A positive loop between relish and cuticle proteins and their roles in regulating AMPs expression during bacterial infection in Eriocheir sinensis.

Cuticle proteins (CPs) are the vital components of the cuticle and chitin lining covering the digestive tract of crustaceans. In this study, four new CP genes (designated as EsCP3, EsCP4, EsCP5, and EsCP8) were initially cloned and identified from the Chinese mitten crab Eriocheir sinensis. EsCP3/4/5/8 included 375, 411, 381, and 570 bp open reading frame encoding 124, 136, 126, and 189 amino acid proteins, respectively. Except for EsCP8, EsCP3/4/5 all contained a Chitin_bind_4 domain. EsCP3/4/5/8 were clustered into different groups in the phylogenetic tree. Quantitative real-time PCR results indicated that four EsCP genes have different patterns of tissue distribution. Changes in the expression levels of these four EsCP genes were observed in the intestine of crabs under Vibrio parahaemolyticus challenge. RNA interference assay showed that the knockdown of EsCPs in the intestine could inhibit the expression of antimicrobial peptides (AMPs), including crustins and anti-lipopolysaccharide factors. In addition, the knockdown of EsRelish in the intestine decreased the expression levels of these four EsCP genes. These results indicated that EsCPs were involved in regulating the expression of AMPs, and EsCPs were regulated by EsRelish.

Design and synthesis of TH19P01-Camptothecin based hybrid peptides inducing effective anticancer responses on sortilin positive cancer cells.

Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1.

The selective chemical modification of the 6-amino group of adenosine of the premature termination codon induces readthrough to produce full-length peptide in the reconstituted E. Coli translation system.

Nonsense mutations in the coding region turn amino acid codons into termination codons, resulting in premature termination codons (PTCs). In the case of the in-frame PTC, if translation does not stop at the PTC but continues to the natural termination codon (NTC) with the insertion of an amino acid, known as readthrough, the full-length peptide is formed, albeit with a single amino acid mutation. We have previously developed the functionality-transfer oligonucleotide (FT-Probe), which forms a hybrid complex with RNA of a complementary sequence to transfer the functional group, resulting in modification of the 4-amino group of cytosine or the 6-amino group of adenine. In this study, the FT-Probe was used to chemically modify the adenosines of the PTC (UAA, UAG, and UGA) of mRNA, which were assayed for the readthrough in a reconstituted Escherichia coli translation system. The third adenosine-modified UAA produced three readthrough peptides incorporating tyrosine, glutamine and lysine at the UAA site. It should be noted that the additional modification with a cyclodextrin only induced glutamine incorporation. The adenosine modified UGA induced readthrough very efficiently with selective tryptophan incorporation. Readthrough of the modified UGA is caused by inhibition of the RF2 function. This study has demonstrated that the chemical modification of the adenosine 6-amino group of the PTC is a strategy for effective readthrough in a prokaryotic translation system.

In-silico binding affinity of a phage display library screened novel peptide against various FABPs.

In accordance to the American Heart Association (AHA), cardiovascular diseases (CVDs) are the leading cause of death around the globe, causing more than 19.1 million deaths in 2020. Heart-type fatty acid binding protein (H-FABP) is required for the metabolism of fatty acids (FA) inside cardiomyocytes is reported as a biomarker for myocardial damage. As early as one hour after an Acute myocardial infarction (AMI), H-FABP can be used to detect myocardial ischemia. Thus, H-FABP based detection can reduce the burden on the emergency department. A peptide-based detection system can provide point-of-care diagnostics for CVDs. There is a lot of research being done on peptide-based detection, and it has a lot of potential to help with unmet medical diagnostic needs. A twelve (12) amino acid peptide has been discovered using Phage Display Library Screening. The affinity of peptide with H-FABP and other FABPs has been done using molecular docking and ADMET profile has been done. Molecular docking of small peptides against the target protein can play a crucial role in recognizing peptide binding sites and poses. The docking study was done using the HDOCK server and the visualization of the docked complex was done using Pymol and UCSF chimera. The molecular simulation study of three protein-peptide complexes were done which also validated the binding affinity of peptide with the proteins. The RMSD, RMSF and radius of gyration are also analyzed. The results indicate that H-FABP shows higher level of binding interaction with the peptide having bond length ranging from 2.3 to 3.4 Å. The screened peptide is suitable for H-FABP binding and can be used for prognosis purposes in the heart ischemic conditions.

