Multiple Mechanisms Of Action Research Articles

Antiviral mechanisms of two broad-spectrum monoclonal antibodies for rabies prophylaxis and therapy.

Rabies is an acute and lethal encephalomyelitis caused by lyssaviruses, among which rabies virus (RABV) is the most prevalent and important for public health. Although preventable through the post-exposure administration of rabies vaccine and immunoglobulins (RIGs), the disease is almost invariably fatal since the onset of clinical signs. Two human neutralizing monoclonal antibodies (mAbs), RVC20 and RVC58, have been shown to be effective in treating symptomatic rabies. To better understand how these mAbs work, we conducted structural modeling and in vitro assays to analyze their mechanisms of action, including their ability to mediate Fc-dependent effector functions. Our results indicate that both RVC20 and RVC58 recognize and lock the RABV-G protein in its pre-fusion conformation. RVC58 was shown to neutralize more potently the extra-cellular virus, while RVC20 mainly acts by reducing viral spreading from infected cells. Importantly, RVC20 was more effective in promoting effector functions compared to RVC58 and 17C7-RAB1 mAbs, the latter of which is approved for human rabies post-exposure treatment. These results provide valuable insights into the multiple mechanisms of action of RVC20 and RVC58 mAbs, offering relevant information for the development of these mAbs as treatment for human rabies.

Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies.

Background Cancer remains a critical global health challenge and a leading cause of mortality. Flavonoids found in fruits and vegetables have gained attention for their potential anti-cancer properties. Fisetin, abundantly present in strawberries, apples, onions, and other plant sources, has emerged as a promising candidate for cancer prevention. Epidemiological studies linking a diet rich in these foods to lower cancer risk have sparked extensive research on fisetin's efficacy. Objective This review aims to comprehensively explore the molecular mechanisms of fisetin's anticancer properties and investigate its potential synergistic effects with other anticancer drugs. Furthermore, the review examines the therapeutic and preventive effects of fisetin against various cancers. Methods A systematic analysis of the available scientific literature was conducted, including research articles, clinical trials, and review papers related to fisetin's anticancer properties. Reputable databases were searched, and selected studies were critically evaluated to extract essential information on fisetin's mechanisms of action and its interactions with other anticancer drugs. Results Preclinical trials have demonstrated that fisetin inhibits cancer cell growth through mechanisms such as cell cycle alteration, induction of apoptosis, and activation of the autophagy signaling pathway. Additionally, fisetin reduces reactive oxygen species levels, contributing to its overall anticancer potential. Investigation of its synergistic effects with other anticancer drugs suggests potential for combination therapies. Conclusion Fisetin, a bioactive flavonoid abundant in fruits and vegetables, exhibits promising anticancer properties through multiple mechanisms of action. Preclinical trials provide a foundation for further exploration in human clinical trials. Understanding fisetin's molecular mechanisms is vital for developing novel, safe, and effective cancer prevention and treatment strategies. The potential synergy with other anticancer drugs opens new avenues for combination therapies, enhancing cancer management approaches and global health outcomes.

Laterosporulin25: A probiotically produced, novel defensin-like bacteriocin and its immunogenic properties.

Although multiple vaccines have been developed against infectious diseases, the rapid emergence of new pathogens develops an urgent need for novel strategies to combat infectious diseases. Antimicrobial peptides (AMPs) are excellent agents to fight against infectious diseases having unique multiple mechanisms of action against various pathogens. Apart from the direct applications, AMPs can also be developed as subunit vaccines or could be used as a highly immunogenic carrier protein with highly antigenic but non-immunogenic antigens. Here in the present study, we have identified a novel defensin-like bacteriocin, laterosporulin25 (LS25) upon genome mining of Brevibacillus laterosporus DSM25, a probiotic bacterial strain. By using immunoinformatic tools, we have studied the immunogenic and physiochemical properties of LS25. LS25 is characterized as defensin-like bacteriocin, having 51 amino acids and a molecular weight of 5862.7Da. The modeled tertiary structure of LS25 is docked with TLR3 and TLR4-MD2 complex to confirm the facilitation of induced immune response that is further validated using molecular dynamics simulations and In-silico immune stimulations. Overall, detailed immunoinformatics analysis suggested LS25 as a potential candidate to be used as an adjuvant or carrier protein for subunit vaccine development, however, further in-vitro and in-vivo experiments are essential to validate its potential.

