Therapeutic Potential Research Articles

Interrogating the Antiobesity Efficacy of Flacourtia Inermis Roxb. Fruits in High Fat Diet-induced Obese Rats

Background Flacourtia inermis Roxb. (Salicaceae) is an underutilized edible fruit known for its antioxidant-rich bioactive compounds. This study explores the antiobesity potential of F. inermis ethanolic fruit extract (FF2) in a high-fat diet (HFD) induced obesity model using Wistar albino rats. Materials and Methods Wistar albino rats were randomly assigned into five groups (n = 6). Group 1 served as the normal control and received a normal diet (ND), while Groups II–V were induced with obesity by being fed an HFD for 10 weeks. Group II acted as the obese control, receiving 100% HFD throughout the study. Groups III, IV, and V also received HFD throughout the study but were supplemented with Orlistat (30 mg/kg b.w), and FF2 extract at doses of 200 mg/kg, and 400 mg/kg, respectively, from week 11 until week 15. Treatment impact of FF2 on body weight, body mass index (BMI), serum lipid levels, glucose levels, liver function parameters, and histopathological evaluations of liver and adipose tissue were investigated. Results The study unveiled that F. inermis fruits exerted potent antiobesity effects, with FF2 treatment (at 200 mg/kg and 400 mg/kg) substantially decreasing body weight gain and BMI in comparison to the HFD group. Supplementation of FF2 alongside an HFD reduced body weight gain, glucose levels, and serum lipid profile. Both doses of FF2 counteracted the adverse effects induced by HFD, with lower triglycerides (TG), total cholesterol, and LDL cholesterol levels, and higher HDL cholesterol levels in the treated groups compared to the positive control. Additionally, FF2 extract showed dose-dependent improvements in serum lipid and glucose levels, as well as, hepatic profile, indicated by decreased AST, ALP, and ALT levels, suggesting potential benefits in managing dyslipidemia, hyperglycemia, and liver health associated with obesity. Histological examination of white adipose tissue provided further evidence of the antiobesity effect. Conclusion The study highlights FF2’s therapeutic potential in managing obesity and associated metabolic disorders. Further investigations into FF2’s mechanisms and clinical application are essential for its development as an antiobesity therapeutic agent in functional food formulations.

Characteristic alterations of gut microbiota and serum metabolites in patients with chronic tinnitus: a multi-omics analysis

ABSTRACT Chronic tinnitus is a central nervous system disorder. Currently, the effects of gut microbiota on tinnitus remain unexplored. To explore the connection between gut microbiota and tinnitus, we conducted 16S rRNA sequencing of fecal microbiota and serum metabolomic analysis in a cohort of 70 patients with tinnitus and 30 healthy volunteers. We used the weighted gene co-expression network method to analyze the relationship between the gut microbiota and the serum metabolites. The random forest technique was utilized to select metabolites and gut taxa to construct predictive models. A pronounced gut dysbiosis in the tinnitus group, characterized by reduced bacterial diversity, an increased Firmicutes/Bacteroidetes ratio, and some opportunistic bacteria including Aeromonas and Acinetobacter were enriched. In contrast, some beneficial gut probiotics decreased, including Lactobacillales and Lactobacillaceae. In serum metabolomic analysis, serum metabolic disturbances in tinnitus patients and these differential metabolites were enriched in pathways of neuroinflammation, neurotransmitter activity, and synaptic function. The predictive models exhibited great diagnostic performance, achieving 0.94 (95% CI: 0.85–0.98) and 0.96 (95% CI: 0.86–0.99) in the test set. Our study suggests that changes in gut microbiota could potentially influence the occurrence and chronicity of tinnitus, and exert regulatory effects through changes in serum metabolites. Overall, this research provides new perceptions into the potential role of gut microbiota and serum metabolite in the pathogenesis of tinnitus, and proposes the “gut-brain-ear” concept as a pathomechanism underlying tinnitus, with significant clinical diagnostic implications and therapeutic potential. IMPORTANCE Tinnitus affects millions of people worldwide. Severe cases may lead to sleep disorders, anxiety, and depression, subsequently impacting patients’ lives and increasing societal healthcare expenditures. However, tinnitus mechanisms are poorly understood, and effective therapeutic interventions are currently lacking. We discovered the gut microbiota and serum metabolomics changes in patients with tinnitus, and provided the potential pathological mechanisms of dysregulated gut flora in chronic tinnitus. We proposed the innovative concept of the “gut-brain-ear axis,” which underscores the exploration of gut microbiota impact on susceptibility to chronic tinnitus through serum metabolic profile modulation. We also reveal novel biomarkers associated with chronic tinnitus, offering a new conceptual framework for further investigations into the susceptibility of patients, potential treatment targets for tinnitus, and assessing patient prognosis. Subsequently, gut microbiota and serum metabolites can be used as molecular markers to assess the susceptibility and prognosis of tinnitus.Furthermore, fecal transplantation may be used to treat tinnitus.

