Harmine and exendin-4 combination therapy safely expands human ß cell mass in vivo in a mouse xenograft system.

Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing ß cells are reduced in number in most people with diabetes, but most individuals still have some residual ß cells. However, none of the many diabetes drugs in common use increases human ß cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human ß cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on ß cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human ß cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human ß cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human ß cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human ß cell mass occurred through mechanisms that included enhanced human ß cell proliferation, function, and survival. The increase in human ß cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.

Animal Venoms as Potential Source of Anticonvulsants.

Epilepsy affects millions of people worldwide, and there is an urgent need to develop safe and effective therapeutic agents. Animal venoms contain diverse bioactive compounds like proteins, peptides, and small molecules, which may possess medicinal properties against epilepsy. In recent years, research has shown that venoms from various organisms such as spiders, ants, bees, wasps, and conus snails have anticonvulsant and antiepileptic effects by targeting specific receptors and ion channels. This review underscores the significance of purified proteins and toxins from these sources as potential therapeutic agents for epilepsy. In conclusion, this review emphasizes the valuable role of animal venoms as a natural resource for further exploration in epilepsy treatment research.

Unlocking nature's arsenal: Nanotechnology for targeted delivery of venom toxins in cancer therapy.

AIM: The aim of the present review is to shed light on the nanotechnological approaches adopted to overcome the shortcomings associated with the delivery of venom peptides which possess inherent anti-cancer properties. BACKGROUND: Venom peptides although have been reported to demonstrate anti-cancer effects, they suffer from several disadvantages such as in vivo instability, off-target adverse effects, limited drug loading and low bioavailability. This review presents a comprehensive compilation of different classes of nanocarriers while underscoring their advantages, disadvantages and potential to carry such peptide molecules for in vivo delivery. It also discusses various nanotechnological aspects such as methods of fabrication, analytical tools to assess these nanoparticulate formulations, modulation of nanocarrier polymer properties to enhance loading capacity, stability and improve their suitability to carry toxic peptide drugs. CONCLUSION: Nanotechnological approaches bear great potential in delivering venom peptide-based molecules as anticancer agents by enhancing their bioavailability, stability, efficacy as well as offering a spatiotemporal delivery approach. However, the challenges associated with toxicity and biocompatibility of nanocarriers must be duly addressed. PERSPECTIVES: The everlasting quest for new breakthroughs for safer delivery of venom peptides in human subjects is fuelled by unmet clinical needs in the current landscape of chemotherapy. In addition, exhaustive efforts are required in obtaining and purifying the venom peptides followed by designing and optimizing scale up technologies.

Toxin-derived peptides: An unconventional approach to alleviating cerebral stroke burden and neurobehavioral impairments.

Cerebral stroke is a pressing global health concern, ranking as the second leading cause of mortality and resulting in persistent neurobehavioral impairments. Cerebral strokes, triggered by various embolic events, initiate complex signaling pathways involving neuroexcitotoxicity, ionic imbalances, inflammation, oxidative stress, acidosis, and mitochondrial dysfunction, leading to programmed cell death. Currently, the FDA has approved tissue plasminogen activator as a relatively benign intervention for cerebral stroke, leaving a significant treatment gap. However, a promising avenue has emerged from Earth's toxic creatures. Animal venoms harbor bioactive molecules, particularly neuropeptides, with potential in innovative healthcare applications. These venomous components, affecting ion channels, receptors, and transporters, encompass neurochemicals, amino acids, and peptides, making them prime candidates for treating cerebral ischemia and neurological disorders. This review explores the composition, applications, and significance of toxin-derived peptides as viable therapeutic agents. It also investigates diverse toxins from select venomous creatures, with the primary objective of shedding light on current stroke treatments and paving the way for pioneering therapeutic strategies capable of addressing neurobehavioral deficits.

African polyvalent antivenom can maintain pharmacological stability and ability to neutralise murine venom lethality for decades post-expiry: evidence for increasing antivenom shelf life to aid in alleviating chronic shortages.

