Ingenol

Roots of Euphorbia fischeriana and Euphorbia ebracteolata are recorded as the source plant of traditional Chinese medicine "Langdu," containing active ingredients with anticancer and anti-AIDS activity. However, the two species have specific patterns in the graphic distribution. Compared with E. ehracteolata, E. fischeriana distributes in higher latitude and lower temperature areas and might have experienced cold stress adaptation. To reveal the molecular mechanism of environmental adaptation, RNA-seq was performed toward the roots, stems, and leaves of E...

Diacylglycerol (DAG)-sensing C1 domains of Protein kinase C (PKC) isoforms are targets for therapeutic intervention in cancers, neurodegenerative disorders, and HIV latency reversal. High-resolution structural information on the C1 domains complexed to DAG or exogenous PKC agonists remained elusive for nearly 3 decades. This is attributed to the extreme hydrophobicity of the C1 complexes and the need to create an optimal membrane-mimicking environment to facilitate the complex formation and crystallization...

Ingenol, as the precursor of the marketed drug ingenol mebutate, has been proven to have a variety of bioactivities. The purpose of this study was to identify the metabolites of ingenol using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q/TOF-MS) combined with UNIFI software. Plasma, urine and fecal samples of rats were obtained and analyzed. A total of 18 metabolites were detected and identified in rat, including five phase II metabolites (M14-M18). Moreover, as microbial biotransformation is helpful to obtain sufficient reference standards of metabolites, the co-culture of ingenol with the fungus Cunninghamella elegans bio-110930 was also studied and yielded 4 phase I metabolites, in which reference standards of three metabolites were further obtained by preparative scale biotransformation...

IMPORTANCE: Treatment of actinic keratosis (AK) aims to prevent cutaneous squamous cell carcinoma (cSCC). However, whether AK can progress into invasive cSCC is a matter of debate, and little is known about the effect of treatment on preventing cSCC. OBJECTIVES: To evaluate the risk of invasive cSCC and factors that may contribute to increased risk in patients with multiple AKs. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of a multicenter randomized clinical trial, 624 patients with a minimum of 5 AKs within an area of 25 to 100 cm2 on the head were recruited from the Department of Dermatology of 4 hospitals in the Netherlands...

There have been multiple direct and indirect comparison studies evaluating different field therapies used in the treatment of actinic keratosis (AK). A recent clinical trial directly compared 5% fluorouracil (5-FU), imiquimod, ingenol mebutate, and methyl aminolevulinate photodynamic therapy (MAL-PDT), reporting that 5-FU was superior to the other treatments in achieving sustained clearance of 75 percent or greater of AK lesions compared to baseline. In this commentary, the author reviews and discusses the methods and results of this comparison study and propose these results are limited by a number of factors, such as the selected primary % clearance endpoint, grade range of included AKs, and treatments included in the comparison, when considered in the context of other clinical and real-world comparison studies evaluating AK field therapies...

Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle...

Thrombocytopenia, a most common complication of radiotherapy and chemotherapy, is an important cause of morbidity and mortality in cancer patients. However, there are still no approved agents for the treatment of radiation- and chemotherapy-induced thrombocytopenia (RIT and CIT, respectively). In this study, a drug screening model for predicting compounds with activity in promoting megakaryocyte (MK) differentiation and platelet production was established based on machine learning (ML), and a natural product ingenol was predicted as a potential active compound...

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Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP)...

Immunotherapy has led to an expansion of the treatment of malignancies, but its effect in prostate cancer (PCa) patients is modest. Chemoimmunotherapy is a promising approach that has attracted substantial attention. Although the widely used clinical chemotherapeutic drug doxorubicin (DOX) elicits immunogenic cell death (ICD), its weak ICD effect and the abnormal vasculature of tumors severely limit its efficacy in chemoimmunotherapy. Ingenol-3-angelate (I3A), an emerging antitumor drug with dual chemotherapeutic and immune response-eliciting effects, is expected to exert synergistic effects when administered in combination with DOX...

Porokeratosis is a keratinization disorder with unclear etiopathogenesis, varied clinical presentation and characteristic histopathology, and is usually unresponsive to current therapeutic options. Until now, it was considered to be a clonal disorder with immunity, ultra violet radiation and other factors playing important roles in etiopathogenesis. It is now known that abnormalities in the mevalonate pathway are responsible for this clonal keratinization abnormality. New variants of porokeratosis like eruptive bullous, pruriginous, lichen planus like, follicular variants and porokeratoma have been described...