Neuroinflammation evoked mechanisms for neuropathic itch in the spared nerve injury mouse model of neuropathic pain.

A large portion of neuropathic pain suffering patients may also concurrently experience neuropathic itch, with a negative impact on the quality of life. The limited understanding of neuropathic itch and the low efficacy of current anti-itch therapies dictate the urgent need of a better comprehension of molecular mechanisms involved and development of relevant animal models. This study was aimed to characterize the itching phenotype in a model of trauma-induced peripheral neuropathy, the spared nerve injury (SNI), and the molecular events underlying the overlap with the nociceptive behavior. SNI mice developed hyperknesis and spontaneous itch 7-14 days after surgery that was prevented by gabapentin treatment. Itch was associated with pain hypersensitivity, loss of intraepidermal nerve fiber (IENF) density and increased epidermal thickness. In coincidence with the peak of scratching behavior, SNI mice showed a spinal overexpression of IBA1 and GFAP, microglia and astrocyte markers respectively. An increase of the itch neuropeptide B-type natriuretic peptide (BNP) in NeuN+ cells, of its downstream effector interleukin 17 (IL17) along with increased pERK1/2 levels occurred in the spinal cord dorsal horn and DRG. A raise in BNP and IL17 was also detected at skin level. Stimulation of HaCat cells with conditioned medium from BV2-stimulated SH-SY5Y cells produced a dramatic reduction of HaCat cell viability. This study showed that SNI mice might represent a model for neuropathic itch and pain. Collectively, our finding suggest that neuropathic itch might initiate at spinal level, then affecting skin epidermis events, through a glia-mediated neuroinflammation-evoked BNP/IL17 mechanism.

Octa-Arginine-Conjugated Liposomal Nimodipine Incorporated in a Temperature-Responsive Gel for Nasoencephalic Delivery.

Nimodipine is the primary clinical drug used to treat cerebral vasospasm following subarachnoid hemorrhage. Currently, tablets have low bioavailability when taken orally, and injections contain ethanol. Therefore, we investigated a new method of nimodipine administration, namely, nasoencephalic administration. Nasal administration of nimodipine was carried out by attaching the cell-penetrating peptide octa-arginine (R8) to liposomes of nimodipine and incorporating it into a temperature-sensitive in situ gel. The prepared liposomes and gels underwent separate evaluations for in vitro characterization. In vitro release exhibited a significant slow-release effect. In vitro toad maxillary cilia model, RPMI 2650 cytotoxicity, and in vivo SD rat pathological histotoxicity experiments showed that all the dosage from the groups had no significant toxicity to toad maxillary cilia, RPMI 2650 cells, and SD rat tissues and organs, and the cilia continued to oscillate up to 694 ± 10.15 min, with the survival rate of the cells being above 85%. A transwell nasal mucosa cell model and an isolated porcine nasal mucosa model were established, and the results showed that the osmolality of the R8-modified nimodipine liposomal gel to nasal mucosal cells and isolated porcine nasal mucosa was 30.41 ± 2.14 and 65.9 ± 7.34 µg/mL, respectively, which was significantly higher than that of the NM-Solution and PEGylated nimodipine liposome gel groups. Animal fluorescence imaging studies revealed that the R8-modified nimodipine liposomal gel displayed increased brain fluorescence intensity compared to the normal liposomal gel. Pharmacokinetic results showed that after transnasal administration, the AUC(0-∞) of the R8-modified nimodipine liposomal gel was 11.662 ± 1.97 µg·mL-1, which was significantly higher than that of the plain nimodipine liposomal gel (5.499 ± 2.89 µg·mL-1). Brain-targeting experiments showed that the brain-targeting efficiencies of the PEGylated nimodipine liposome gel and R8-modified PEGylated nimodipine liposome gels were 20.44 and 33.45, respectively, suggesting that R8/PEG/Lip-NM-TSG significantly increased the brain-targeting of the drug.