INTRODUCTION: Antivenom is a lifesaving medicine for treating snakebite envenoming, yet there has been a crisis in antivenom supply for many decades. Despite this, substantial quantities of antivenom stocks expire before use. This study has investigated whether expired antivenoms retain preclinical quality and efficacy, with the rationale that they could be used in emergency situations when in-date antivenom is unavailable. METHODS: Using WHO guidelines and industry test requirements, we examined the in vitro stability and murine in vivo efficacy of eight batches of the sub-Saharan African antivenom, South African Institute for Medical Research polyvalent, that had expired at various times over a period of 30 years. RESULTS: We demonstrate modest declines in immunochemical stability, with antivenoms older than 25 years having high levels of turbidity. In vitro preclinical analysis demonstrated all expired antivenoms retained immunological recognition of venom antigens and the ability to inhibit key toxin families. All expired antivenoms retained comparable in vivo preclinical efficacy in preventing the lethal effects of envenoming in mice versus three regionally and medically important venoms. CONCLUSIONS: This study provides strong rationale for stakeholders, including manufacturers, regulators and health authorities, to explore the use of expired antivenom more broadly, to aid in alleviating critical shortages in antivenom supply in the short term and the extension of antivenom shelf life in the longer term.

Effect of glucagon like peptide-1 receptor agonist exenatide, used as an intracranial pressure lowering agent, on cognition in Idiopathic Intracranial Hypertension.

BACKGROUND: Cognitive function can be affected in conditions with raised intracranial pressure (ICP) such as idiopathic intracranial hypertension (IIH). Drugs used off label to treat raised ICP also have cognitive side effects, underscoring the unmet need for effective therapeutics which reduce ICP without worsening cognition. The Glucagon Like Peptide-1 (GLP-1) receptor agonist, exenatide, has been shown to significantly reduce ICP in IIH, therefore this study aimed to determine the effects of exenatide on cognition in IIH. METHODS: This was an exploratory study of the IIH:Pressure trial (ISTCRN 12678718). Women with IIH and telemetric ICP monitors (n = 15) were treated with exenatide (n = 7) or placebo (n = 8) for 12 weeks. Cognitive function was tested using the National Institute of Health Toolbox Cognitive Battery at baseline and 12 weeks. RESULTS: Cognitive performance was impaired in fluid intelligence ((T-score of 50 = population mean), mean (SD) 37.20 (9.87)), attention (33.93 (7.15)) and executive function (38.07 (14.61)). After 12-weeks there was no evidence that exenatide compromised cognition (no differences between exenatide and placebo). Cognition improved in exenatide treated patients in fluid intelligence (baseline 38.4 (8.2), 12 weeks 52.9 (6.6), p = 0.0005), processing speed (baseline 43.7 (9.4), 12 weeks 58.4 (10.4), p = 0.0058) and episodic memory (baseline 49.4 (5.3), 12 weeks 62.1 (13.2), p = 0.0315). CONCLUSIONS: In patients with raised ICP due to IIH, exenatide, a drug emerging as an ICP lowering agent, does not adversely impact cognition. This is encouraging and has potential to be relevant when considering prescribing choices to lower ICP.

Targeting Dysregulated Ion Channels in Liver Tumors with Venom Peptides.

The regulation of cellular processes by ion channels has become central to the study of cancer mechanisms. Designing molecules that can modify ion channels specific to tumor cells is a promising area of targeted drug delivery and therapy. Despite their potential in drug discovery, venom peptides-a group of natural products-have largely remained understudied and under-characterized. In general, venom peptides display high specificity and selectivity for their target ion channels. Therefore, they may represent an effective strategy for selectively targeting the dysregulation of ion channels in tumor cells. This review examines existing venom peptide therapies for different cancer types and focuses on the application of snail venom peptides in hepatocellular carcinoma (HCC), the most common form of primary liver cancer worldwide. We provide insights into the mode of action of venom peptides that have been shown to target tumors. We also explore the benefit of using new computational methods like de novo protein structure prediction to screen venom peptides and identify potential druggable candidates. Finally, we summarize the role of cell culture, animal, and organoid models in developing effective therapies against HCC and highlight the need for creating models that represent the most disproportionately affected ethnicities in HCC.

Glucagon-like peptide-1 analogues in monogenic syndromic obesity: Real-world data from a large cohort of Alström syndrome patients.