Nanoengineering of Phosphate/Phosphonate Drugs via Competitive Replacement with Metal‐Phenolic Networks to Overcome Breast Tumor with Lung and Bone Metastasis

AbstractPhosphate and phosphonate drugs are vital in building organisms, regulating physiological processes, and exhibiting diverse biological activities, including antiviral, antibacterial, antineoplastic, and enzyme‐inhibitory effects. However, their therapeutic potential is limited by the lack of advanced nanoengineering technologies. Herein, a competitive coordination strategy for nanoengineering phosphate/phosphonate drugs is introduced. By leveraging the difference in coordination capabilities between polyphenols and phosphates/phosphonates with metal ions, various phosphate/phosphonate‐based nanodrugs using metal‐phenolic networks (MPNs) as templates and phosphate/phosphonate drugs as competitive agents are constructed. The dynamic nature of these coordination bonds imparts stimuli‐responsiveness to the nanodrugs, allowing for targeted release and therapy. As a proof of concept, Fe3+ and galangin are used to form the MPN template, zoledronic acid and cGAMP as competitive agents, and DOX as the loaded drug to construct DOX@Fe‐galangin@Fe‐zoledronic acid‐cGAMP nanodrugs. The results demonstrate that, by triggering pyroptosis and activating the cGAS‐STING pathway, the nanodrugs exhibit potent cytotoxicity and accurate selectivity in eradicating orthotopic breast tumors, and activate an antitumor immune response against lung and bone metastases. Because the competitive coordination strategy is applicable to a variety of phosphate/phosphonate agents, it holds significant potential for enhancing the clinical efficacy of phosphate/phosphonate drugs and advancing nanodrug development for complex therapeutic applications.

Bioactive Phytophenolics of Vitex negundo Reveal Therapeutic Antifungal Potentials against Candida albicans

Bioactive Phytophenolics of Vitex negundo Reveal Therapeutic Antifungal Potentials against Candida albicans

Pharmacodynamic effects and exploratory efficacy of afimetoran, a TLR7/8 inhibitor, in patients with cutaneous lupus erythematosus

