Search Results (19)

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2Is) have significantly improved the management of diabetes mellitus (DM). In the general population, these drugs have additional benefits, such as weight loss, improvement of liver steatosis, and a cardiorenal protective effect. However, data regarding the effects of GLP-1RAs or SGLT-2Is in the treatment of posttransplant diabetes mellitus (PTDM), obesity, and their potential cardiorenal protective effects in liver transplant (LT) recipients remain limited. PTDM increases the risk of developing graft steatosis, experiencing major cardiovascular events (MACEs), and developing chronic kidney disease and reduces long-term survival in LT recipients. The aim of this systematic review was to evaluate the efficacy and safety of GLP-1RAs and SGLT-2Is in the treatment of PTDM in LT recipients. Methods: Twelve retrospective studies (five specifically conducted in LT recipients and seven in mixed solid organ transplant cohorts, including LT recipients) that collectively enrolled 402 LT recipients treated with GLP-1RAs and/or SGLT-2Is for PTDM were selected. Results: GLP-1Ras and SGLT-2Is reduced serum glycated hemoglobin levels, body weight, and insulin requirements in LT recipients. Some studies reported benefits in reducing graft steatosis, improving renal function, and in reducing the occurrence of MACEs. Common adverse events included gastrointestinal symptoms, which rarely required treatment discontinuation. Conclusions: GLP-1RAs and SGLT-2Is represent promising treatment options for PTDM in LT recipients, offering metabolic benefits with manageable side effects. However, further prospective studies are needed to establish the long-term safety and efficacy, as well as the favorable impact on patient survival, of these drugs in LT recipients. Full article

Background: Colorectal cancer (CRC) is one of the common malignant tumors. Chemotherapeutic agents represented by doxorubicin (DOX) are common adjuvant therapies for patients with advanced CRC. However, DOX suffers from dose-dependent cardiotoxicity and myelosuppression due to a lack of targeting and specificity, which severely limits its clinical application. Methods: Herein, we constructed a zeolitic imidazolate framework-8 (ZIF-8) modified by a novel peptide (LT peptide) to deliver the chemotherapeutic drug doxorubicin (DOX) for the targeted treatment of CRC. Results: In this study, LT-PEG@DOX@ZIF-8 nanoparticles were prepared by a simple method with suitable particle size and zeta potential, which were also capable of pH-responsive drug release. In vitro assays exhibited that LT-PEG@DOX@ZIF-8 nanoparticles were effectively taken up by C26 cells, significantly inhibited cell proliferation, and induced apoptosis. Furthermore, in mice models with colorectal tumors, LT-PEG@DOX@ZIF-8 nanoparticles also displayed specific tumor aggregation and exerted anti-tumor effects to prolong the survival of the mice. Conclusions: In conclusion, LT-PEG@DOX@ZIF-8 provides a promising strategy for the delivery of DOX to effectively treat CRC. Full article

Background and Objectives: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. Materials and Methods: The study was conducted on four groups of six adult male Wistar rats. Diabetes was produced by administration of streptozotocin 65 mg/kg ip. in a single dose. Before the administration of streptozotocin, after 72 h, and after 8 weeks, the serum values of glucose, SOD, MDA, and total antioxidant capacity (TAS) were determined. After 8 weeks, the animals were anesthetized and sacrificed, and the lungs were harvested and examined by optical microscopy. Pulmonary fibrosis, the extent of lung lesions, and the lung wet-weight/dry-weight ratio were evaluated. Results: The obtained results showed that MK significantly reduced pulmonary fibrosis (3.34 ± 0.41 in the STZ group vs. 1.73 ± 0.24 in the STZ+MK group p < 0.01) and lung lesion scores and also decreased the lung wet-weight/dry-weight (W/D) ratio. SOD and TAS values increased significantly when MK was administered to animals with diabetes (77.2 ± 11 U/mL in the STZ group vs. 95.7 ± 13.3 U/mL in the STZ+MK group, p < 0.05, and 25.52 ± 2.09 Trolox units in the STZ group vs. 33.29 ± 1.64 Trolox units in the STZ+MK group, respectively, p < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. Conclusions: The obtained data showed that by blocking the action of peptide leukotrienes on cysLT1 receptors, montelukast significantly reduced the lung lesions caused by diabetes. The involvement of these leukotrienes in the pathogenesis of fibrosis and other lung diabetic lesions was also demonstrated. Full article

Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug doxorubicin (DOX). Peptide–drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. However, peptide ligands composed of natural L-configuration amino acids have the defects of easy enzymatic degradation and insufficient biological stability. In this study, two new PDCs (^LT7-SS-DOX and ^DT7-SS-DOX) were designed and synthesized by conjugating a transferrin receptor (TfR) peptide ligand ^LT7 (HAIYPRH) and its retro-inverso analog ^DT7 (hrpyiah), respectively, with DOX via a disulfide bond linker. Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the ^DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to ^LT7-SS-DOX. In conclusion, the coupling of antitumor drugs with the ^DT7 peptide ligand can be used as a promising strategy for the further development of stable and efficient PDCs with the potential to facilitate TfR-targeted drug delivery. Full article

On the verge of a theranostic approach to personalised medicine, copper-64 is one of the emerging radioisotopes in nuclear medicine due to its exploitable nuclear and biochemical characteristics. The increased demand for copper-64 for preclinical and clinical studies has prompted the development of production routes. This research aims to compare the (p,n) reaction on nickel-64 solid versus liquid targets and evaluate the effectiveness of [⁶⁴Cu]CuCl₂ solutions prepared by the two routes. As new treatments for neurotensin receptor-overexpressing tumours have developed, copper-64 was used to radiolabel Neurotensin (8-13) and Neuromedin N. High-quality [⁶⁴Cu]CuCl₂ solutions were prepared using ACSI TR-19 and IBA Cyclone Kiube cyclotrons. The radiochemical purity after post-irradiation processing reached 99% (LT) and 99.99% (ST), respectively. The irradiation of a solid target with 11.8 MeV protons and 150 μAh led to 704 ± 84 MBq/μA (17.6 ± 2.1 GBq/batch at EOB). At the end of the purification process (1 h, 90.90% activity yield), the solution for peptide radiolabelling had a radioactive concentration of 1340.4 ± 70.1 MBq/mL (n.d.c.). The irradiation of a liquid target with 16.9 MeV protons and 230 μAh resulted in 3.7 ± 0.2 GBq/batch at EOB, which corresponds to an experimental production yield of 6.89 GBq.cm3/(g.µA)_sat. Benefiting from a shorter purification process (40 min), the activity yielded 90.87%, while the radioactive concentration of the radiolabelling solution was lower (492 MBq/mL, n.d.c.). The [⁶⁴Cu]CuCl₂ solutions were successfully used for the radiolabelling of DOTA-NT(8-13) and DOTA-NN neuropeptides, resulting in a high RCP (>99%) and high molar activity (27.2 and 26.4 GBq/μmol for LT route compared to 45 and 52 GBq/μmol for ST route, respectively). The strong interaction between the [⁶⁴Cu]Cu-DOTA-NT(8-13) and the colon cancerous cell lines HT29 and HCT116 proved that the specificity for NTR had not been altered, as shown by the uptake and retention data. Full article

Breast cancer is the leading cause of death among females in developed countries. Although the implementation of screening tests and the development of new therapies have increased the probability of remission, relapse rates remain high. Numerous studies have indicated the connection between cancer-initiating cells and slow cellular cycle cells, identified by their capacity to retain long labeling (LT+). In this study, we perform new assays showing how stem cell self-renewal modulating proteins, such as PEDF, can modify the properties, percentage of biomarker-expressing cells, and carcinogenicity of cancer stem cells. The PEDF signaling pathway could be a useful tool for controlling cancer stem cells’ self-renewal and therefore control patient relapse, as PEDF enhances resistance in breast cancer patient cells’ in vitro culture. We have designed a peptide consisting of the C-terminal part of this protein, which acts by blocking endogenous PEDF in cell culture assays. We demonstrate that it is possible to interfere with the self-renewal capacity of cancer stem cells, induce anoikis in vivo, and reduce resistance against docetaxel treatment in cancer patient cells in in vitro culture. We have also demonstrated that this modified PEDF protein produces a significant decrease in the percentage of expressed cancer stem cell markers. Full article

The Antarctic Peninsula has rapidly warmed up in past decades, and global warming has exhibited an asymmetric trend; therefore, it is interesting to understand whether nocturnal or diurnal warming is the most relevant for plant cold deacclimation. This study aimed to evaluate the effect of diurnal and nocturnal warming on Antarctic vascular plant’s freezing resistance under laboratory conditions. This was studied by measuring the lethal temperature for 50% of tissue (LT₅₀), ice nucleation temperature (INT), and freezing point (FP) on Deschampsia antarctica and Colobanthus quitensis plants. Additionally, soluble carbohydrates content and dehydrin levels were analyzed during nocturnal and diurnal temperatures increase. Nocturnal warming led to a 7 °C increase in the LT₅₀ of D. antarctica and reduced dehydrin-like peptide expression. Meanwhile, C. quitensis warmed plants reduce their LT₅₀ to about 3.6 °C. Both species reduce their sucrose content by more than 28% in warming treatments. Therefore, nocturnal warming leads to cold deacclimation in both plant species, while C. quitensis plants are also cold-deacclimated upon warm days. This suggests that even when the remaining freezing resistance of both species allows them to tolerate summer freezing events, C. quitensis can reach its boundaries of freezing vulnerability in the near future if warming in the Antarctic Peninsula progress. Full article