AIM: To examine the real-world efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). METHODS: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non-alcoholic fatty liver disease. RESULTS: In total, 30 patients, with a mean age of 31 ± 11 years and a male to-female ratio of 2:1, completed 6 months of treatment with GLP-1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP-1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6-7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7-15.3) mmol/mol, equating to 6% weight loss (P < .01) and 1.1% absolute reduction in HbA1c (P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. CONCLUSIONS: Data from our centre highlight the non-inferiority of GLP-1 RAs in monogenic syndromic obesity to the available GLP-1 RA-use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity.

Sustained metabolic benefits of ΔTRTX-Ac1, a tarantula venom-derived peptide, when administered together with exenatide in high-fat fed mice.

AIM: The aim of the present study was to assess the long-term therapeutic efficacy of a recently discovered 28 amino acid peptide, Δ-theraphotoxin-Ac1 (Δ-TRTX-Ac1), originally isolated from venom of the Aphonopelma chalcodes tarantula. Δ-TRTX-Ac has previously been shown to improve pancreatic beta-cell function and suppress appetite. MATERIALS AND METHODS: Δ-TRTX-Ac1 was administered twice daily in high-fat fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF/STZ mice, for 28 days both alone and in combination with the venom-derived glucagon-like peptide-1 (GLP-1) mimetic, exenatide. RESULTS: Initial pharmacokinetic profiling of ΔTRTX-Ac1 revealed a plasma half-life of 2 h in mice, with ΔTRTX-Ac1 also evidenced in the pancreas 12 h post-injection. Accordingly, HFF-STZ mice received twice-daily injections of Δ-TRTX-Ac1, exenatide or a combination of both peptides for 28 days. As anticipated, HFF/STZ mice presented with hyperglycaemia, impaired glucose tolerance, decreased plasma and pancreatic insulin and disturbed pancreatic islet morphology. Administration of ΔTRTX-Ac1 reduced body weight, improved glucose tolerance and augmented pancreatic insulin content while decreasing glucagon content. Exenatide had similar benefits on body weight and pancreatic hormone content while also reducing circulating glucose. ΔTRTX-Ac1 decreased energy expenditure on day 28 whereas exenatide had no impact. All treatment regimens restored pancreatic islet and beta-cell area towards lean control levels, which was linked to significantly elevated beta-cell proliferation rates. In terms of benefits of combined ΔTRTX-Ac1 and exenatide treatment over individual agents, there was augmentation of glucose tolerance and ambulatory activity with combination therapy, and these mice presented with increased pancreatic glucagon. CONCLUSION: These data highlight the therapeutic promise of ΔTRTX-Ac1 for diabetes, with suggestion that benefits could be enhanced through combined administration with exenatide.

Screening for Inflammatory Markers Identifies IL-18Rα as a Potential Link between Exenatide and Its Anti-Inflammatory Effect: New Results from the Combat-JUDO Randomized Controlled Trial.

INTRODUCTION: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. METHODS: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. RESULTS: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. CONCLUSIONS: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.

Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review.

Malaria is an infectious disease caused by Plasmodium spp. and it is mainly transmitted to humans by female mosquitoes of the genus Anopheles. Malaria is an important global public health problem due to its high rates of morbidity and mortality. At present, drug therapies and vector control with insecticides are respectively the most commonly used methods for the treatment and control of malaria. However, several studies have shown the resistance of Plasmodium to drugs that are recommended for the treatment of malaria. In view of this, it is necessary to carry out studies to discover new antimalarial molecules as lead compounds for the development of new medicines. In this sense, in the last few decades, animal venoms have attracted attention as a potential source for new antimalarial molecules. Therefore, the aim of this review was to summarize animal venom toxins with antimalarial activity found in the literature. From this research, 50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs.

[Genetic aspects of type 1 glucagon peptide agonists clinical efficacy: A review].

