Mechanism Of Action Research Articles

Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function

We discuss the article by Koizumi et al published in the World Journal of Gastroenterology . Our focus is on the therapeutic targets for fibrosis associated with alcohol-related liver disease (ALD) and the mechanism of action of elafibranor (EFN), a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and peroxisome PPAR δ (PPARδ). EFN is currently in phase III clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis. ALD progresses from alcoholic fatty liver to alcoholic steatohepatitis (ASH), with chronic ASH eventually leading to fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. The pathogenesis of ALD is driven by hepatic steatosis, oxidative stress, and acetaldehyde toxicity. Alcohol consumption disrupts lipid metabolism by inactivating PPARα, exacerbating the progression of ALD. EFN primarily activates PPARα, promoting lipolysis and β-oxidation in ethanol-stimulated HepG2 cells, which significantly reduces hepatic steatosis, apoptosis, and fibrosis in an ALD mouse model. Additionally, alcohol disrupts the gut-liver axis at several interconnected levels, contributing to a proinflammatory environment in the liver. EFN helps alleviate intestinal hyperpermeability by restoring tight junction protein expression and autophagy, inhibiting apoptosis and inflammatory responses, and enhancing intestinal barrier function through PPARδ activation.

Cinnamaldehyde in Focus: Antimicrobial Properties, Biosynthetic Pathway, and Industrial Applications

Trans-cinnamaldehyde (TCA), a major bioactive compound derived from cinnamon (Cinnamomum spp.), has garnered significant attention for its diverse therapeutic properties. Its broad-spectrum antimicrobial activity, targeting both Gram-positive and Gram-negative bacteria as well as various fungi, positions TCA as a potent natural antimicrobial agent. Beyond its antimicrobial effects, TCA demonstrates promising antidiabetic and anti-inflammatory activities, making it a valuable compound in medicinal and cosmetic applications. Recent studies have highlighted its role in disrupting microbial membranes, inhibiting biofilm formation, and modulating key metabolic pathways in pathogens. Furthermore, TCA has gained popularity in cosmetics due to its antimicrobial activity, antioxidant properties, and skin-friendly profile. This review provides a comprehensive overview of TCA’s antimicrobial potential, focusing on its mechanisms of action and its market and industrial applications. We also discuss the biosynthetic pathway of TCA, exploring both its natural production in cinnamon and advances in biotechnological production methods. As the demand for sustainable and natural antimicrobial agents grows, TCA emerges as a promising candidate for diverse applications. Finally, this review explores future directions for optimizing TCA production through metabolic engineering and synthetic biology approaches to meet industrial-scale demands.

Review of Thymic Peptides and Hormones: From Their Properties to Clinical Application

Abstract Background The thymus is the main lymphoid organ that regulates the functions of the immune system, protecting against pathogens, tumors, antigens, and mediators of tissue damage. It produces a family of hormone-like peptides that can modulate physiological processes such as stimulation or suppression of immune responses, angiogenesis, and wound healing. Objective This review aims to comprehensively characterize the properties of thymic peptides and their clinical applications. Methodology This article discusses the structure, biological properties, mechanism of action, and therapeutic applications of the most important thymic hormones (thymosin alpha 1, thymosin beta-4, thymulin, and thymopoietin), as well as preparations that are purified thymic extracts. Results Thymic peptides and extracts act in multiple manners on the immune system: they stimulate the differentiation and maturation of T cells, regulate the activity of natural killer cells and dendritic cells, and induce the release of proinflammatory cytokines, and their immunomodulatory effects have been confirmed in numerous clinical studies. An important feature of thymus preparations is their therapeutic safety—even long-term use does not cause side effects. Conclusions A wide range of therapeutic uses, i.e., from defensive and immunomodulatory tasks to participation in tissue regeneration processes, has led to the use of thymic peptides in the treatment of neoplastic diseases, viral infections, autoimmune diseases or immunodeficiencies. Further investigation of the mechanisms of action of thymic peptides may contribute to the discovery of new therapeutic targets.

