroprotective, hepatoprotective, cardioprotective, and other health benefits. Plant-derived bioactive compounds have received far more attention in recent decades than synthetic bioactive compounds in the treatment of many diseases, including neurodegeneration. By selecting suitable plant-derived bioactive compounds and/or plant formulations, we can fine tune the standard therapies because the therapeutic efficacy of the drugs is greatly enhanced by combinations. A plethora of in vitro and in vivo studies have demonstrated plant-derived bioactive compounds' immense potential, as proven by their capacity to influence the expression and activity of numerous proteins implicated in oxidative stress, neuroinflammation, apoptosis, and aggregation. Thus, this review mostly focuses on the antioxidant, anti-inflammatory, anti-aggregation, anti-cholinesterase, and anti-apoptotic properties of several plant formulations and plant-derived bioactive compounds and their molecular mechanisms against neurodegenerative disorders.

Prospective Epigenetic Actions of Organo-Sulfur Compounds against Cancer: Perspectives and Molecular Mechanisms.

Major epigenetic alterations, such as chromatin modifications, DNA methylation, and miRNA regulation, have gained greater attention and play significant roles in oncogenesis, representing a new paradigm in our understanding of cancer susceptibility. These epigenetic changes, particularly aberrant promoter hypermethylation, abnormal histone acetylation, and miRNA dysregulation, represent a set of epigenetic patterns that contribute to inappropriate gene silencing at every stage of cancer progression. Notably, the cancer epigenome possesses various HDACs and DNMTs, which participate in the histone modifications and DNA methylation. As a result, there is an unmet need for developing the epigenetic inhibitors against HDACs and DNMTs for cancer therapy. To date, several epigenetically active synthetic inhibitors of DNA methyltransferases and histone deacetylases have been developed. However, a growing body of research reports that most of these synthetic inhibitors have significant side effects and a narrow window of specificity for cancer cells. Targeting tumor epigenetics with phytocompounds that have the capacity to modulate abnormal DNA methylation, histone acetylation, and miRNAs expression is one of the evolving strategies for cancer prevention. Encouragingly, there are many bioactive phytochemicals, including organo-sulfur compounds that have been shown to alter the expression of key tumor suppressor genes, oncogenes, and oncogenic miRNAs through modulation of DNA methylation and histones in cancer. In addition to vitamins and microelements, dietary phytochemicals such as sulforaphane, PEITC, BITC, DADS, and allicin are among a growing list of naturally occurring anticancer agents that have been studied as an alternative strategy for cancer treatment and prevention. Moreover, these bioactive organo-sulfur compounds, either alone or in combination with other standard cancer drugs or phytochemicals, showed promising results against many cancers. Here, we particularly summarize and focus on the impact of specific organo-sulfur compounds on DNA methylation and histone modifications through targeting the expression of different DNMTs and HDACs that are of particular interest in cancer therapy and prevention.

Phytocompounds from the Medicinal and Dietary Plants: Multi-target Agents for Cervical Cancer Prevention and Therapy.

Cervical cancer is the fourth leading cause of cancer death among women worldwide. Due to cervical cancer's high incidence and mortality, there is an unmet demand for effective diagnostic, therapeutic, and preventive agents. At present, the preferred treatment strategies for advanced metastatic cervical cancer include surgery, radiotherapy, and chemotherapy. However, cervical cancer is gradually developing resistance to chemotherapy, thereby reducing its efficacy. Over the last several decades, phytochemicals, a general term for compounds produced from plants, have gained attention for their role in preventing cervical cancer. This role in cervical cancer prevention has garnered attention on the medicinal properties of fruits and vegetables. Phytochemicals are currently being evaluated for their ability to block proteins involved in carcinogenesis and chemoresistance against cervical cancer. Chemoresistance to cancer drugs like cisplatin, doxorubicin, and 5-fluorouracil has become a significant limitation of drug-based chemotherapy. However, the combination of cisplatin with other phytochemicals has been identified as a promising alternative to subjugate cisplatin resistance. Phytochemicals are promising chemo-preventive and chemotherapeutic agents as they possess antioxidant, anti-inflammatory, and anti-proliferative potential against many cancers, including cervical cancer. Furthermore, the ability of the phytochemicals to modulate cellular signaling pathways through up and down regulation of various proteins has been claimed for their therapeutic potential. Phytochemicals also display a wide range of biological functions, including cell cycle arrest, apoptosis induction, inhibition of invasion, and migration in cervical cancer cells. Numerous studies have revealed the critical role of different signaling proteins and their signaling pathways in the pathogenesis of cervical cancer. Here, we review the ability of several dietary phytochemicals to alter carcinogenesis by modulating various molecular targets.

Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNß in the skin of C57BL/6 mice. IFNα and IFNß were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

Hidradenitis Suppurativa: Consequences of Microbiome Dysbiosis on Immune Dysregulation and Disease Severity.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition characterized by the formation of nodules, abscesses, and sinus tracts with tunnels that primarily involves the skin folds. HS affects approximately 1% of the population, but its pathogenesis is unclear. Dysbiosis of skin microbiome is a major cause of HS and alterations of microbiome composition and diversity can be seen in the skin of patients with HS. These disruptions may contribute to the immune dysfunction seen in HS. Understanding these alterations and their contributions to the pathogenesis of HS could help guide future treatment. In addition to dysbiosis promoting immune dysregulation, HS may promote dysbiosis via differences in expression of antimicrobial peptides (AMPs). In this review, we have discussed the role of skin and gut microbiome in manifestation of HS and the consequences of dysbiosis on the immune system.