Background: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin condition occurring alone or as a manifestation of systemic lupus erythematosus (SLE). There is an unmet need for safe and effective CLE-focused treatments. Afimetoran is an investigational, first-in-class, potent oral inhibitor of toll-like receptors (TLRs) 7/8. Given the involvement of TLRs 7/8 in SLE, afimetoran may have therapeutic potential for CLE. A phase 1b randomized, double-blind, placebo-controlled study (NCT04493541) demonstrated preliminary safety and efficacy of afimetoran in patients with active CLE. We assessed the pharmacodynamics, safety, and efficacy of afimetoran and its impact on CLE pathobiology. Methods: Patients aged 18–65 years with SLE and cutaneous manifestations by EULAR/ACR 2019 classification criteria or biopsy-proven CLE, and modified CLE Disease Area and Severity Index-Activity (CLASI-A) score ≥6, were randomized 2:1 to once-daily afimetoran (30 mg) or placebo for 16 weeks with a 4-week post-treatment follow-up period. The primary endpoints were safety and tolerability; efficacy was exploratory. Transcriptomics and cytokine analyses were performed using peripheral whole blood and serum, respectively, at baseline (pre-dose) and each study visit (weeks 1, 2, 4, 8, 12, 16, and 20 [post-dose]). Statistical analyses compared data from the 13 randomized patients with thirteen age-, ethnicity-, and gender-matched healthy volunteers. Treatment responses were evaluated longitudinally in each treatment arm. The dataset was analyzed using a linear regression model. Gene set variation analysis (GSVA) was performed for pathway enrichment. Results: 13 patients with CLE were randomized (afimetoran, n=8; placebo, n=5); 12 patients completed 16 weeks of treatment and 1 discontinued after 6 weeks due to COVID-19. Compared with placebo, afimetoran demonstrated a favorable safety profile with no serious adverse events, and showed a greater reduction in CLASI-A scores as early as week 4, which persisted to week 20. Improvement in the molecular disease profile was rapid (week 1), sustained through the 16-week treatment period, and the 4-week post-treatment follow-up period. Expression of interferon (IFN) pathway genes was significantly reduced with afimetoran compared with baseline (ΔGSVA enrichment score [ES]=1.57, P<0.0001) and placebo (ΔGSVA ES=0.56, P<0.01); this effect was maintained through week 16 and ≥4 weeks post-treatment. Expression of TLR7 and TLR8 pathway genes and key cytokines (interleukin [IL]-6, tumor necrosis factor α, IL-18, IFNγ, macrophage inflammatory protein-1 alpha [CCL3/MiP1α] or beta [CCL4/MiP1β]) were greatly reduced with afimetoran treatment. GSVA demonstrated robust pharmacodynamic activity on immune cell populations, including immature and activated dendritic cells, macrophages, and inflammatory pathway signatures. Conclusion: In patients with CLE, afimetoran was safe, well tolerated, and demonstrated durable efficacy beyond the treatment period. Afimetoran’s clinical effects and potent pharmacodynamic impact on the molecular disease profile suggest a substantial therapeutic benefit for patients with CLE.

Ferulic acid: therapeutic potential due to its antioxidant properties, role in plant growth, and stress tolerance

Ferulic acid: therapeutic potential due to its antioxidant properties, role in plant growth, and stress tolerance

Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases

Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.

Multi-omics analysis reveals the role of the autophagy-related gene AGT in chemotherapy resistance in colorectal cancer and the therapeutic potential of its inhibitors

Multi-omics analysis reveals the role of the autophagy-related gene AGT in chemotherapy resistance in colorectal cancer and the therapeutic potential of its inhibitors

Abstract A012: Aging drives TNBC lung metastasis dependency on FGFR-triggered metabolic reprogramming exposing an age-induced liability with therapeutic potential