HCS-Splice: A High-Content Screening Method to Advance the Discovery of RNA Splicing-Modulating Therapeutics.

Nucleic acid therapeutics have demonstrated an impressive acceleration in recent years. They work through multiple mechanisms of action, including the downregulation of gene expression and the modulation of RNA splicing. While several drugs based on the former mechanism have been approved, few target the latter, despite the promise of RNA splicing modulation. To improve our ability to discover novel RNA splicing-modulating therapies, we developed HCS-Splice, a robust cell-based High-Content Screening (HCS) assay. By implementing the use of a two-colour (GFP/RFP) fluorescent splicing reporter plasmid, we developed a versatile, effective, rapid, and robust high-throughput strategy for the identification of potent splicing-modulating molecules. The HCS-Splice strategy can also be used to functionally confirm splicing mutations in human genetic disorders or to screen drug candidates. As a proof-of-concept, we introduced a dementia-related splice-switching mutation in the Microtubule-Associated Protein Tau (MAPT) exon 10 splicing reporter. We applied HCS-Splice to the wild-type and mutant reporters and measured the functional change in exon 10 inclusion. To demonstrate the applicability of the method in cell-based drug discovery, HCS-Splice was used to evaluate the efficacy of an exon 10-targeting siRNA, which was able to restore the correct alternative splicing balance.

DVL, lectin from Dioclea violacea seeds, has multiples mechanisms of action against Candida spp via carbohydrate recognition domain

Lectins are proteins of non-immunological origin with the ability to bind to carbohydrates reversibly. They emerge as an alternative to conventional antifungals, given the ability to interact with carbohydrates in the fungal cell wall inhibiting fungal growth. The lectin from D. violacea (DVL) already has its activity described as anti-candida in some species. Here, we observed the anti-candida effect of DVL on C. albicans, C. krusei and C. parapsilosis and its multiple mechanisms of action toward the yeasts. Additionally, it was observed that DVL induces membrane and cell wall damage and ROS overproduction. DVL was also able to cause an imbalance in the redox system of the cells, interact with ergosterol, inhibit ergosterol biosynthesis, and induce cytochrome c release from the mitochondrial membrane. These results endorse the potential application of DVL in developing a new antifungal drug to fight back against fungal resistance.

Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence.

There is no doubt that significant progress has been made in tumor therapy in the past decades. However, the discovery of new molecules with potential antitumor properties still remains one of the most significant challenges in the field of anticancer therapy. Nature, especially plants, is a rich source of phytochemicals with pleiotropic biological activities. Among a plethora of phytochemicals, chalcones, the bioprecursors of flavonoid and isoflavonoids synthesis in higher plants, have attracted attention due to the broad spectrum of biological activities with potential clinical applications. Regarding the antiproliferative and anticancer effects of chalcones, multiple mechanisms of action including cell cycle arrest, induction of different forms of cell death and modulation of various signaling pathways have been documented. This review summarizes current knowledge related to mechanisms of antiproliferative and anticancer effects of natural chalcones in different types of malignancies including breast cancers, cancers of the gastrointestinal tract, lung cancers, renal and bladder cancers, and melanoma.