Photodynamic Therapy in Acne Vulgaris: A Systematic Review

Acne is a multifactorial disorder of the pilosebaceous unit. Photodynamic therapy (PDT) is an energy-based treatment shown to be safe in acne vulgaris, although the mechanism of action of PDT in acne is incompletely understood. This review summarizes the clinical features of and treatment efficacy in acne patients treated with PDT. A systematic review of Medline, Embase, and the Cochrane Database of Systematic Reviews was conducted. Title, abstract, full-text screening, and data extraction were completed using Covidence. Studies reporting the use of PDT in patients with acne were included while clinical features and treatment responses were extracted. Treatment outcomes were scored as complete response, partial response, and no response. After screening a total of 1122 studies, 82 studies met the inclusion criteria, representing 56 prospective studies, 25 randomized controlled trials, and 1 retrospective study. Results representing 4340 patients with acne (mean age 24.4 years; 52% females) treated with PDT are summarized. Overall, 2154 (50%) participants underwent aminolevulinic acid PDT, 452 (10%) participants underwent methyl aminolevulinate PDT, 28 (<1%) participants underwent daylight PDT, and 1706 (39%) underwent other modalities of PDT. The average follow-up period after study completion was 3 months, ranging from 2 weeks to 13 months. A partial response was observed in treated patients with outcome measures including clinical response, lesion count, pain, recurrence, and patient satisfaction. This systematic review provides preliminary data summarizing the clinical features and treatment efficacy in patients with acne treated with PDT. Our results suggest a partial clinical response when using PDT to manage acne. Future studies should focus on standardizing study protocols and drawing direct comparisons between PDT and other modalities for acne treatment.

Microwave Energy for Managing Hidradenitis Suppurativa

Title: Microwave energy for managing Hidradenitis Suppurativa Nicole Bielecki PA-C and Aaron Hoover MD Front Range Dermatology, Greeley, CO 80634 Introduction: Treating hidradenitis suppurativa (HS) is challenging due to its chronic, recurring nature and resistance to conventional therapies like antibiotics, anti-inflammatories, and surgery. Even with new biological treatments, there are challenges with injection site reactions. The associated pain, drainage, malodor, and scarring also significantly impact patients' mental well-being, underscoring the need for novel treatments. Four cases presented here suggest that microwave energy (ME) therapy can reduce pain, erythema and inflammation in HS lesions and even assist to resolve moderate and smaller lesions. Precise and brief surface-based applications of microwave energy to HS lesions from an FDA-cleared microwave device intended for the coagulation of soft tissue were used to generate localized hyperthermic conditions in HS and pre-HS lesions. The rapid heating of the tissues led to subsequent clearance of moderate and small HS lesions. This was accompanied with a reduction in inflammation, draining and pain associated with these HS cases. While the outcomes are promising, the exact mechanism of action needs further investigation. These cases strongly support further research and demonstrate that ME holds promise as a novel, non-invasive treatment modality for the management of HS. Procedure: A total of 25 HS lesions from five patients were treated with ME energy. Five repetitive 2-second pulses of 3 to 4W of ME operating at 8GHz were applied to the full area of these lesions. Three to four treatment sessions were given ranging from 7 to 14 days apart. Two patients received ME as a monotherapy, whereas the others began regimens of isotretinoin, adalimumab, or secukinumab at the same time as the first ME treatment. Results: These five patient cases demonstrate how ME treatments can lead to a rapid reduction in reported pain and erythema as well as clinical-assessed clearance of several early and moderate state HS lesions. Two of these patients only received ME as a monotherapy. However, based on clinical experience, even patients typically on medications will not typically show improvements within 7-14 days, suggesting that ME was having a rapid impact to manage pain and inflammation associated with HS lesions and in some cases assisting to resolve these lesions entirely. Conclusions: These cases report the first step in clinical feasibility and safety of microwave energy and shows promise as a novel modality for the management of HS. Although still in the early days of feasibility work, this non-invasive, fast, well-tolerated and simple treatment of microwave energy shows promise as a novel modality for the management of HS. Financial support: This work was supported by Emblation Ltd.