Is it necessary to stop glucagon-like peptide-1 receptor agonists prior to endoscopic procedure? A retrospective study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective in diabetes and obesity, reducing hyperglycemia by increasing insulin release and delaying gastric emptying. However, they can cause gastroparesis, raising concerns about aspiration during procedures. Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration. AIM: To evaluate the effect of GLP-1 RAs on gastric residual contents during endoscopic procedures. METHODS: A retrospective chart review at BronxCare Health System, New York, from January 2019 to October 2023, assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures. Two groups were compared based on dietary status before the procedure. Data included demographics, symptoms of gastroparesis, opiate use, hemoglobin A1c, GLP-1 agonist indication, endoscopic details, and aspiration occurrence. IBM SPSS was used for analysis, calculating means, standard deviations, and applying Pearson's chi-square and t-tests for associations, with P < 0.05 as being significant. RESULTS: During the study, 306 patients were included, with 41.2% on a clear liquid/low residue diet and 58.8% on a regular diet before endoscopy. Most patients (63.1%) were male, with a mean age of 60 ± 12 years. The majority (85.6%) were on GLP-1 RAs for diabetes, and 10.1% reported digestive symptoms before endoscopy. Among those on a clear liquid diet, 1.5% had residual food at endoscopy compared to 10% on a regular diet, which was statistically significant (P = 0.03). Out of 31 patients with digestive symptoms, 13% had residual food, all from the regular diet group (P = 0.130). No complications were reported during or after the procedures. CONCLUSION: The study reflects a significant rise in GLP-1 RA use for diabetes and obesity. A 24-hour liquid diet seems safe for endoscopic procedures without aspiration. Patients with upper gastrointestinal symptoms might have a higher residual food risk, though not statistically significant. Further research is needed to assess risks based on diabetes duration, gastroparesis, and GLP-1 RA dosing, aiming to minimize interruptions in therapy during procedures.

Structural, Biochemical Characterization and Molecular Mechanism of Cerastokunin: A New Kunitz-Type Peptide with Potential Inhibition of Thrombin, Factor Xa and Platelets.

The current investigation focused on separating Cerastes cerastes venom to produce the first Kunitz-type peptide. Based on its anti-trypsin effect, Cerastokunin, a 7.75 kDa peptide, was purified until homogenity by three steps of chromatography. Cerastokunin was found to include 67 amino acid residues that were obtained by de novo sequencing using LC-MALDI-MSMS. Upon alignment with Kunitz-type peptides, there was a high degree of similarity. Cerastokunin's 3D structure had 12% α-helices and 21% ß-strands with pI 8.48. Cerastokunin showed a potent anticoagulant effect by inhibiting the protease activity of thrombin and trypsin as well as blocking the intrinsic and extrinsic coagulation pathways. In both PT and aPPT, Cerastokunin increased the blood clotting time in a dose-dependent way. Using Lys48 and Gln192 for direct binding, Cerastokunin inhibited thrombin, Factor Xa and trypsin as shown by molecular docking. Cerastokunin exhibited a dose-response blockade of PARs-dependent pathway platelet once stimulated by thrombin. An increased concentration of Cerastokunin resulted in a larger decrease of tail thrombus in the mice-carrageenan model in an in vivo investigation when compared to the effects of antithrombotic medications. At all Cerastokunin doses up to 6 mg/kg, no in vivo toxicity was seen in challenged mice over the trial's duration.

Synergistic integration of a rhodamine-labelled tripeptide into AIE-active fluorogenic probe: Enabling nanomolar detection of Al3+ ions through test strips, thin films, and Arduino-assisted optosensing platform.