Portopulmonary hypertension (PoPH) and hepatopulmonary syndrome are severe pulmonary complications associated with liver cirrhosis (LC) and portal hypertension. Three key pathways, involving endothelin, nitric oxide, and prostacyclin, have been identified in the development and progression of pulmonary arterial hypertension (PAH). To obtain a good effect with PAH-specific drugs in PoPH patients, it is important to diagnose PoPH at an early stage and promptly initiate therapy. The majority of therapeutic drugs are contraindicated for Child-Pugh grade C LC, and their effects decrease in the severe PAH stage. Among many LC patients, the measurement of serum brain natriuretic peptide levels might be useful for detecting PoPH. Previously, liver transplantation (LT) for PoPH was contraindicated; however, the indications for LT are changing and now take into account how well the PoPH is controlled by therapeutic drugs. In Japan, new registration criteria for deceased-donor LT have been established for PoPH patients. PoPH patients with a mean pulmonary arterial pressure <35 mmHg and pulmonary vascular resistance <400 dyn/s/cm⁻⁵ are indicated for LT, regardless of whether they are using therapeutic drugs. Combined with PAH-specific drugs, LT may lead to excellent long-term outcomes in PoPH patients. We aimed to review current therapies for PoPH, including LT. Full article

This study was conducted to explore the effects of the joint application of Lactobacillus plantarum and Bacillus subtilis on growth performance, immune function, antioxidant capacity, intestinal integrity, and gut microbiota composition in weaned piglets. The piglets were allocated randomly into 4 dietary groups, which were a control diet (NC), NC + 150 ppm mucilage sulfate (PC), and 3 additional diets containing 1 kg/t (LT), 1.5 kg/t (MT), or 2 kg/t (HT) mixture of Lactobacillus plantarum and Bacillus subtilis, respectively. Results showed that joint application of Lactobacillus plantarum and Bacillus subtilis increased ADFI and ADG of weaned piglets in d 14~28 and d 28~42 (p < 0.05), and decreased serum concentrations of DAO, IL-1β, TNF-α, and IL-2. The LT group increased jejunal and colonic sIgA contents compared with the PC group (p < 0.05). Groups of MT and HT increased colonic mRNA expression of host defense peptides and tight junction proteins compared with the NC and PC groups. The joint application of Lactobacillus plantarum and Bacillus subtilis increased the abundance of colonic Lactobacillus compared with NC and PC groups (p < 0.10). In conclusion, the joint application of Lactobacillus plantarum and Bacillus subtilis as an antibiotics alternative improved growth performance via promoting immune function and intestinal integrity of weaned piglets. Full article

Lasiodiplodia theobromae is a causal agent of grapevine trunk disease, and it poses a significant threat to the grape industry worldwide. Fungal effectors play an essential role in the interaction between plants and pathogens. However, few studies have been conducted to understand the functions of individual effectors in L. theobromae. In this study, we identified and characterized a candidate secreted effector protein, LtCSEP1, in L. theobromae. Gene expression analysis suggested that transcription of LtCSEP1 in L. theobromae was induced at the early infection stages in the grapevine. Yeast secretion assay revealed that LtCSEP1 contains a functional signal peptide. Transient expression of LtCSEP1 in Nicotiana benthamiana suppresses BAX-trigged cell death and significantly inhibits the flg22-induced PTI-associated gene expression. Furthermore, the ectopic expression of LtCSEP1 in N. benthamiana enhanced disease susceptibility to L. theobromae by downregulating the defense-related genes. These results demonstrated that LtCSEP1 is a potential effector of L. theobromae, which contributes to suppressing the plant’s defenses. Full article

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset). We compared antiangiogenic factors soluble Fms-like Tyrosine Kinase-1 (sfLt-1), placental growth factor (PlGF), and soluble endoglin (sEng)), lipid and carbohydrate metabolism in maternal plasma, and lipid metabolism in the placenta from assays of fatty acid oxidation, fatty acid esterification, and triglyceride levels in all groups. Antiangiogenic factors sFlt-1, sFlt-1/PlGF ratio, and sEng showed a positive correlation with triglyceride, free fatty acid, and C-peptide maternal serum levels. However, there was no relationship between angiogenic factors and placental lipid metabolism parameters. Free fatty acids were predictive of elevated sFlt-1 and sEng, while C-peptide was predictive of an elevated sFlt1/PlGF ratio. The findings in this study generate a model to predict elevated antiangiogenic factor values and the relationship between them with different products of lipid and carbohydrate metabolism in maternal serum and placenta in preeclampsia. Full article