Netarsudil-induced reticular epithelial oedema: An uncommon side effect

Netarsudil ophthalmic solution 0.02% (Netalo) is a new drug in the armamentarium for lowering intraocular pressure in open-angle glaucoma or ocular hypertension. It is a rho-associated protein kinase (ROCK) and norepinephrine transporter inhibitor with multiple mechanisms of action at various cellular levels. Apart from its effect on glaucoma, it has been reported to be beneficial in acute corneal endothelial damage. Its reported common side effects are conjunctival hyperaemia, corneal verticillata and subconjunctival haemorrhage. Corneal oedema arising from its use has been infrequently reported from abroad. We have presented two cases of such oedema acutely induced by Netarsudil, in the absence of any pre-existing corneal problems and which resolved on discontinuation. Such incidences warrant further studies to understand their clinical significance, the mechanism of corneal oedema arising from ROCK inhibitors and the use of these drugs in patients with compromised corneas.

CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in patients with advanced neuroendocrine tumors (NETs)—A phase IIa study.

e16235 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. The Phase I trial in Asia determined an MTD of 600 mg daily (300 mg BID) with a favorable safety profile. The best response was stable disease with measurable tumor reduction in one patient with NET. We present preliminary results for this ongoing Phase IIa study. Methods: Eligible patients had advanced NETs (low/intermediate grade lung or WHO grade 1 or 2 gastrointestinal or pancreatic origin) which were refractory to standard of care therapy and progressed within 6 months prior to screening. Patients received oral CVM-1118 at 200 to 300 mg BID (400 to 600 mg daily) in 28-day cycles. Pharmacokinetics (PK) was assessed. The primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of overall response (DoR), time-to-progression (TTP), and overall survival (OS). Planned enrollment is 33 evaluable patients. Results: As of February 10, 2023, 30 patients were enrolled, of which 21 evaluable patients (12 M/9 F; median age 61 y, range 37–82 y) were predominately grade 2 pNET (12/21, 57%) or GI NET (8/21, 38%). The majority (14/21, 67%) had disease progression after prior treatment with chemotherapy or small molecule inhibitor (median of 1 prior therapy). The duration of CVM-1118 treatment ranged from 1.4–34.6 mos (median 3.8 mos) with 4/21 (19%) patients remaining on treatment for more than 20 mos (range 22–34 mos). The median PFS was 6.9 mos (95% CI 3.3–10.3 mos), which exceeded the historical estimate for PFS of 4–6 mos (Raymond et al., 2011; Yao et al., 2016). The 8-mo and 12-mo PFS rates were 42% (95% CI 25–64%) and 29% (95% CI 14–50%), respectively. The DCR was 66.7% (95% CI 45–83%) with an ORR of 4.8% (1 PR with ongoing tumor reduction of 46% in pNET group). The most common treatment-related AEs ≥ grade 3 included ALT/AST increased (3.3%), diarrhea (3.3%), anemia (3.3%), neutrophil count decreased (3.3%), and tumor lysis syndrome (3.3%). No CVM-1118-related SAEs were reported. PK results showed CVM-1118 was rapidly metabolized to the active metabolite CVM-1125 in all patients following oral dosing. On Day 1, the mean drug exposure of CVM-1125 was Cmax 418 ng/mL and AUC0-24 2170 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~2.2 hr. No clear correlation between drug exposure and adverse effects or tumor reduction was observed. Conclusions: CVM-1118 has demonstrated a durable DCR with acceptable safety and tolerability. PK results showed good drug exposure with T1/2 of CVM-1125 ~2.2 hr. These data support future studies in patients with advanced NETs. Raymond E et al., 2011. N Eng J Med 364(6): 501-513. Yao JC et al., 2016. Lancet 387(10022): 968-977. Clinical trial information: NCT03600233 .

ID: 211698 Comparing SCS and Conventional Medical Management in Patients With No Prior Back Surgery (SOLIS RCT)

Use of Spinal Cord Stimulation (SCS) as a treatment for chronic pain has been historically designated for patients who have had at least one prior spinal surgery. However, in light of the opioid drug crisis and with the often-mixed clinical success of invasive back surgery procedures, there is growing interest in utilizing SCS in chronic pain patients who have not yet undergone any previous surgical intervention. Moreover, recently commercially-available SCS devices offer substantially more technological capabilities and neurostimulative approaches than older-generational systems. Here, we describe our clinical assessment of SCS in patients with no prior history of surgery implanted with a device capable of selectable and highly customizable programming engaging multiple mechanisms of action in a prospective, multicenter, randomized controlled trial.