Peptide-fluorophore conjugates (PFCs) have been expeditiously utilized for metal ion recognition owing to their distinctive characteristics. Selective detection and quantification of aluminum is essential to minimize health and environmental risks. Herein, we report the synthesis and characterization of a new chemoprobe with aggregation-induced emission characteristics by chemically conjugating rhodamine-B fluorophore with a tripeptide. The probe revealed ß-sheet secondary conformation in both solid and solution states, as confirmed by FT-IR, PXRD, and CD experiments. AIE characteristics of the probe in water-MeCN mixtures revealed the formation of spherically shaped nanoaggregates with an average size of 353 ± 7 nm, as confirmed by SEM, TEM, and DLS studies. The probe exhibited a large stokes shift (175 nm) and displayed selective colorimetric and fluorometric responses towards Al3+ ions with an extremely low detection limit (51 nm) and a fast response time (≤15 s). Comparative NMR studies confirmed the cleavage of spirolactam ring upon aluminum binding. The probe's practicality was enhanced through integration into test strips and thin films, allowing solid-phase detection of Al3+ ions. Furthermore, an RGB-Arduino enabled optosensing device has been developed to enable instant quantifiable analysis of aluminum concentrations in real-time conditions.

Patients with type 2 diabetes who achieve reduced postprandial glucose levels during insulin intensive therapy may have a better recovery of ß-cell function.

OBJECTIVES: To explore parameters that may determine the improvement in C-peptide levels in patients with type 2 diabetes (T2D) receiving continuous subcutaneous insulin infusion (CSII) therapy. METHODS: The trial included a lead-in period for collecting baseline parameters and correcting hyperglycemia, a 4-day CGM period, and a 2-3 weeks treatment period. After screening, patients were hospitalized and randomized to the metformin add-on NovoRapid group or the Prandilin group. Once the glycemic target was reached, all patients underwent a 4-day CGM, with treatments maintained for 2-3 weeks. OGTTs were performed at baseline and endpoint. The primary endpoint was identifying factors contributing to better ß-cell function recovery after CSII therapy. RESULTS: A total of 99 recruited patients were admitted as inpatients and achieved glycemic control within 3.8 ± 1.1 days. Of these, 83 (84 %) patients showed improvement in C-peptide levels, while 16 (16 %) did not show any change in C-peptide levels at the endpoint. Pearson analysis showed a negative correlation between the incremental AUC of glucose concentration (from 0700 to 1000) and the increase in incremental AUC of C-peptide levels (r = -0.199, P < 0.05). CONCLUSIONS: Drug-naïve T2D patients with lower postprandial glucose concentration during CSII therapy exhibit better ß-cell function recovery.

Development of a 2A peptide-based multigene expression system and its application for enhanced production of ganoderic acids in Ganoderma lucidum.

Ganoderma has received much attention for its medicinal value, but the manipulation of multiple genes remains a challenge, hindering the genetic engineering of this species for the development of cell factories. Here, we first showed that the presence of an intron is necessary for the efficient expression of the endogenous cDNA of carboxin-resistant gene (cbx) in G. lucidum. Then, the self-cleaving function of 2 A peptide was investigated in G. lucidum by linking cbx cDNA to the codon-optimized hygromycin B-resistant gene (ophph) using the 2A-peptide sequence. The results showed that cbx cDNA and ophph can be successfully expressed in G. lucidum in a bicistronic manner from a single transcript. Moreover, the expression of both genes was not affected by the order within the 2 A cassette. In addition, simultaneous expression of cbx cDNA, ophph, and codon-optimized yellow fluorescent protein gene (opyfp) was conducted for the first time in G. lucidum using the 2 A peptide-based approach. The developed method was successfully applied to express both cDNA of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (hmgr) and squalene epoxidase gene (se) for enhanced production of ganoderic acids (GAs) in G. lucidum. The engineered strain produced the maximum content of GA-Mk, GA-T, GA-S, and GA-Me were 26.56±3.53,39.58±3.75, 16.54±2.16, and 19.1±1.87 µg/100 mg dry weight, respectively. These values were 3.85-, 4.74-, 3.65-, and 3.23-fold higher than those produced by the control strain. The developed method will be useful for the manipulation of complex metabolic or regulatory pathways involving multiple genes in Ganoderma.

Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinson's Disease in Patients with Type 2 Diabetes: A Population-Based Cohort Study.

BACKGROUND: Previous studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a disease-modifying effect in the development of Parkinson's disease (PD), but population studies yielded inconsistent results. OBJECTIVE: The aim was to compare the risk of PD associated with GLP-1RAs compared to dipeptidyl peptidase 4 inhibitors (DPP4i) among older adults with type 2 diabetes (T2D). METHODS: Using U.S. Medicare administrative data from 2016 to 2020, we conducted a population-based cohort study comparing the new use of GLP-1RA with the new use of DPP4i among adults aged ≥66 years with T2D. The primary endpoint was a new diagnosis of PD. A stabilized inverse probability of treatment weighting (sIPTW)-adjusted Cox proportional hazards regression model was employed to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for PD between GLP-1RA and DPP4i users. RESULTS: This study included 89,074 Medicare beneficiaries who initiated either GLP-1RA (n = 30,091) or DPP4i (n = 58,983). The crude incidence rate of PD was lower among GLP-1RA users than DPP4i users (2.85 vs. 3.92 patients per 1000 person-years). An sIPTW-adjusted Cox model showed that GLP-1RA users were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95% CI, 0.63-0.95). Our findings were largely consistent across different subgroup analyses such as sex, race, and molecular structure of GLP-1RA. CONCLUSION: Among Medicare beneficiaries with T2D, the new use of GLP-1RAs was significantly associated with a decreased risk of PD compared to the new use of DPP4i. © 2024 International Parkinson and Movement Disorder Society.

Treatment patterns of patients with migraine eligible for anti-CGRP pathway monoclonal antibodies.

Introduction: Migraine is a debilitating neurological disorder, with a wide range of symptoms and disease burden, underscoring the heterogeneity of patients' disease characteristics and treatment needs. To characterize the profile of migraine patients in the US who may be eligible for preventive treatment with an anti-CGRP pathway mAb and to better understand treatment patterns and real-world use of acute and preventive medications for migraine, we conducted a retrospective cohort study of adult patients. Methods: These patients were identified as having migraine using diagnosis codes or migraine-specific medication use (first = index) in the IQVIA PharMetrics® Plus database. Patients were required to have ≥ 12 months of continuous enrollment in medical and pharmacy benefits prior to index (baseline) and after index (follow-up). Patients were stratified into chronic migraine (CM) and non-chronic migraine (non-CM) by diagnosis codes. Based on acute migraine-specific medication dispensing data in the follow-up period, non-CM patients were divided into 3 cohorts: highest, middle, and lowest tertile of total units of dispensed acute migraine-specific medication (gepants, ditans, ergot derivatives, and triptans). Migraine medication use was captured in the baseline and follow-up periods. Results: A total of 22,584 CM and 216,807 non-CM patients (72,269 patients in each tertile) were identified and included in the study. Over the follow-up, CM patients had a mean of 70 units of acute migraine-specific medications dispensed, while the highest, middle, and lowest tertile of non-CM patients had a mean of 92, 29, and 10 units, respectively. Anti-calcitonin gene-related peptide pathway mAbs were dispensed for 28.9% of CM patients, and for 6.9%, 4.1%, and 2.9% of non-CM patients in the highest, middle, and lowest tertiles, respectively. Conclusion: A lower proportion of non-CM patients had use of anti-calcitonin gene-related peptide pathway mAbs compared to CM patients, confirming the unmet need with appropriate preventive medication. There appears to be a persistent gap in management of patients without a diagnosis of CM who are dispensed high quantities of acute migraine-specific medications.

Extracellular vesicle-liposome hybrids via membrane fusion using cell-penetrating peptide-conjugated lipids.