Infection by high-risk human papillomaviruses (hrHPVs), including HPV type 16 (HPV16), is a major risk factor for oral squamous cell carcinomas (OSCCs). However, the pathogenic mechanism by which hrHPVs promote oral carcinogenesis remains to be elucidated. Here, we demonstrated that the suppression of a transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2), which is a key molecule in the transportation of viral antigenic peptides into MHC class-I cells, is affected by the E6 protein of HPV16. Mechanistically, HPV-mediated immune evasion is principally mediated via the signal-transduction network of a lymphotoxin (LT) pathway, in particular LTα₁β₂ and LTβR. Our analysis of transcriptomic data from an HNSCC cohort from the Cancer Genome Atlas (TCGA) indicated that expression of TAP genes, particularly TAP2, was downregulated in HPV-infected cases. We further demonstrated that LTα₁β₂ and LTβR were upregulated, which was negatively correlated with TAP1 and TAP2 expression in HPV-positive clinical OSCC samples. Taken together, our findings imply that HPV16 E6 regulates the machinery of the antigenic peptide-loading system and helps to clarify the role of oncogenic viruses in the context of oral carcinoma. Full article

White Spot Syndrome Virus (WSSV) has emerged as one of the most prevalent and lethal viruses globally and infects both shrimps and crabs in the aquatic environment. This study aimed to investigate the occurrence of WSSV in different ghers of Bangladesh and the virulence of the circulating phylotypes. We collected 360 shrimp (Penaeus monodon) and 120 crab (Scylla sp.) samples from the south-east (Cox’s Bazar) and south-west (Satkhira) coastal regions of Bangladesh. The VP28 gene-specific PCR assays and sequencing revealed statistically significant (p < 0.05, Kruskal–Wallis test) differences in the prevalence of WSSV in shrimps and crabs between the study areas (Cox’s Bazar and Satkhira) and over the study periods (2017–2019). The mean Log load of WSSV varied from 8.40 (Cox’s Bazar) to 10.48 (Satkhira) per gram of tissue. The mean values for salinity, dissolved oxygen, temperature and pH were 14.71 ± 0.76 ppt, 3.7 ± 0.1 ppm, 34.11 ± 0.38 °C and 8.23 ± 0.38, respectively, in the WSSV-positive ghers. The VP28 gene-based phylogenetic analysis showed an amino-acid substitution (E→G) at the 167th position in the isolates from Cox’s Bazar (referred to as phylotype BD2) compared to the globally circulating one (BD1). Shrimp PL artificially challenged with BD1 and BD2 phylotypes with filtrates of tissue containing 0.423 × 10⁹ copies of WSSV per mL resulted in a median LT50 value of 73 h and 75 h, respectively. The in vivo trial showed higher mean Log WSSV copies (6.47 ± 2.07 per mg tissue) in BD1-challenged shrimp PL compared to BD2 (4.75 ± 0.35 per mg tissue). Crabs infected with BD1 and BD2 showed 100% mortality within 48 h and 62 h of challenge, respectively, with mean Log WSSV copies of 12.06 ± 0.48 and 9.95 ± 0.37 per gram tissue, respectively. Moreover, shrimp antimicrobial peptides (AMPs), penaeidin and lysozyme expression were lower in the BD1-challenged group compared to BD2 challenged shrimps. These results collectively demonstrated that relative virulence properties of WSSV based on mortality rate, viral load and expression of host immune genes in artificially infected shrimp PL could be affected by single aa substitution in VP28. Full article

Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1⁺ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8⁺ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2D^b than H-2K^b under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2D^b after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function. Full article

Background: Marine fish meat has been widely used for the extraction of bioactive peptides. This study was aimed to optimize the preparation of monkfish muscle peptides (LPs) using response surface methodology (RSM) and explore the antioxidant activities of <1 kDa LPs. Methods: Peptides were prepared from the muscles of monkfish (Lophius litulon), and five proteases were tested to hydrolyze muscle proteins. The hydrolysate that was treated using neutrase showed the highest degree of hydrolysis (DH) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activities. Results: The optimized conditions were as follows: water/material ratio of 5.4:1, a time span of 5 h, pH of 7.0, enzyme concentration of 2000 U/g, and temperature of 45 °C; the maximum DPPH scavenging activity and DH were 92.861% and 19.302%, respectively. LPs exhibited appreciable antioxidant activities, including DPPH radical, hydroxyl radical, 2,2′-azinobis-3-ethylbenzthiazoline-6-sulphonate (ABTS) radical, and superoxide anion scavenging activities. LPs attenuated H₂O₂-related oxidative injury in RAW264.7 cells, reduced the reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and increased the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels. Conclusion: We concluded that LPs could be an ideal source of bioactive peptides from monkfish and also have pharmaceutical potential. Full article