The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial

N-acetylcysteine (NAC) is a novel therapeutic agent with multiple mechanisms of action in the central nervous system and a favourable side effect profile. Clinical evidence indicates that adjunctive NAC may reduce the severity of depressive symptoms in individuals with major depressive disorder (MDD). A 12-week randomised controlled trial of 2,000 mg/day adjunctive NAC for MDD found no significant improvement at the primary endpoint (week 12) but did see improvements at the post-discontinuation interview (week 16). Within the context of patient-centered treatment, mixed-methods qualitative analysis was also included to explore factors that may determine individual responses to adjunctive NAC treatment. These data were drawn, under blinded conditions, from clinician notes recorded in the case report form. Using the DSM-5 symptom profile for MDD as the initial framework, themes were developed and explored. Frequencies were compared between placebo and NAC groups. Per protocol analysis of individual themes across the six interviews revealed group differences in favour of NAC for overall depressive affect, optimism, relationships and reduced functional impairment. This study provides further evidence for the utility of the mixed methods approach complimenting the primary findings using traditional quantitative analyses, as well as being able to capture additional, often more subtle, evidence of individual symptom-level change that reflects improvement in functional abilities in response to NAC supplementation. The use of mixed methods to explore outcomes from psychiatric studies should be considered in future to work towards improved patient-centred care and both confirm quantitative findings and generate novel hypotheses.

Computational Assessment of a Dual-Action Ru(II)-Based Complex: Photosensitizer in Photodynamic Therapy and Intercalating Agent for Inducing DNA Damage.

A combined quantum-mechanical and classical molecular dynamics study of a recent Ru(II) complex with potential dual anticancer action is reported here. The main basis for the multiple action relies on the merocyanine ligand, whose electronic structure allows the drug to be able to absorb within the therapeutic window and in turn efficiently generate 1O2 for photodynamic therapy application and to intercalate within two nucleobases couples establishing reversible electrostatic interactions with DNA. TDDFT outcomes, which include the absorption spectrum, triplet states energy, and spin-orbit matrix elements, evidence that the photosensitizing activity is ensured by an MLCT state at around 660 nm, involving the merocyanine-based ligand, and by an efficient ISC from such state to triplet states with different characters. On the other hand, the MD exploration of all the possible intercalation sites within the dodecamer B-DNA evidences the ability of the complex to establish several electrostatic interactions with the nucleobases, thus potentially inducing DNA damage, though the simulation of the absorption spectra for models extracted by each MD trajectory shows that the photosensitizing properties of the complex remain unaltered. The computational results support that the anti-tumor effect may be related to multiple mechanisms of action.

The Suppressive Effect of Rebastinib on Triple-negative Breast Cancer Tumors Involves Multiple Mechanisms of Action.

High resistance of triple-negative breast cancer has prompted scientists to look for new targets susceptible to treatment. CDK16 has been suggested as a promising target whose inhibition can lead to tumor growth suppression. Rebastinib, a potent inhibitor of CDK16, has been reported to exhibit anti-tumor activity both in vitro and in vivo. The anticancer activity of rebastinib was studied in vitro using cell proliferation, cell cycle arrest and cell apoptosis assays and in vivo in xenograft tumor models using MDA-MB-231 and MDA-MB-468-derived tumors. The safety and drug-like properties of rebastinib were assessed using a panel of Absorption, Distribution, Metabolism, and Excretion (ADME) assays, Ames tests, human Ether-a-go-go Related Gene (hERG) experiments and pharmacokinetic studies in mice and rats. Rebastinib demonstrates antitumor activity against breast cancer both in vitro and in vivo. However, the response of the tumor strongly depends on the type of triple-negative breast cancer. Rebastinib-induced cell cycle arrest was observed in G0/G1 phase suggesting a more complex mechanism than just CDK16 inhibition. ADME and PK studies confirmed the drug-like properties and reasonable safety of rebastinib. Our studies confirmed rebastinib to be a promising drug candidate for breast cancer treatment with high oral bioavailability and reasonable safety. Our data suggest that the mechanism of action of rebastinib is not limited to CDK16 inhibition but also involves other pathways. This does not diminish the importance of rebastinib as a drug candidate, but reveals the presence of several mechanisms, suggesting a wider scope of possible applications.