Extracellular vesicles (EVs) are natural carriers for intercellular communication within the human body. Mimicking and utilizing EVs by combining them with artificial nanocarriers such as liposomes for drug delivery has garnered considerable attention. However, current technologies for manipulating EVs to facilitate their fusion with liposomes are limited; the existing technique of polyethylene glycol (PEG)-induced fusion is highly inefficient for fusion. In our previous study, we demonstrated that membrane fusion could be induced by Tat peptide (YGRKKRRQRRR)-conjugated poly(ethylene glycol)-phospholipids (Tat-PEG-lipids), in which the Tat peptide and lipid domain facilitate membrane attachment and subsequent fusion between cells and liposomes. This approach is promising for forming EV and liposomal hybrids. In this study, we aim to fuse EVs and liposomes using Tat-PEG-lipids. We isolated and characterized EVs derived from HEK293T cell culture medium and treated a mixture of EVs and liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and cholesterol (1:1, molar ratio), with Tat-PEG-lipids with different lipid chain lengths. Here, we used nonanoyl (C9), dodecanoyl (C12), and myristoyl (C14) groups as lipid anchors with 5 kDa PEG chains. Dynamic light scattering analysis revealed a large increase in the apparent size of mixture of EVs and liposomes by adding Tat-PEG-lipids (especially C14, C12, followed by C9). Fluorescence resonance energy transfer, confocal laser scanning microscopy, and transmission electron microscopy, used to analyze the reaction process, revealed that the membrane fusion occurred between EVs and liposomes but not their aggregates. The short lipid domain of Tat-PEG-lipids effectively induced membrane fusion and the formation of hybrid EVs and liposomes. Thus, Tat-PEG-lipids (C9 and C12) could be promising candidates for inducing membrane fusion to fabricate EV-liposome hybrids.

Decrease in the Internal Cerebral Vein Pulsation With Improvement of Patent Ductus Arteriosus in Premature Infants at the Risk of Intraventricular Hemorrhage: Two Interesting Case Reports.

Recently, augmenting the pulsation of the internal cerebral vein (ICV) has been reported to be a predictor of premature intraventricular hemorrhage (IVH); however, prophylaxis for IVH has not yet been established. Venous pulsation is a marker of central venous pressure elevation and may be improved after heart failure treatment. Herein, we report two cases of low-birth-weight infants (29 weeks and 31 weeks of gestational age), who exhibited improvements in ICV pulsation with relief of hemodynamically significant patent ductus arteriosus (hs-PDA) following indomethacin administration. ICV flow patterns were continuously flat early after birth. Thereafter, both patients demonstrated ICV pulsation augmentation with PDA progression and brain natriuretic peptide (BNP) elevation at 52 h and 39 h after birth (in infants born at 29 and 31 weeks of gestational age, respectively). After relieving PDA with indomethacin administration, both infants exhibited an improvement in ICV pulsation with decreased BNP levels. In both cases, ICV pulsation increased when PDA became hemodynamically significant with BNP elevation, and the pulsation improved by reduction in ductal flow with decreasing BNP when PDA was relieved by indomethacin administration. The association between hs-PDA and elevated ICV pulsation indicates that hs-PDA likely leads to heightened central venous pressure. Additionally, indomethacin treatment was effective in reducing the exacerbated ICV pulsation caused by heart failure due to hs-PDA. These cases suggest that treatment for heart failure might improve the augmented ICV pulsation, which is related to the development of premature IVH. However, further studies are needed to confirm this association.

Efficacy of Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists for Weight Loss Management in Non-Diabetic Patients.