Latency reversal agents (LRAs), such as protein kinase C (PKC) agonists, constitute a promising strategy for exposing and eliminating the HIV-1 latent reservoir. PKC agonists activate NF-κB and induce deleterious pro-inflammatory cytokine production. Adjuvant pharmacological agents, such as ruxolitinib, a JAK inhibitor, have previously been combined with LRAs to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 reactivation in vitro. Histone deacetylase inhibitors (HDACi) are known to dampen pro-inflammatory cytokine secretion in the context of other diseases and synergize with LRAs to reactivate latent HIV-1...

Euphorbia pekinensis Rupr. (EP) (Euphorbiaceae), as Traditional Chinese Medicine (TCM), exhibits therapeutic effects on tumors in clinical practice. Anti-angiogenesis may be an underlying molecular mechanism of EP's actions. However, the anti-angiogenic active ingredients of EP remain unclear. The screening and analysis of anti-angiogenic agents were essential for the sufficient utilization and development of EP. Thus, we established a UPLC-QTOF-MS method based on a transgenic zebrafish model to screen anti-angiogenesis activity components in EP...

BACKGROUND: Topical agents for actinic keratosis (AK), along with cryotherapy and phototherapy, are the most commonly used therapies for areas of skin with multiple AKs. Multiple options for the topical treatment of AK exist; newer therapies aim to balance efficacy with an acceptable safety and tolerability profile for the patient. OBJECTIVE: To describe the safety and tolerability of FDA-approved topical agents for the treatment of AK. METHODS: A systematic review of phase III clinical trials of topical agents for AK available on PubMed and clinicaltrials...

The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4+ T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4+ T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9...

Squamous cell carcinoma in situ (SCCis), also known as Bowen's disease, is a common superficial malignancy of the skin. Treatment of SCCis is important to prevent invasion into the dermis as well as metastases. Treatment of SCCis may be challenging based on the location of the tumor, advanced age, immunosuppression, medical comorbidities, or desire for noninvasive treatment. SCCis on the lower leg can be particularly challenging to treat due to poor wound healing in the setting of suboptimal circulation. This report reviews the evidence for various treatment options of SCCis, including their advantages, disadvantages, and efficacy, with an emphasis on treatment of SCCis of the lower extremity...

Euphorbia species have a rich history of ethnomedicinal use and ethnopharmacological applications in drug discovery. This is due to the presence of a wide range of diterpenes exhibiting great structural diversity and pharmacological activities. As a result, Euphorbia diterpenes have remained the focus of drug discovery investigations from natural products. The current review documents over 350 diterpenes, isolated from Euphorbia species, their structures, classification, biosynthetic pathways, and their structure-activity relationships for the period covering 2013-2020...

BACKGROUND: Mycosis fungoides (MF) is a cutaneous lymphoma; most patients present with early, skin-limited disease and are managed by dermatologists. OBJECTIVE: The purpose of this study was to systematically review and assess the evidence on topical treatments for early-stage (IA, IB, IIA) MF. METHODS: We performed a literature search via MEDLINE, Embase, Web of Science, and Cochrane databases. Grading Recommendations Assessment, Development and Evaluation (GRADE) criteria were used to assess the certainty of the data...

INTRODUCTION: Protein kinase C (PKC) is a promising drug target for various therapeutic areas. Natural products derived from plants, animals, microorganisms, and marine organisms have been used by humans as medicine from prehistoric times. Recently, several compounds derived from plants have been found to modulate PKC activities through competitive binding with ATP binding site, and other allosteric regions of PKC. As a result fresh race has been started in academia and pharmaceutical companies to develop an effective naturally derived small-molecule inhibitor to target PKC activities...

Ingenol mebutate, isolated from Euphorbia peplus , is an ingenane-type diterpenoid, primarily used for the topical treatment of actinic keratosis, a premalignant skin condition. The aim of our work was to investigate other Euphorbia species to find structurally similar diterpenes that can be used as alternatives to ingenol mebutate. Pharmacological investigation of Euphorbia candelabrum , Euphorbia cotinifolia , Euphorbia ramipressa , and Euphorbia trigona revealed the potent keratinocyte (HPV-Ker cell line) inhibitory activity of these spurge species...