Impact of Diet and Exercise Interventions on Cognition and Brain Health in Older Adults: A Narrative Review.

The ability to preserve cognitive function and protect brain structure from the effects of the aging process and neurodegenerative disease is the goal of non-pharmacologic, lifestyle interventions focused on brain health. This review examines, in turn, current diet and exercise intervention trends and the collective progress made toward understanding their impact on cognition and brain health. The diets covered in this review include the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), ketogenic diet, intermittent fasting, and weight loss management. The exercise approaches covered in this review include endurance, resistance, combined exercise programs, yoga, tai chi, and high-intensity interval training. Although valuable evidence is building concerning how diet and exercise influence cognitive performance and brain structure, many of the open questions in the field are concerned with why we see these effects. Therefore, more strategically designed intervention studies are needed to reveal the likely multiple mechanisms of action in humans.

Treatment of limb combat blast wounds using negative pressure

Blast injury (BI) is a combat multifactorial injury resulting from the impulse action of the complex traumatic factors by the mine munition explosion, characterized an interconnected and increasingly severe impact, massive deep tissue damage and the development of a general contusion-shock syndrome. For severe BI with large skin and soft tissue defects, it is advisable to use negative pressure wound therapy (NPWT). Objective. To analyze the effectiveness of using the NPWT system in patients with blast injuries. Methods. Publications were searched in electronic systems Google Scholar, PubMed, ScienceDirect, archives of specialized journals. The results of treatment using NPWT of 134 patients were analyzed: 130 (97 %) men and 4 (3 %) women, average age 36.6 years (22‒64). According to the types of injuries, the patients were distributed as follows: blast injury — 128 (95.5%), bullet injuries — 6 (4.5 %). The results. The goal of BI treatment by negative pressure is to improve wound healing through multiple mechanisms of action at the macroscopic and microscopic levels. The use of NPWT reduces the risk of infectious complications, prevents excessive progression necrosis of affected tissues, accelerates the growth of granulation tissues and reduces pain syndrome. The result of the treatment is the wound preparation for primary healing or, in the case of significant soft tissue damage, the creation of favorable conditions for performing plastic surgeries. In general, NPWT accelerates treatment times, reduces risks of complication level and improves functional results. This current own research coincides with the results of majority authors and allows us to continue work in this direction. Conclusions. Treatment of blast injury wounds with the use of vacuum bandages and devices for creating negative pressure is an effective approach that contributes to the reduction of infectious complications, the growth of granulation tissue, facilitates further skin plasticity of the defect, accelerates the recovery time of the wounded and his rehabilitation.

Astrocytic Chitinase-3-like protein 1 in neurological diseases: Potential roles and future perspectives.

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with multiple neurological disorders and serves as a biomarker for the early detection of several neurodegenerative diseases. Aberrant CHI3L1 expression is also reportedly associated with brain tumor migration and metastasis, as well as contributions to immune escape, playing important roles in brain tumor progression. CHI3L1 is synthesized and secreted mainly by reactive astrocytes in the central nervous system. Thus, targeting astrocytic CHI3L1 could be a promising approach for the treatment of neurological diseases, such as traumatic brain injury, ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and glioma. Based on current knowledge of CHI3L1, we assume that it acts as a molecule mediating several signaling pathways driving the initiation and progression of neurological disorders. This narrative review is the first to introduce the potential roles of astrocytic CHI3L1 in neurological disorders. We also equally explore astrocytic CHI3L1 mRNA expression under physiological and pathological conditions. Inhibiting CHI3L1 and disrupting its interaction with its receptors through multiple mechanisms of action are briefly discussed. These endeavors highlight the pivotal roles of astrocytic CHI3L1 in neurological disorders and could contribute to the development of effective inhibitors based on the strategy of structure-based drug discovery, which could be an attractive therapeutic approach for neurological disease treatment.