Abstract The clinical manifestation of metastasis in a vital organ is the final stage of breast cancer progression and the main culprit of breast cancer related mortality. This remain especially problematic in the case of triple negative breast cancer (TNBC), the most aggressive type of breast cancer, often diagnosed in its metastatic form and for which chemotherapies are still the major therapeutic option. Typically, TNBC is seen as a disease of younger women, however, 20% of TNBCs occur in patients aged 65 and older, whose prognosis is equally staggering. Unfortunately, due to co-morbidities, tolerability of chemotherapies, as well as severe reduction in quality of life, majority of women above age 65 can’t or decide not to receive chemotherapy ultimately cutting their lives short. Metastatic outgrowth is largely dictated by the ability of TNBC disseminated cancer cells (DCCs) to thrive distal organs and is largely dependent on the physiology of the specific organs. However, how the aging process, a major driver of changes in organismal physiology, affects the interaction between the host organ and TNBC DCCs remains unknown. Here, we adapted several traditional syngeneic models of TNBC metastasis to old mice of different strains and coupled with RNA-seq to unveil molecular adaptations of TNBC DCCs to the aging lung. We show that the changes that occur in the lung with aging drives an increase in mitochondrial fitness in TNBC DCCs, an adaptation that is necessary for metastasis to thrive in the old lung environment. Mechanistically, our data show that the expression of FGF19, a gut hormone not normally expressed in TNBC DCCs, drives this increase in mitochondrial fitness in the old lung through an autocrine signaling axis impinging on activation of FGF-19 cognate receptor family, FGFRs. Inhibition of FGF19-FGFR signaling using an FDA- approved FGFR inhibitor not only blocks the age-induced increase in mitochondrial fitness but also effectively abolishes lung metastasis in old, but not in young, immune competent and immune compromised mice. We traced this to age-specific metastatic adaptation of TNBC lung metastasis to the increase in bile acids, the canonical regulators of FGF19 expression, in the old lung environment. Together, our work demonstrates an important contribution of age-driven metabolic reprogramming of the host to the traits that enable metastasis to thrive in the lung and provides rationale for the use of FDA-approved FGFR inhibitors for the treatment of breast cancer lung metastasis in the most vulnerable of stage IV metastatic TNBC patients, the elderly. Citation Format: Stanislav Drapela, Shiun Chang, Rojan Chimeh Rad, Vanessa Rubio, Didem Ilter, Paulo Rodriguez, Ana P. Gomes. Aging drives TNBC lung metastasis dependency on FGFR-triggered metabolic reprogramming exposing an age-induced liability with therapeutic potential [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 A012.

The Role of Urinary Extracellular Vesicles in Kidney Cancer: Diagnostic and Therapeutic Potential

Renal cancer ranks as the 14th most common cancer globally, with renal cell carcinoma (RCC) being the primary variant, arising from renal tubular epithelial cells; clear cell RCC constitutes about 80% of cases. Despite their limitations, surgery and targeted therapy remain the mainstays of RCC treatment. Regardless of advancements in RCC research, substantial obstacles continue to exist, such as delayed diagnosis, advanced distant metastasis, and drug resistance. As urine is an easily accessible biofluid, the identification of EVs has paved the way for novel biomarker research. Urinary extracellular vesicles (uEVs) are a novel source of biomarkers with potential applications in cancer detection and management, utilizing a less invasive approach. New data indicate that uEVs are crucial in several areas of RCC, containing tumor development, metastasis, immune evasion, and response to drugs. These vesicles facilitate intercellular communication by transporting a variety of bioactive substances, including RNA, DNA, proteins, and lipids, and are released into the extracellular space by the majority of cell types. uEVs RNAs and proteins are presently being investigated for their possible application as diagnostic biomarkers for different types of kidney cancer. This review summarizes the most recent research examining the potential of uEVs cargo as a biomarker for the diagnosis, prognosis, and treatment of renal cancer.

Abstract C048: Intrapatient heterogeneity and targeting microenvironment protection mechanisms in melanoma metastasis