Вплив червоного та синього електромагнітного випромінювання на каталазну активність зародків в’юна Misgurnus fossilis L.

Photobiomodulation therapy is widely used to treat various pathological conditions. This therapy is based on the use of monochromatic light radiation. The light of the visible spectrum induces different biological effects at the molecular and cellular levels, both therapeutic and toxic. The obtained effect depends on the length of radiation, exposure, etc. One of the possible mechanisms of such influence is the regulation of pro-oxidant-antioxidant homeostasis. In order to clarify the mechanism of action of electromagnetic radiation (EMR) of different spectral composition, catalase (CAT) activity was investigated in germ cells of loach Misgurnus fossilis L. during embryogenesis. Since, loach embryos are an adequate system that reflects the physiological state of the cell both under normal conditions and as a result of the influence of various pharmacological, physical and chemical agents. The resulting zygotes were irradiated (10 min) with blue and red LEDs (λ = 460 and 660 nm, respectively). The activity of CAT was determined by the ability of hydrogen peroxi­de to form a stable colored complex with molybdenum salts. It was established that EMR of the red spectrum has the most pronounced biological effects and caused significant changes in catalase activity during embryogenesis relative to control and blue light. The maximum increase of the indicator occurs at the stage of 16 blastomeres, and at the stage of 8 and 10 divisions, a gradual decrease in enzymatic activity is observed. Irradiation by the light of the blue spectrum lasting 10 min did not cause significant changes in catalase activi­ty relative to the control at the early stages of loach embryogenesis. The obtained results suggest that CAT, one of the key enzymes of the antioxidant defense system, undergoes photoactivation under the influence of red light.

Evaluation of Changes in Laboratory Parameters from a Phase 2b Trial of Zasocitinib (TAK-279), an Oral, Selective TYK2 Inhibitor, in Patients with Moderate-to-Severe Plaque Psoriasis

Background: Zasocitinib (TAK-279) is an oral, allosteric, and highly selective tyrosine kinase 2 inhibitor. In a recent phase 2b trial (NCT04999839), more patients with moderate-to-severe plaque psoriasis treated with zasocitinib 15 and 30 mg once daily achieved 75% improvement in the psoriasis area and severity index at Week 12 (primary endpoint) than those receiving placebo (PBO; p < 0.001). Here we report an assessment of laboratory parameters from this study. Methods: In this randomized, multicenter, double-blinded, PBO-controlled study, adults with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive oral zasocitinib (2, 5, 15 or 30 mg) or PBO once daily for 12 weeks. The safety analysis set included all patients who received ≥1 dose of the assigned study treatment. Laboratory parameters assessed throughout the trial included creatine kinase (CK), as well as hematologic (neutrophils, lymphocytes, hemoglobin, platelets), hepatic and renal (alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, estimated glomerular filtration rate), and lipid (cholesterol, triglycerides) parameters. Results: In total, 259 patients were included in the safety analysis set. Longitudinal changes in all laboratory parameters were generally similar in the PBO and zasocitinib groups. Mean values of most laboratory parameters remained within normal ranges during the study. There was no relationship between zasocitinib treatment and cytopenia. Some CK elevations were observed in both the PBO and zasocitinib groups, but most were transient or reversible and of Common Terminology Criteria for Adverse Events Grade 1 or 2 (Grade ≥2 events occurred in 2 [3.8%], 2 [4.0%], 6 [11.5%], 4 [7.5%] and 3 [5.8%] patients, in the PBO, and 2, 5, 15 and 30 mg groups, respectively), and were not associated with rhabdomyolysis. Mean triglyceride values were slightly higher than normal ranges at baseline and Week 12 in all treatment groups, including PBO, and were mainly asymptomatic, mild-to-moderate elevations. These changes were not accompanied by increases in serum cholesterol levels. Conclusion: Zasocitinib treatment did not result in adverse changes in hematologic, hepatic, renal or lipid parameters that are associated with Janus kinase (JAK) inhibition, suggesting that the mechanism of action of zasocitinib is distinct from that of JAK1/2/3 inhibition. Further phase 3 studies of zasocitinib in psoriasis are ongoing to confirm these observations (NCT06088043; NCT06108544).