Concomitant Cannabidiol Does Not Impact Safety and Effectiveness of Diazepam Nasal Spray for Seizure Clusters: Post Hoc Analysis of a Phase 3 Safety Study (P9-1.012)

<h3>Objective:</h3> To examine potential effects of concomitant cannabidiol on safety and effectiveness of diazepam nasal spray (Valtoco^®). <h3>Background:</h3> Cannabidiol (CBD) is used as an antiseizure drug with multiple mechanisms of action. In clinical studies, the FDA-approved oral solution of CBD (Epidiolex^®) has altered the safety and effectiveness of benzodiazepines, especially clobazam. Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. This post hoc analysis from a long-term, open-label safety study examines safety and effectiveness of diazepam nasal spray in patients also receiving CBD treatment. <h3>Design/Methods:</h3> Patients (6–65 years) received age- and weight-based doses of diazepam nasal spray to treat seizure clusters. Seizures and drug administration were recorded in patient diaries. CBD use and treatment-emergent adverse events (TEAEs) were collected. Diazepam nasal spray second dose usage within 24 hours of the first was a proxy for effectiveness. <h3>Results:</h3> Of 163 patients treated with ≥1 dose of diazepam nasal spray, 119 (73.0%) did not receive CBD, 23 (14.1%) received oral-solution CBD, and 21 (12.9%) received other CBD. Patients receiving any CBD were more likely to have epileptic encephalopathies than patients with no CBD (63.6% vs 30.3%). Rates of TEAEs and serious TEAEs were higher in patients receiving CBD (90.9%, 45.5%) than no CBD (79.0%, 25.2%); treatment-related TEAEs were similar (18.2% vs 17.7%). Effectiveness measured by second dose use was similar between the CBD (14.7%) and no CBD groups (11.5%). <h3>Conclusions:</h3> CBD does not appear to influence the safety of diazepam nasal spray. In this cohort, incidence of epileptic encephalopathies in patients receiving CBD may underlie the overall rates of TEAEs in this population. Treatment-related TEAEs were similar across groups. These results suggest that CBD does not alter safety/effectiveness of diazepam nasal spray and support concomitant use in appropriate patients. <b>Disclosure:</b> Dr. Peters has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurelis. Dr. Peters has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurelis. Dr. Puri has received personal compensation for serving as an employee of neurelis. Dr. Puri has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurelis. Dr. Puri has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurelis. Dr. Puri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Dr. Segal has received personal compensation for serving as an employee of Lundbeck. Dr. Segal has received personal compensation for serving as an employee of Eisai. Dr. Segal has received personal compensation for serving as an employee of Neurelis. Dr. Segal has received personal compensation for serving as an employee of Zogenix. Dr. Segal has received personal compensation for serving as an employee of Aquestive. Dr. Segal has received personal compensation for serving as an employee of Greenwich Biosciences. Dr. Segal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Aquestive. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Segal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Greenwhich Bioscience. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Greenwhich Bioscience. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurelis. Dr. Gustin has received personal compensation for serving as an employee of Neurelis. Dr. Gustin has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for The Recovery Research Network Foundation. Dr. Misra has received personal compensation for serving as an employee of Neurelis, Inc. An immediate family member of Dr. Misra has received personal compensation for serving as an employee of Neurocrine Biosciences. Dr. Misra has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RubiconMD. Dr. Misra has received intellectual property interests from a discovery or technology relating to health care. Dr. Rabinowicz has received personal compensation for serving as an employee of Neurelis, Inc. Dr. Rabinowicz has stock in Neurelis, Inc. Enrique Carrazana has received personal compensation for serving as an employee of Neurelis. Enrique Carrazana has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Neurelis, Alexza, Zogenix. Enrique Carrazana has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Hawaii-Biotech, CND Life Sciences. Enrique Carrazana has stock in Neurelis, Marinus, .