Abstract Intrapatient tumor heterogeneity contributes to immunotherapy and targeted therapy resistance in cutaneous metastatic melanoma patients. More than 50% of melanoma patients develop brain metastases (MBM) during disease progressionand these patients have a very poor prognosis with a median overall survival of 4 months. To assess how tumors persist through treatments and adapt to and rely on organ-specific microenvironments, we utilized samples from a patient who had received anti-CTLA4, BRAFi/MEKi, and BRAFi/MEKi+CDK4/6i treatments during the LOGIC2 clinical trial. Eight short-term melanoma cultures (STMCs) were established from different metastatic site biopsies at chronological time points throughout the patient’s treatment and subsequent post-mortem resection of the bone, ovary, and brain metastatic sites. While the initial treatment naïve metastatic tumor in the breast was BRAF V600E mutant, NRAS Q61 mutations were acquired after treatment with CDK4/6i in the bone and ovary tumors. We performed single-cell RNA sequencing and identified that each STMC consists of 2-10 different subpopulations. By cell viability assay, we determined all STMCs were resistant to CDK4/6i, however had varying degrees of response to BRAFi and MEKi in vitro. Two STMCs (MM150604, MM150859) were sensitive to both BRAFi and MEKi. We identified HER3 was upregulated in the sensitive STMCs and more specifically, HER3 expression was elevated in the MBM STMC and in other MBM patient tumors in publicly available datasets. In publicly available data of the MBM tumor microenvironment (TME), neurons produce NRG1 and NRG2 while astrocytes and pericytes produce NRG2, exogenous sources of NRGs in the MBM TME that act as ligands for the HER3 receptor. Treatment with recombinant NRG1 partially rescued the growth of MBM cells and restored MAPK and AKT-mTOR signaling in the presence of BRAFi/MEKi suggesting that the brain microenvironment may play a role in drug tolerance. This novel finding demonstrates a unique role of HER3 in MBM and targeting the NRG-HER3 signaling axis could have therapeutic potential in melanoma patients with active brain metastases. Citation Format: Haley P. Wilson, Glenn L. Mersky, Jelan I. Haj, Jessica L.F. Teh, Phil F. Cheng, Signe Caksa, Manal Mustafa, Isabella Trachtenberg, Francis J. Waltrich Jr, Casey D. Stefanski, Vivian Chua, Dan A. Erkes, Mitchell P. Levesque, Reinhard Dummer, Timothy J. Purwin, Claudia Capparelli, Andrew E. Aplin. Intrapatient heterogeneity and targeting microenvironment protection mechanisms in melanoma metastasis [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 C048.

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.

Impact of Hyaluronic Acid and Other Re-Epithelializing Agents in Periodontal Regeneration: A Molecular Perspective

This narrative review delves into the molecular mechanisms of hyaluronic acid (HA) and re-epithelializing agents in the context of periodontal regeneration. Periodontitis, characterized by chronic inflammation and the destruction of tooth-supporting tissues, presents a significant challenge in restorative dentistry. Traditional non-surgical therapies (NSPTs) sometimes fail to fully manage subgingival biofilms and could benefit from adjunctive treatments. HA, with its antibacterial, antifungal, anti-inflammatory, angiogenic, and osteoinductive properties, offers promising therapeutic potential. This review synthesizes the current literature on the bioactive effects of HA and re-epithelializing agents, such as growth factors and biomaterials, in promoting cell migration, proliferation, and extracellular matrix (ECM) synthesis. By modulating signaling pathways like the Wnt/β-catenin, TGF-β, and CD44 interaction pathways, HA enhances wound healing processes and tissue regeneration. Additionally, the role of HA in facilitating cellular crosstalk between epithelial and connective tissues is highlighted, as it impacts the inflammatory response and ECM remodeling. This review also explores the combined use of HA with growth factors and cytokines in wound healing, revealing how these agents interact synergistically to optimize periodontal regeneration. Future perspectives emphasize the need for further clinical trials to evaluate the long-term outcomes of these therapies and their potential integration into periodontal treatment paradigms.

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.

Spinal cord stimulation induces Neurotrophin-3 to improve diabetic foot disease.

Low-extremity ischemic disease is a common complication in diabetic patients, leading to reduced quality of life and potential amputation. This study investigated the therapeutic effect of spinal cord stimulation (SCS) on patients with diabetic foot disease and a rat model of diabetic foot injury. SCS was applied to patients with diabetic foot disease, with clinical assessments performed before and after therapy. Blood levels of NGF, BDNF, and NT-3 were determined by ELISA. A rat model of diabetic foot injury was established to validate NT-3's role in SCS therapy. SCS therapy improved the condition of patients with diabetic ischemic foot disease and promoted wound healing in the rat model. NT-3 levels significantly increased after SCS therapy in both patients and rats. Recombinant NT-3 administration improved wound healing and re-vascularization in the rat model, while NT-3 neutralization abrogated SCS's therapeutic effect. SCS improves the condition of patients with diabetic ischemic foot disease by inducing NT-3 production. Both SCS and NT-3 supplementation show therapeutic potential for ameliorating diabetic foot disease.

