Search Results (1,059)

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. The strongly hygroscopic metformin (1-1-dimethylbiguanide), first synthesized 1922 and resuscitated as an oral antidiabetic (type 2 of the elderly) compound first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977–1997). It was then released in the USA after a short-term prospective trial in healthy overweight “young” type 2 diabetics (mean age 53 years) in 1995 for oral treatment of type 2 diabetes. It was, however, prescribed to mostly multimorbid older patients (above 60–65 years of age). Metformin is now the most used oral drug for type 2 diabetes worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase in their intestinal concentration (up to 300-fold compared to that measured in the blood), to reduced absorption of glucose from the diet, to increased excretion of glucose through the stool, and to decrease in insulin serum level through increased hepatic uptake and decreased production. Intravenously injected F18-labeled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is like that observed in patients after bowel-cleansing or chronically taking different types of laxatives, where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to “attraction” of glucose from the hepatocyte into the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Furthermore, these compounds have also a diuretic effect (loss of sodium and water in the urine) Acute gastrointestinal side effects accompanied by fluid loss often lead to the drugs’ dose reduction and strongly limit adherence to therapy. Main long-term consequences are “chronic” dehydration, deficiency of vitamin B12 and of iron, and, as observed for all the biguanides, to “chronic” increase in fasting and postprandial lactate plasma level as a laboratory marker of a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Metformin is not different from the other biguanides: synthalin B, buformin, and phenformin. The mechanism of action of the biguanides as antihyperglycemic substances and their side effects are comparable if not even stronger (abdominal pain, nausea, vomiting, diarrhea, fluid loss) to those of laxatives. Full article

Today’s primary challenges include identifying efficient, affordable, and environmentally sustainable substances to serve as raw materials in industrial, agricultural, and medicinal applications. This study aimed to evaluate the chemical composition and biological properties (namely antioxidant and allelopathic activities) of the methanolic extract derived from the above-ground portions of Artemisia judaica collected in Jazan, Saudi Arabia. GC-MS was used to evaluate the chemical composition of the methanolic extract derived from Artemisia judaica. GC-MS analysis revealed a total of 22 volatile compounds in the extract. The most prominent compounds identified were 2-ethylhexanoic acid, 5-hydroxy-6-(1-hydroxyethyl)-2,7-dimethoxynaphtho-quinone, and piperitone. The extract demonstrated strong antioxidant activity in both the DPPH and ABTS radical scavenging assays, comparable to the standard antioxidant ascorbic acid. The IC₅₀ value for the extract was 31.82 mg/mL in the DPPH assay and 39.93 mg/mL in the ABTS testing. Additionally, the extract exhibited dose-dependent inhibition of seed germination, root growth, and shoot growth of the weed Chenopodium murale in allelopathic bioassays. The most significant suppression was observed in shoot growth with an IC₅₀ value of 45.90 mg/mL, which was lower than the IC₅₀ values for root development and seed germination of C. murale, recorded at 56.16 mg/mL and 88.80 mg/mL, respectively. Furthermore, the findings indicated that methanolic extracts had significant lethal toxic effects on the life cycle of Aedes aegypti. Future research will focus on extracting uncontaminated substances and evaluating the biological effects of each specific constituent. Full article

Entomopathogenic fungi are among the most promising non-chemical alternatives for the control of many serious phytophagous insect pests, such as moth species. The present research investigates the use of the little-studied entomopathogenic fungus Beauveria varroae as a biocontrol agent against the notorious pests Helicoverpa armigera and Sesamia nonagrioides in laboratory conditions. Conidial suspensions of B. varroae were prepared at 10³-10⁴-10⁵-10⁶-10⁷-10⁸ conidia/mL to assess their insecticidal potential. In this study, we used 100 3rd-instar larvae for each concentration. During the lab bioassays, almost complete mortality of 35–96.6% was recorded for H. armigera larvae and 40–96.6% for S. nonagrioides larvae 10 days after exposure. The lethal effect of the entomopathogen was related to both dose and exposure time of the entomopathogen, with higher concentrations resulting in increased mortality. The survival effect of S. nonagrioides and H. armigera larvae was dependent on the hazard effect of the used dose and the exposure time. These findings indicate that B. varroae has potential as a biocontrol agent. Further research will elucidate this new isolate and optimize application methods in field conditions. Full article