Antibacterial Activity of Clindamycin/BPO in Combination With Adapalene

Introduction: Acne guidelines recommend the addition of benzoyl peroxide (BPO) to antibiotics to reduce resistance in Cutibacterium acnes (C. acnes). Pairing the antibiotic/BPO combination with a retinoid, such as adapalene, may further increase treatment efficacy, although research on adapalene’s antibacterial activity is limited. To determine if adapalene improves antimicrobial activity, this in vitro study evaluated minimum inhibitory concentration (MIC) of clindamycin, adapalene, and BPO alone or in combination against both susceptible and resistant C. acnes isolates. Methods: Part 1a: C. acnes sensitivity to clindamycin, adapalene, or BPO was assessed via MIC values obtained by the broth microdilution method, with lower MIC indicating higher susceptibility. Part 1b: The effect (synergistic, additive, antagonistic, or indifferent [no interaction]) of combining adapalene with clindamycin or BPO on C. acnes inhibition was evaluated using a checkerboard assay, wherein two test compounds are combined in varying concentrations. Part 2: Susceptibility to single formulations of clindamycin, adapalene, and BPO, and fixed-dose combination formulations of an antibiotic (clindamycin or erythromycin) with BPO was determined by measuring antibacterial zone of inhibition using agar diffusion method, with larger diameter indicating increased bacterial inhibition. Results: Part 1a: Clindamycin demonstrated strain-dependent activity (MIC range: <0.125-64 μg/ml), while BPO and adapalene had no/low activity as indicated by high MIC (>512 and >64, respectively) against the 6 acne-associated strains tested. Part 1b: The combination of adapalene with clindamycin resulted in an additive effect for 3 and no interaction for 1 strain, whereas adapalene with BPO did not result in any interaction against the 4 acne-associated strains tested. Part 2: Activity of single formulations varied, with adapalene 0.1% having no activity (zone of inhibition: 0 cm) against any of the 8 acne-associated C. acnes strains tested. The fixed-dose combination formulations had generally similar activity against all strains tested (range: 0.9-5 cm). Conclusions: In these in vitro analyses, adapalene and BPO had no/low activity against C. acnes, whereas clindamycin alone or in combination formulations demonstrated strain-dependent activity. The relatively high MIC of BPO is not unexpected and aligns with previous studies in which the in vitro activity of BPO was low compared to its high in vivo antimicrobial activity. Further, addition of the retinoid adapalene had an additive effect on the antimicrobial activity of clindamycin against 3 out of 4 C. acnes strains tested, but no effect on the activity of BPO in vitro. Taken together, these data suggest that when combined with clindamycin/BPO, adapalene may enhance antimicrobial activity, while also bringing its own, unique retinoid mechanism of action to the triple combination, adding to clindamycin's bacteriostatic and anti-inflammatory properties. Funding: Ortho Dermatologics

Effect and mechanism of different exogenous biomolecules on the thermal‐induced gel properties of surimi: A review

AbstractSurimi products are favored by domestic and foreign consumers due to their distinctive gelatinous texture, rich nutrition, and convenient consumption. Gel properties are key evaluation indicators for the quality of surimi products, which was mainly determined by the gel‐forming ability of the myofibrillar protein (MP). In recent years, the surimi processing industry has faced challenges in product quality that limits the further development, and how to effectively improve the gel properties of surimi products has become one of the key scientific problems to be solved in surimi processing industry. A viable strategy for improving the product quality involves combining surimi with exogenous additives, such as proteins, polysaccharides, and lipids, to enhance the gel‐forming ability of MP. At present, there is limited literature review to systematically investigate the role of these exogenous additives in interacting with MPs in surimi gel system and their effect on the gel properties of heat‐induced surimi. Therefore, in this review, we systematically discussed the formation mechanism and influencing factors of surimi gel, the interactions of exogenous biomolecules (proteins, polysaccharides, and lipids) with surimi protein, as well as their effects on the gel properties of surimi product. The aim of this review was to help us with a better understanding for the intrinsic action mechanisms of complex surimi system and provide some theoretical guidance for the improvement of gel quality and development of surimi products.