Abstract A021: HRI inhibition by hemin as a novel targeted therapy for glioblastoma via the integrated stress response

Abstract The treatment of glioblastoma (GBM), a highly malignant brain tumor, is critically hindered by the ineffectiveness of current modalities such as surgery, radiation, and chemotherapy. These traditional methods fail to completely remove the tumor mass and lack the ability to discriminate between cancerous and normal brain cells, often resulting in damage to healthy tissue and recurrence of the disease. This underscores an urgent necessity to develop novel therapeutic strategies that can target tumor cells with precision, offering hope for improved survival rates and quality of life for GBM patients. This study investigates targeted therapy, focusing on the Integrated Stress Response (ISR) that cancer cells harness to survive hypoxic stress. Specifically, it demonstrates that EIF2AK1, which encodes Heme-regulated eIF2α kinase (HRI), is activated under hypoxia and co-expressed with the glioma stem cell marker SOX2, which specifically happens in glioma cells, increasing the targeted accuracy of the repurposing drug. This correlation, indicating hypoxia-driven stemness, is confirmed at both the genetic level and through Gene Set Enrichment Analysis (GSEA). Furthermore, GSEA in Spatial Transcriptomics shows hypoxia-induced glycolysis, disrupting the tumor microenvironment and causing necrotic cell death. Stemness phenotype is induced in the peripheral cells due to the unfavorable hypoxic environment. Hemin, an HRI inhibitor, has been repurposed to inhibit ISR and mitigate hypoxia. Treatment with Hemin on the U87 cell line resulted in IC50 values of 23.50 µM and 52.46 µM at 24 and 48 hours, respectively, surpassing Temozolomide's efficacy. A decrease in HRI expression after the Hemin treatment suggests the and ISR activity and, potentially, hypoxia. This would reverse the unfavorable microenvironment so that the stemness phenotype doesn’t spread. Potentially, invasiveness and recurrences of GBM in clinic situation would decrease, thus potentially improving patient prognosis. The therapeutic potential of Hemin is enhanced by its ability to kill glioma cells directly and accurately in the glioma cell in original TME when cells are proliferating with adequate oxygen. Therefore, this study demonstrates the therapeutic potential of repurposing Hemin, an HRI inhibitor, to precisely target hypoxia-induced glioma stem cells in glioblastomas, disrupting the aggressive tumor microenvironment to potentially improve patient prognosis. Citation Format: Xingchuan Ma. HRI inhibition by hemin as a novel targeted therapy for glioblastoma via the integrated stress response [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 A021.

PinX1 plays multifaceted roles in human cancers: a review and perspectives.

Pin2/TRF1 interacting protein X1 (PinX1), a telomerase inhibitor, is located at human chromosome 8p23. This region is important for telomere length maintenance and chromosome stability, both of which are essential for regulating human ageing and associated diseases. We investigated the research progress of PinX1 in human cancers. In cancers, the expression levels of PinX1 mRNA and protein vary according to cancer cell types, and PinX1 plays a critical role in the regulation of cancer development and progression. Additionally, a review of the literature indicates that PinX1 is involved in mitosis and affects the sensitivity of cancer cells to radiation-induced DNA damage. Therefore, PinX1 has therapeutic potential for cancer, and understanding the function of PinX1 in the regulation of cancers is crucial for improving treatment. In this review, we discuss the expression level of PinX1 in a variety of cancers and how it affects the implicated pathways. Additionally, we outline the function of PinX1 in cancer cells and provide a theoretical basis for PinX1-related cancer therapy. PinX1 has promising prospects in future cancer therapeutics. This review may provide theoretical support for researchers in this field.