Otilonium Bromide Prevents Cholinergic Changes in the Distal Colon Induced by Chronic Water Avoidance Stress, a Rat Model of Irritable Bowel Syndrome.

Irritable Bowel syndrome (IBS) is a highly widespread gastrointestinal disorder whose symptomatology mainly affect the large intestine. Among the risk factors, psychosocial stress is the most acknowledged. The repeated water avoidance stress (rWAS) is considered an animal model of psychosocial stress that is capable of mimicking IBS. Otilonium bromide (OB), which is orally administered, concentrates in the large bowel and controls most of the IBS symptoms in humans. Several reports have shown that OB has multiple mechanisms of action and cellular targets. We investigated whether the application of rWAS to rats induced morphological and functional alterations of the cholinergic neurotransmission in the distal colon and whether OB prevented them. The results demonstrated that rWAS affects cholinergic neurotransmission by causing an increase in acid mucin secretion, in the amplitude of electrically evoked contractile responses, abolished by atropine, and in the number of myenteric neurons expressing choline acetyltransferase. OB counteracted these changes and also showed an intrinsic antimuscarinic effect on the post-synaptic muscular receptors. We assume that the rWAS consequences on the cholinergic system are linked to corticotrophin-releasing factor-1 (CRF1) receptor activation by the CRF hypothalamic hormone. OB, by interfering with the CFR/CRFr activation, interrupted the cascade events responsible for the changes affecting the rWAS rat colon.

Bioactive Compounds of the Mediterranean Diet as Nutritional Support to Fight Neurodegenerative Disease.

Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress, and neuronal depletion. They include selective malfunction and progressive loss of neurons, glial cells, and neural networks in the brain and spinal cord. There is an urgent need to develop new and more effective therapeutic strategies to combat these devastating diseases because, today, there is no treatment that can cure degenerative diseases; however, we have many symptomatic treatments. Current nutritional approaches are beginning to reflect a fundamental change in our understanding of health. The Mediterranean diet may have a protective effect on the neurodegenerative process because it is rich in antioxidants, fiber, and omega-3 polyunsaturated fatty acids. Increasing knowledge regarding the impact of diet on regulation at the genetic and molecular levels is changing the way we consider the role of nutrition, resulting in new dietary strategies. Natural products, thanks to their bioactive compounds, have recently undergone extensive exploration and study for their therapeutic potential for a variety of diseases. Targeting simultaneous multiple mechanisms of action and a neuroprotection approach with the diet could prevent cell death and restore function to damaged neurons. For these reasons, this review will be focused on the therapeutic potential of natural products and the associations between the Mediterranean-style diet (MD), neurodegenerative diseases, and markers and mechanisms of neurodegeneration.

The antidiabetic effect of methanolic extract of Holarrhena pubescens seeds is mediated through multiple mechanisms of action

Holarrhena pubescens is widely used in Indian and Chinese medicine in the treatment of diabetes. The current work determined the oral hypoglycemic and antidiabetic effects of seed extract in rats. The probable mechanism of action was evaluated in-vitro by α - glucosidase inhibition, glucose metabolism in insulinoma (INS-1) cells to reflect secretion of insulin, and protein glycation inhibition. Its potential for herb-drug interaction was evaluated in the cytochrome P450 3A4 (CYP3A4) inhibition assay. The seed extract increased serum insulin levels and reduced serum blood glucose levels in the oral glucose tolerance test. It also reduced the serum glucose levels in streptozocin-induced diabetes. The extract also inhibited α –glucosidase enzyme activity and demonstrated that it can increase the secretion of insulin from INS to 1-rat insulinoma cell line cells in-vitro in a concentration-dependent manner. However, it had a very weak inhibitory effect on protein glycation and it did not affect the activity of CYP3A4. The results of the study showed that H. pubescens seed extract increases insulin secretion and inhibits glucose absorption both in-vivo and in-vitro with a weak protein glycation inhibitory effect. The herb is devoid of CYP3A4 inhibitory effect indicating that it may not have pharmacokinetic interaction with the drug metabolized by this enzyme.