Abstract IA025: Targeting the gut microbiome for cancer immunotherapy

Abstract Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The impaired response to immunotherapy in patients treated with antibiotics supports this role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analyzed the underlying mechanisms. Gut microbial communities (microbiotypes) with non-uniform geographic distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts Now, a better understanding of the taxonomy of the species involved and of their mechanisms of action has been achieved. Defined bacterial species have been shown to promote a response to immune checkpoint inhibitors through the production of different products or metabolites, although a suppressive effect of Gram(-) bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on patients’ microbiota composition can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, the interest in modulating the microbiota composition to improve patients’ responsiveness to therapy has been mounting. Our data of a fecal microbiota transfer clinical trial in anti-PD1 refractory melanoma patients has provided clinical proof of concept of the possibility to target the gut microbiota composition in cancer therapy. Also, both in clinical studies and in experimental animals, diets rich in fibers improve the response to immunotherapy by modifying the gut microbiome suggesting the possibility of dietary approaches to target the microbiota composition in cancer therapy. However, while many early clinical studies have analyzed the association of the microbiota composition with the response to anti-PD-1 in cancer patients, emerging evidence suggests that the association may be context dependent and different types of mono or combination immunotherapies may be differentially regulated by the microbiota, Thus, a more personalized approach depending original gut microbiota composition of the patients and the type of immunotherapy protocol selected may be necessary for optimal clinical results. Citation Format: Giorgio Trinchieri. Targeting the gut microbiome for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA025.

Abstract C047: AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial

Abstract Introduction: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed across solid tumor samples using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates, with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). Preclinical efficacy studies used either AGX101 (in human tumor xenograft models, to study the tumor cell killing MoA) or AGXB01, a rodent surrogate of AGX101, to study vascular and immune MoAs and all three MoAs in syngeneic mouse cancer models. The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: TMFS41 is broadly expressed across solid tumors with increasing scoring intensity in higher grade tumors. In non-human primates, AGX101 exhibited a favorable safety profile, being tolerated at relatively high doses and with dose dependent, monitorable, and reversible effects. In preclinical efficacy studies, AGXB01 and AGX101 as monotherapies demonstrated robust efficacy through each of the three MoAs in multiple syngeneic, xenograft, and orthotopic tumor models in mice and rats as well as non-tumor models of angiogenesis. Measured by exposure, TI was large. Additionally, AGXB01 was shown to potentiate the effects of ICIs in syngeneic mouse models (CT26, Renca, and B16-F10), suggesting a potential synergistic approach in cancer therapy. The first dose level of AGX101 monotherapy in humans has cleared without DLTs. Conclusion: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing. Citation Format: Ildefonso Ismael Rodriguez Rivera, Meredith S. Pelster, Shou-Ching Jaminet, Paul Jaminet, Glen J. Weiss. AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C047.

L-arginine Supplementation in Endurance Athletes: A Systematic Review of Recovery Mechanisms and Performance Enhancement

L-arginine, a semi-essential amino acid, has garnered significant attention for its potential to enhance athletic performance, particularly within endurance sports. Recognized for its multifaceted roles in cardiovascular, immune, and metabolic functions, L-arginine serves as a precursor to biologically active molecules, including nitric oxide (NO), creatine, and polyamines, which are integral to muscle function and recovery. Through its ability to stimulate NO production, L-arginine promotes vasodilation, enhancing blood flow and oxygen delivery to active muscles, thereby improving exercise efficiency and endurance. Additionally, L-arginine influences muscle protein synthesis (MPS) via activation of the mTOR signaling pathway, aids in ammonia detoxification within the urea cycle, and supports cellular energetics by facilitating ATP production. These mechanisms collectively underscore its potential to support prolonged physical exertion, reduce muscle fatigue, and expedite post-exercise recovery. This systematic review examines current evidence on L-arginine supplementation in endurance athletes, focusing on its physiological impacts, mechanisms of action, and potential to enhance recovery and performance. Despite promising findings, variability in individual responses and mixed results across studies highlight the need for refined dosing strategies and further research into long-term safety and efficacy. This review provides a comprehensive overview of L-arginine's potential as a supplement in sports nutrition, aiming to inform evidence-based recommendations for its application in endurance training and recovery strategies.