2D4, a humanized monoclonal antibody targeting CD132, is a promising treatment for systemic lupus erythematosus

AbstractCurrent therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness. To address this limitation, our focus was on CD132, a subunit common to six inflammatory factor receptors implicated in SLE. Our study revealed heightened CD132 expression in SLE patients’ lymphocytes, contributing to the production of pro-inflammatory cytokines and immunoglobulins. We developed a novel humanized anti-CD132 monoclonal antibody, named as 2D4. 2D4 efficiently blocked IL-21 and IL-15, with limited effectiveness against IL-2, thereby suppressing T and B cells without disrupting immune tolerance. In the mouse immunization model, 2D4 virtually inhibited T cell-dependent, antigen-specific B-cell response. In lupus murine models, 2D4 mitigated inflammation by suppressing multiple pro-inflammatory cytokines and anti-dsDNA antibody titers, also diminishing proteinuria and glomerulonephritis. Compared to Belimumab, 2D4 exhibited superior efficacy in ameliorating the inflammatory state and preserving renal function. Moreover, 2D4 exhibited the ability to inhibit the production of pro-inflammatory factors and autoantibodies in PBMCs from individuals with SLE, highlighting its therapeutic potential for SLE individuals. Potent, 2D4 has the potential to significantly improve clinical outcomes in SLE and other complex autoimmune disorders.

Synthesis of liposomal nanoparticles to load 4-farnesyloxycoumarin and investigating its anti-cancer and anti-metastatic effects.

The aim of this study was to load 4-farnesyloxycoumarin (4-FLC) in nanoliposomes (4-FLC-LNPs) and evaluate its anti-cancer and anti-metastatic effects. 4-FLC-LNPs were synthesized using a combination of lecithin-cholesterol-polyethylene glycol. The physicochemical properties were evaluated using DLS, FTIR, and microscopy methods. The toxicity against breast cancer (MCF-7), prostate cancer (PS3), pancreatic cancer (PANC), gastric cancer (AGS), and normal cell lines (HUVEC) was evaluated using the MTT assay. Fluorescent staining and flow cytometry were used to assess the occurrence of apoptosis. Molecular analysis methods were used to study the apoptosis and metastasis effects of these nanoliposomes. The antioxidant power of 4-FLC-LNPs was measured using the ABTS and DPPH free radicals methods. 4-FLC-LNPs exhibit a spherical morphology, with an average size of 57.43 nm, a polydispersity index of 0.29, and a zeta potential of -31.4 mV. They demonstrate an encapsulation efficiency of 82.4% for 4-FLC. The IC50 value of 4-FLC-LNPs against the breast cancer cell line was reported as the most sensitive, at approximately 60 μg/mL. ABTS and DPPH results were reported at approximately 30 µg/mL. The inductive effects of nanoliposomes on the apoptosis process were confirmed by an increase in the number of apoptotic cells, as well as the arrest of cells in various phases of cell growth. The increased expression of BAX and decreased expression of Bcl-2, MMP-2, and MMP-9 confirmed the pro-apoptotic and anti-metastatic effects of 4-FLC-LNPs. These finding validate the therapeutic potential of 4-FLC-LNPs, which may be utilized in preclinical studies.

Unlocking the promise of MANF in diseases: Mechanistic insights and therapeutic potentials.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a ubiquitous neurotrophic factor that exhibits a variety of physiological functions and plays a critical role in the exploitation of therapeutic potential across a range of diseases, including cardiovascular disorders, nervous system diseases, metabolic imbalances, and cancers. In the context of cardiac diseases, MANF significantly promotes cardiomyocyte survival and improves cardiac functionality. Furthermore, MANF not only provides neuroprotection by shielding neurons from damage and promoting nerve regeneration in neurological disorders, but also involves in insulin resistance, lipid metabolism disturbances and fat-containing liver lesions. However, the oncogenic or tumor suppressive function of MANF in cancer remains unclear, requiring further investigation to elucidate its precise role in the process of cancer initiation and progression. This review aims to summarize the latest advancements in understanding the molecular pathways, intricate mechanisms, and therapeutic potential of MANF in the prevention and treatment of various diseases, emphasizing its multifaceted contributions to health and disease management.