A review of publications devoted to the analysis of genetic polymorphisms of the gene encoding the glucagon-like peptide type 1 receptor and some other genes directly and indirectly involved in the implementation of its physiological action is presented. The aim of the study: to search for information on genes polymorphism that can affect the effectiveness of glucagon-like peptide type 1 agonists. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was based on PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic source eLIBRARY.RU from 1993 to 2022. The several genes polymorphisms (GLP1R, TCF7L2, CNR1, SORCS1, WFS1, PPARD, CTRB1/2) that may affect the course and therapy of type 2 diabetes mellitus, metabolic syndrome and obesity, was described. Single nucleotide substitutions in some regions of these genes can both decrease and increase the clinical efficacy of the treatment of diabetes mellitus and metabolic syndrome with the help of type 1 glucagon-like peptide agonists: exenatide, liraglutide. Data on the role of genetic variations in the structure of the products of these genes in the effectiveness of other type 1 glucacone-like peptide agonists have not been found.

The ß3-subunit modulates the effect of venom peptides ProTx-II and OD1 on NaV 1.7 gating.

The voltage-gated sodium channel NaV 1.7 is involved in various pain phenotypes and is physiologically regulated by the NaV -ß3-subunit. Venom toxins ProTx-II and OD1 modulate NaV 1.7 channel function and may be useful as therapeutic agents and/or research tools. Here, we use patch-clamp recordings to investigate how the ß3-subunit can influence and modulate the toxin-mediated effects on NaV 1.7 function, and we propose a putative binding mode of OD1 on NaV 1.7 to rationalise its activating effects. The inhibitor ProTx-II slowed the rate of NaV 1.7 activation, whilst the activator OD1 reduced the rate of fast inactivation and accelerated recovery from inactivation. The ß3-subunit partially abrogated these effects. OD1 induced a hyperpolarising shift in the V1/2 of steady-state activation, which was not observed in the presence of ß3. Consequently, OD1-treated NaV 1.7 exhibited an enhanced window current compared with OD1-treated NaV 1.7-ß3 complex. We identify candidate OD1 residues that are likely to prevent the upward movement of the DIV S4 helix and thus impede fast inactivation. The binding sites for each of the toxins and the predicted location of the ß3-subunit on the NaV 1.7 channel are distinct. Therefore, we infer that the ß3-subunit influences the interaction of toxins with NaV 1.7 via indirect allosteric mechanisms. The enhanced window current shown by OD1-treated NaV 1.7 compared with OD1-treated NaV 1.7-ß3 is discussed in the context of differing cellular expressions of NaV 1.7 and the ß3-subunit in dorsal root ganglion (DRG) neurons. We propose that ß3, as the native binding partner for NaV 1.7 in DRG neurons, should be included during screening of molecules against NaV 1.7 in relevant analgesic discovery campaigns.

The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial.

Therapeutics to reduce intracranial pressure are an unmet need. Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling. Here, we translate these findings into patients by conducting a randomized, placebo-controlled, double-blind trial to assess the effect of exenatide, a GLP-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure >25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 h, 24 h and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28 ± 9, body mass index 38.1 ± 6.2 kg/m2, intracranial pressure 30.6 ± 5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 h -5.7 ± 2.9 cmCSF (P = 0.048); 24 h -6.4 ± 2.9 cmCSF (P = 0.030); and 12 weeks -5.6 ± 3.0 cmCSF (P = 0.058). No serious safety signals were noted. These data provide confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlight the potential to utilize GLP-1 receptor agonist in other conditions characterized by raised intracranial pressure.

Pharmacogenetic interactions of medications administered for weight loss in adults: a systematic review and meta-analysis.

Aim: To analyze roles of single nucleotide variants (SNVs) on weight loss with US FDA-approved medications. Materials & methods: We searched the literature up until November 2022. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. Results: 14 studies were included in qualitative analysis and seven in meta-analysis. SNVs in CNR1, GLP-1R, MC4R, TCF7L2, CTRB1/2, ADIPOQ, SORCS1 and ANKK1 were evaluated relative to weight loss with glucagon-like peptide-1 agonists (13 studies) or naltrexone-bupropion (one study). CNR1 gene (rs1049353), GLP-1R gene (rs6923761, rs10305420), TCF7L2 gene (rs7903146) were associated with weight loss in at least one study involving glucagon-like peptide-1 agonist(s). The meta-analysis did not identify any consistent effect of SNVs. Conclusion: Pharmacogenetic interactions for exenatide, liraglutide, naltrexone-bupropion and weight loss were identified, but the directionality was inconsistent.

Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve ß-Cell Mass and Function in Type 2 Diabetes?

Improvement of insulin secretion by pancreatic ß-cells and preservation of their mass are the current challenges that future antidiabetic drugs should meet for achieving efficient and long-term glycemic control in patients with type 2 diabetes (T2D). The successful development of glucagon-like peptide 1 (GLP-1) analogues, derived from the saliva of a lizard from the Helodermatidae family, has provided the proof of concept that antidiabetic drugs directly targeting pancreatic ß-cells can emerge from venomous animals. The literature reporting on the antidiabetic effects of medicinal plants suggests that they contain some promising active substances such as polyphenols and alkaloids, which could be active as insulin secretagogues and ß-cell protectors. In this review, we discuss the potential of several polyphenols, alkaloids and venom peptides from snake, frogs, scorpions and cone snails. These molecules could contribute to the development of new efficient antidiabetic medicines targeting ß-cells, which would tackle the progression of the disease.

Health-related quality of life in food and venom induced anaphylaxis and role of influencing factors.

The impact on health-related quality of life (HRQL) plays a key role for patients suffering from allergies and anaphylaxis. In this narrative review we review the HRQL in allergic patients suffering from food and venom allergy, both being the most frequent elicitors of severe allergic, potential life-threatening reactions and provide an overview on the current knowledge and identified gaps. The data show that for food and venom allergy standardized assessment tools to measure HRQL are available and have been successfully applied. Our analysis shows that multiple factors can modulate HRQL in these patient groups. These include sociodemographic data like patients' age and sex, fear of accidental reactions but also external factors like the social environment and the appreciation of the seriousness of the condition by others. External factors may have a significant impact on HRQL and should be considered in patient-related outcome assessments to avoid biased measurements possibly affecting the results. The assessment of the quality of life in the context of specific immunotherapy should consider lifestyle factors and ideally, the individual change in HRQL should be measured. Although there are many data indicating a negative impact on HRQL in food allergic children and their caregivers, limited data are existing from adults with food allergy and venom allergic patients from all age groups. Also, the use of standardized questionnaires should be extended to allow for a better comparability of results between studies. Therefore, translation to additional languages is necessary. Taken together, the eliciting allergen, the severity of the allergic disease but moreover multiple external factors impact the outcome in HRQL and should be considered in HRQL assessment.

Biologically Active Peptides from Venoms: Applications in Antibiotic Resistance, Cancer, and Beyond.

Peptides are potential therapeutic alternatives against global diseases, such as antimicrobial-resistant infections and cancer. Venoms are a rich source of bioactive peptides that have evolved over time to act on specific targets of the prey. Peptides are one of the main components responsible for the biological activity and toxicity of venoms. South American organisms such as scorpions, snakes, and spiders are important producers of a myriad of peptides with different biological activities. In this review, we report the main venom-derived peptide families produced from South American organisms and their corresponding activities and biological targets.

Innovative treatments for epilepsy: Venom peptides, cannabinoids, and neurostimulation.

Antiepileptic drugs have been successfully treating epilepsy and providing individuals sustained seizure freedom. However, about 30% of the patients with epilepsy present drug resistance, which means they are not responsive to the pharmacological treatment. Considering this, it becomes extremely relevant to pursue alternative therapeutic approaches, in order to provide appropriate treatment for those patients and also improve their quality of life. In the light of that, this review aims to discuss some innovative options for the treatment of epilepsy, which are currently under investigation, addressing strategies that go from therapeutic compounds to clinical procedures. For instance, peptides derived from animal venoms, such as wasps, spiders, and scorpions, demonstrate to be promising antiepileptic molecules, acting on a variety of targets. Other options are cannabinoids and compounds that modulate the endocannabinoid system, since it is now known that this network is involved in the pathophysiology of epilepsy. Furthermore, neurostimulation is another strategy, being an alternative clinical procedure for drug-resistant patients who are not eligible for palliative surgeries.