Effects of Hyperbaric Oxygen Therapy in Treatment on Diverse Diseases

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) indeed holds significant therapeutic potential across various medical conditions, primarily by increasing the concentration of oxygen delivered to tissues under pressure. Saturating tissues with oxygen allows for the effective alleviation of underlying hypoxia, facilitating healing, tissue repair and mechanisms of action leads to reducing concentration of pro-inflammatory acute phase proteins, interleukins, and cytokines. Conversely, HBOT while also boosting levels of growth factors and other cytokines that promote angiogenesis. REVIEW METHODS: The article was complied by analyzing data from PubMed and Google Scholar regarding effects of hyperbaric therapy. THE STATE OF KNOWLEDGE: Studies indicate that HBOT provides numerous opportunities in the treatment of extensive diseases acress various systems. Neurodegenerative disorders involve progressive nerve cell damage leading to motor or cognitive decline, exacerbated by oxidative stress and inflammation. HBOT has shown promise in delaying disease onset by improving mitochondrial dysfunction in motor neuron disease. In case of intestinal obstruction HBOT reduces intestinal gas volume, diameter of obstructed loops, and improves intestinal contractility. Significant benefits have been observed in conditions such as Crohn's disease and ulcerative colitis. Hyperbaric therapy presents potential benefits for the infertility, improving the environment for blastocyst implantation and pregnancy. CONCLUSION: There is no doubt that HBOT has a beneficial impact on treatment of many systems such as the nervous, cardiovascular, digestive, and skeletal. This innovative approach of hyperbaric therapy extends to selected disorders such as neurodegenerative diseases, Crohn's disease, ulcerative colitis, and infertility.

Abstract B012: Understanding the role of VISTA in regulating T cell function and the therapeutic potential of blocking VISTA in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive and highly metastatic breast cancer subtype with limited effective treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) targeting checkpoint molecules have been widely used and have shown therapeutic efficacy in treating multiple malignancies in the last decade. In TNBC, ICI targeting PD-1, alone or in combination with chemotherapy has been approved for the treatment of patients with both early and advanced stage of the disease. Although, there has been significant clinical benefit achieved from anti-PD-1 and chemotherapy, treatment efficacy is often limited to a subgroup of patients. The limited response to ICIs has been attributed to the increased infiltration of immunosuppressive cells (including MDSCs, neutrophils and tumor-associated macrophages), more importantly, the upregulation of alternative immune checkpoint receptors/ligands that may further suppress cytotoxic T cells (CD8+ T cells) in the tumor microenvironment (TME). Therefore, it has been suggested that targeting other immune checkpoint molecules may be more effective in bolstering anti-tumor immune response. V- domain Ig suppressor of T-cell activation (VISTA) is one of the immune checkpoint molecules attracting increasing attention in the context of anti-tumor immunity due to its broad expression across various cancer types and increased expression upon development of immune checkpoint resistance. However, the role of VISTA in regulating the anti-tumor immune response and its therapeutic potential in TNBC remains unclear. In our study, we observed that VISTA is expressed in TNBC patients, predominantly in neutrophils and macrophages. In the Py230 murine breast cancer model, VISTA expression increased upon paclitaxel (PTX), anti-PD-L1 and paclitaxel combined with anti-PD-L1 treatment compared to the control group, suggesting its potential role as a resistance mechanism in sustaining or further inhibiting T cells. In the Py230 model, VISTA blockade increased the infiltration and activation of CD8+ T cells, as evidenced by the higher number of CD8+ T cells, increased CD69+CD8+ T cells, and Granzyme B production, indicating that VISTA blockade improved CD8+ T cells mediated anti-tumor immunity. To functionally test the role of VISTA, we stimulated CD8+ T cells and co-cultured them with naïve macrophages or tumor educated macrophages in the presence or absence of VISTA blocking antibody. Tumor educated macrophages showed increased immunosuppressive activity which was abrogated with VISTA blockade. Moreover, we found that the immunosuppressive effect of macrophages on T cell activation needs direct cell-cell interaction between VISTA on macrophages and T cells. In conclusion, this study shows the mechanism of action of VISTA in the regulation of T cells mediated anti-tumor immune response and provides the rationale for targeting VISTA in TNBC. Citation Format: Maidinaimu Abudula, Yuliana Astuti, Meirion Raymant Raymant, Vijay Sharma, Michael Schmid, Ainhoa Mielgo. Understanding the role of VISTA in regulating T cell function and the therapeutic potential of blocking VISTA in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B012.