Abstract LB318: SB-4826, a first-in-class oral, covalent inhibitor of SUMO E1 that induces IFN signaling and inhibits tumor growth as monotherapy and in combination with immune checkpoint blockade

Abstract Sumoylation is a reversible post-translational modification of proteins by small ubiquitin-like modifier (SUMO) that regulates protein function and contributes to cellular response to stress. Sumoylation is an essential pathway for all cells and is involved in diverse processes such as inflammation, DNA damage response, signaling and cell survival/apoptosis. Due to its involvement in such cellular functions, sumoylation intersects with the majority of the hallmarks of cancer. Many cancers display elevated expression of SUMO pathway components, a mechanism co-opted by tumors to survive under stressful conditions. In addition to its tumor intrinsic functions, sumoylation has emerged as a novel target for activating anti-tumor immunity due to its role in regulating type I interferon (IFN) signaling. Targeting sumoylation is a compelling anti-cancer strategy due to the multiple mechanisms of action that may drive anti-tumor activity for cancer patients. We report the discovery of SB-4826, a novel, orally active, covalent small molecule inhibitor of the Sumo Activating Enzyme (SUMO E1), the initiating enzyme of the sumoylation cascade. SB-4826 selectively and irreversibly binds an allosteric pocket of SUMO E1 and drives potent biochemical and cellular activity. SB-4826 inhibits global sumoylation in cells and blocks proliferation across a broad panel (100+) of cancer cell lines. Cysteine-proteome profiling by mass spectrometry indicated that Cys-30 of SUMO E1 was the only cysteine-containing peptide (out of 14,541 measured) that met the criteria for covalent engagement indicating exquisite selectivity across the cellular proteome. In an in vivo pharmacodynamic model measuring IFN signaling SB-4826 treatment led to dose- and time-dependent induction of IFN regulated cytokines. SB-4826 treatment resulted in significant tumor growth inhibition in multiple in vivo models. In a syngeneic A20 lymphoma model SB-4826 led to tumor stasis. In a human RAJI xenograft model, SB-4826 induced near-complete inhibition of tumor growth as a single agent and resulted in tumor regression when combined with rituximab. In a mouse CT-26 colorectal tumor model which is generally refractory to anti-PD-1 treatment, SB-4826 significantly inhibited tumor growth as monotherapy and led to 60% complete tumor responses when combined with anti-PD-1. SB-4826 caused increased CD8+ T cell infiltration in CT-26 tumors supporting the role of SB-4826 in inducing IFN signaling and leading to a tumor microenvironment that is more responsive to immune checkpoint inhibition. SUMO E1 is a clinically validated cancer target as evidenced by recent data showing encouraging responses to TAK-981, an IV-administered, ATP-competitive inhibitor. SB-4826 is a differentiated and optimized SUMO E1 inhibitor that is administered orally and demonstrated improved activity in preclinical models. SB-4826 has favorable properties for development, is a new and promising cancer therapy, and is entering phase 1 clinical studies in 2023. Citation Format: Jude R. Canon, Ashley Callinan, Sarah Bradley, Laurie Wang, Mackenzie Kui, Ariel Wein, Gabriele Sulli, Peter Buchowiecki, Fang-Tsao Hong, Miles Kubota, Mary Walton, Victor J. Cee. SB-4826, a first-in-class oral, covalent inhibitor of SUMO E1 that induces IFN signaling and inhibits tumor growth as monotherapy and in combination with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB318.