The rising prevalence of obesity has led to a poor quality of life affecting millions worldwide. The lack of a healthy diet and exercise intervention are the major risk factors leading to obesity, as well as genetics. Obesity can lead to type 2 diabetes mellitus. However, there are many people who are obese and do not have an established diagnosis of diabetes but want to reduce their body weight to improve their quality of life. This review aims to discuss the efficacy of the diabetic pharmacologic agents, glucagon-like peptide-1 (GLP-1) receptor agonists, on body weight. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 and includes a comprehensive search strategy. The articles gathered are from the last five to 10 years. The articles are collected from distinguished databases such as PubMed, Google Scholar, ResearchGate, and Science Direct. Of the 698 studies identified based on the screening methods, 22 were assessed for eligibility and 10 studies were included in the final review. The findings of this systematic review provide a bigger picture of the efficacy and safety of glucagon-like peptide receptor agonist agents. The review thoroughly discusses the risk factors for obesity and provides a treatment strategy that can be utilized in clinical practice in the future. The review concludes that glucagon-like peptide agents act as pharmacologic treatments for reduction in body weight and also serve as cardioprotective agents.

Characterization and molecular docking of tetrapeptides with cellular antioxidant and ACE inhibitory properties from cricket (Acheta domesticus) protein hydrolysate.

Wide-ranging bioactivities of enzymatically digested insect protein to produce peptides have been targeted for functional food development. In this study, fractionated peptides obtained from cricket (Acheta domesticus) protein hydrolysate by alcalase digestion were identified and evaluated for their bioactivities. Peptide fractions F44, F45, and F46, isolated through size exclusion chromatography, demonstrated strong cytoprotective effects on SH-SY5Y and HepG2 cells exposed to H2O2. This was evidenced by a 2-fold decrease in reactive oxygen species (ROS) accumulation in the cells and a 3-fold upregulation of genes encoding antioxidant enzymes. The F45 peptide fractions also showed chemical antioxidant activities ranging from approximately 290 to 393 mg trolox/g peptide, measured by DPPH, ABTS, and FRAP assays. Furthermore, F45 demonstrated the highest angiotensin-converting enzyme I (ACE) inhibitory activity, 57.93 %. F45 induced higher levels of Nrf2, SOD1, SOD2, CAT, GSR, and GPx4 gene expression in SH-SY5Y and HepG2 cells compared to cells treated with H2O2 and no peptides (p < 0.05). Cells treated with H2O2 and F45 exhibited significantly increased antioxidant enzyme activity, including SOD, CAT, GSR, and GPx (p < 0.05). The F45B fraction from F45 was sequenced to obtain FVEG and FYDQ tetrapeptides. Molecular docking analysis revealed their high binding affinity to cellular antioxidant enzymes (SOD, CAT, GSR, GPx1, and GPx4), an antioxidant-related protein (Keap1), and ACE. These results suggest that the novel tetrapeptides from Acheta domesticus demonstrate important biological activities, establishing them as significant cellular antioxidant activities and a potential source of antihypertensive peptides.

Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene ß-Catenin.

The inhibition of intracellular protein-protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co-activator protein and oncogene ß­catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high-affinity binders comprise only large molecular weight Inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α-helical ß­catenin-binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a ß-catenin inhibitor with single-digit micromolar activity in a cell-based assay. This study sheds a light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

[Drug therapy of type-2-diabetes-is metformin dispensable now?] / Arzneitherapie des Diabetes mellitus Typ 2 ­ ist Metformin neuerdings verzichtbar?

Metformin has been recommended as first-line pharmacological therapy in type­2 diabetes (T2D) since 1998. It was the first medication that demonstrated cardiovascular benefits in obese subjects with T2D. Efficacy and safety of metformin have since been demonstrated in further studies and in real-world data on its use in practice. The recommendation of metformin as baseline therapy has reached wide acceptance internationally. During the period 2015-2021, large cardiovascular safety trials showed superiority for cardiovascular morbidity and partly also mortality outcomes for most substances of the novel antidiabetic substance classes of GLP­1 receptor agonists and SGLT­2 inhibitors in people with T2D and very high cardiovascular risk or preexisting cardiovascular disease. The evidence for these two substance classes is now broader than for metformin. Therefore, the question arises as to whether it is still justified to recommend metformin generally as first-line therapy in T2D. This article provides an overview of the study data as well as an overview of the evidence-based guidelines. The status and position of metformin in the treatment of T2D are discussed.