Unleashing the potential of Genistein and its derivatives as effective therapeutic agents for breast cancer treatment.

Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide. Genistein (Gen), a phytoestrogen soy isoflavone, has emerged as a promising agent in the prevention and treatment of breast cancer due to its ability to function as a natural selective estrogen receptor modulator (SERM). This review explores the multifaceted mechanisms through which Gen and its derivatives exert their anticancer effects, including modulation of the PI3K/Akt signaling pathway, regulation of apoptosis, inhibition of angiogenesis, and impacts on DNA methylation and enzyme functions. We discuss the dual roles of Gen in both enhancing and inhibiting estrogen receptor (ER)-dependent pathways., highlighting its complex interactions with ERα and ERβ. Furthermore, the review examines the synergistic effect of combining Gen with conventional chemotherapeutic agents such as doxorubicin, cisplatin, and selenium, as well as other natural compounds like lycopene. Clinical studies suggest that while isoflavones may not significantly influence breast cancer progression in general, the high consumption of soy isoflavones is associated with reduced recurrence rates in breast cancer survivors. Importantly, Gen's ability to modulate key signaling pathways and enhance the efficacy of existing treatments improves its potential as a valuable adjunct in breast cancer therapy. In conclusion, Gen and its derivatives offer a novel and promising approach for treatment of breast cancer. Continued research into their mechanisms of action and clinical applications will be essential in optimizing their therapeutic potential and translating these findings into effective clinical interventions.

Oxidative Stress Mechanism by Gold Compounds: A Close Look at Total ROS Increase and the Inhibition of Antioxidant Enzymes.

The antitumor activity of various gold compounds is a promising field of investigation, attracting researchers seeking potential clinical candidates. To advance this research, they explore the complex mechanisms of action of these compounds. Since the discovery of the strong inhibition of thioredoxin reductase by auranofin, the primary mechanism explored has been the inhibition of this enzyme. This inhibition disrupts the redox balance in cells, promoting oxidative stress and triggering cell death. In this review, we analyzed studies from the past decade that measured cellular ROS increase and examined the coordination structures of gold compounds. We also correlate ROS increase with the inhibition of redox-regulating enzymes, thioredoxin reductase, and glutathione reductase, to elucidate the relationship between these cellular effects and chemical structures. Our data compilation reveals that different structures exhibit varying efficacy: some significantly increase ROS production and inhibit thioredoxin reductase or glutathione reductase, while others elevate ROS levels without affecting these target enzymes, suggesting alternative mechanisms of action. This review consolidates critical evidence, enhancing our understanding of the mechanisms by which these gold complexes act and providing valuable insights for developing new therapeutic strategies against tumor cells.

An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells.

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies.

Exploring the Antiviral Potential of Artemisia annua Through JAK-STAT Pathway Targeting: A Network Pharmacology Approach

Background: Artemisia annua, a plant with antiviral potential, has shown promise against various viral infections, yet its mechanisms of action are not fully understood. This study explores A. annua’s antiviral effects using network pharmacology and molecular docking, focusing on key active compounds and their interactions with viral protein targets, particularly within the JAK-STAT signaling pathway—a critical mediator of immune responses to viral infections. Methods: From the TCMSP database, we identified eight active compounds and 335 drug targets for A. annua, with 19 intersecting targets between A. annua compounds and viral proteins. A protein–protein interaction (PPI) network highlighted 10 key hub genes, analyzed further through Gene Ontology (GO) and KEGG pathways to understand their immune and antiviral roles. ADMET properties of the active compound Patuletin (MOL004112) were assessed, followed by 200 ns molecular dynamics simulations to examine its stability in complex with JAK2. Results: PPI analysis identified JAK2, MAPK3, MAPK1, JAK1, PTPN1, HSPA8, TYK2, RAF1, MAPT, and HMOX1 as key hub genes, with JAK2 emerging as a critical regulator of immune and antiviral pathways. ADMET analysis confirmed Patuletin’s favorable pharmacokinetic properties, and molecular dynamics simulations showed a stable Patuletin-JAK2 complex, with FEL analysis indicating minimal disruption to JAK2’s intrinsic flexibility. Conclusions: These findings highlight JAK2 as a promising target in the antiviral activity of A. annua compounds, particularly Patuletin, supporting its potential as an antiviral agent and providing a foundation for further research on A. annua’s therapeutic applications.

The effects of an educational intervention on women's contraceptive preferences in the immediate postpartum period: A cross-sectional study.

To assess postpartum women's contraceptive preferences and the impact of an educational intervention on these preferences, identifying factors motivating method choices. This cross-sectional quantitative study included women within 48 h after delivery in a public Brazilian hospital. Participants were asked about their contraceptive preferences before and after an educational intervention, which aimed to inform women about the importance of early postpartum contraception, available methods, mechanisms of action, effectiveness, proper use, and side effects. A nursing professional explained contraceptives to postpartum women in individual sessions, demonstrating their use on simulators interactively for about 15 min. Statistical analyses were performed using JAMOVI version 2.3.28 and Microsoft Excel 2016. A total of 402 women (226 adolescents and 176 adults) were included. After the intervention, preference for long-acting reversible contraceptives (LARCs) increased significantly from 157 (39.1%) to 279 (68.7%) (P < 0.001). At the initial assessment, contraceptive preferences were injectable hormonal contraceptives (159 [39.6%]), intrauterine devices (IUDs) (109 [27.1%]), and implants (48 [11.9%]). After the educational intervention, IUDs became the most popular method, at 143 (35.6%), followed by implants (133 [33.1%]) and injectables (81 [20.1%]). Among adolescents, there was a significant increase in implant choice (P < 0.001) and a decrease in injectables and pills (P < 0.001; P = 0.006). Adults showed increased preference for implants (P < 0.001) and IUDs (P < 0.001), with a reduction in injectable hormonal contraceptives (P = 0.005) and tubal ligation (P = 0.006). An educational intervention during postpartum period can influence women's contraceptive choices. Timely education was associated with a significant increase in LARC preference.

Characterization of DsrD and its interaction with the DsrAB dissimilatory sulfite reductase.

Microbial dissimilatory sulfate reduction is a key process in the global sulfur and carbon cycles in anoxic ecosystems. In this anaerobic respiration, sulfate is phosphorylated and reduced to sulfite, which is further reduced to a DsrC-trisulfide by the dissimilatory sulfite reductase DsrAB. DsrD is a small protein that acts as an allosteric activator of DsrAB, increasing the efficiency of sulfite reduction. Here, we report a detailed study of DsrD and its interaction with DsrAB. Sequence similarity analyses show that there are three groups of DsrD in organisms with a reductive-type DsrAB. The protein regions involved in the DsrD-DsrAB interaction and activity-promoting effect were investigated through in vitro and in silico studies, including mutations of conserved DsrD residues. The results reveal that the conserved β-loop of DsrD is involved in the interaction, contributing to a better understanding of its mechanism of action.