Background/Objectives: Haloperidol is a typical antipsychotic drug widely used for acute confusional state, psychotic disorders, agitation, delirium, and aggressive behavior. Methods: The toxicity of haloperidol was studied using zebrafish (ZF) embryos as a model organism. Dechorionated embryos were exposed to various concentrations of haloperidol (0.5–6.0 mg/L). The lethal dose concentration was estimated and was found to be 1.941 mg/L. Results: The impact of haloperidol was dose-dependent and significant from 0.25 mg/L. Haloperidol induced several deformities at sublethal doses, including abnormal somites, yolk sac edema, and skeletal deformities. Haloperidol significantly affected heart rate and blood flow and induced pericardial edema and hyperemia in a dose-dependent manner, suggesting its influence on heart development and function. Embryos exposed to haloperidol during their ontogenetic development had smaller body length and eye surface area than non-exposed ones in a dose-dependent manner. Conclusions: It was found that haloperidol significantly affects the behavior of the experimental organisms in terms of mobility, reflexes to stimuli, and adaptation to dark/light conditions. Full article

We quantified the bioactive compounds of Ethiopian coffee (ETH), spent coffee grounds SCGs from ETH (SCG-ETH), and mixed SCGs (SCG-MIX) prepared by filtration methods and investigated the effect of SCG-ETH on ruminal fermentation as well as the anthelmintic activity of ETH. Three substrates, meadow hay (MH)-barley grain (MH-BG), MH-SCG-ETH, and BG-SCG-ETH (1:1 w/w), were fermented using an in vitro gas production technique. The bioactive compounds were quantitatively analyzed using ultra-high-resolution mass spectrometry. We performed an in vitro larval development test to determine the anthelmintic effect of an aqueous extract of ETH against the gastrointestinal nematode (GIN) Haemonchus contortus. The total content of bioactive compounds was highest in SCG-ETH, followed by SCG-MIX and ETH (35.2, 31.2, and 20.9 mg/g dry matter, respectively). Total gas and methane production (p < 0.001) were decreased by both MH-SCG-ETH and BG-SCG-ETH. The in vitro digestibility of dry matter was higher for MH-SCG-ETH and BG-SCG-ETH than for MH-BG. The aqueous ETH extract exhibited a strong larvicidal effect, with a mean lethal dose of 13.2 mg/mL for 50% mortality and 31.9 mg/L for 99% mortality. SCG substrates have the potential to modulate ruminal fermentation and serve as a source of anthelmintic bioactive compounds against GINs in ruminants. Full article

Influenza and SARS-CoV-2 are often associated with viral pneumonia, resulting from direct exposure of the virus to lung tissue. 3,3′-Diindolylmethane (DIM) is a naturally occurring substance with multi-target activity, including anti-inflammatory and epigenetic modulation. In this study, we evaluated the therapeutic efficacy in vivo of a DIM formulation with fish oil (Cesarox Epi) against influenza A (H1N1) infection in mice and against SARS-CoV-2 infection in Syrian hamsters. In a model of lethal influenza pneumonia induced by A/California/04/2009 (H1N1)pdm09 virus, we showed that 5 days’ treatment with DIM Epi at 10, 20, and 60 mg/kg/day delayed the time to death, prevented body weight loss, and resulted in significant improvements in survival. DIM Epi tested in hamsters infected with SARS-CoV2 Dubrovka (Wuhan-like) strain at doses 50 and 100 mg/kg/day reduced clinical signs, weight loss, temperature elevation, and lung pathology. In both models of infections, treatment with DIM Epi did not significantly decrease viral titer in the animals’ lungs. DIM Epi and Oseltamivir were more effective against influenza infection when given in combination than given singly, while co-administration of DIM Epi with Molnupiravir did not yield an additive benefit against SARS-CoV-2 infection. These findings support DIM Epi as a promising host-directed adjunct therapy for viral pneumonia with potential to enhance outcomes in respiratory infections. Full article

Essential oils have emerged as promising alternatives for pest insect control. However, sublethal effects on insect reproduction and development are rarely explored, despite their relevance to integrated pest management (IPM). This study evaluated the sublethal effects of Piper hispidivervum C. DC. essential oil (EOPH) on the development and population growth of four populations of Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), as well as the persistence of safrole residue in treated corn grains. Population development rates were determined using emergence curves and total emerged adults, while population growth was assessed by counting live insects in the feeding substrate at different storage intervals. Safrole residue persistence was analyzed using solid-phase microextraction in headspace mode (SPME-HS). Sublethal exposure to EOPH significantly reduced the development rate, total emergence, and growth in three of the four populations. The population from Crixás, GO, showed no significant reduction, with a population curve overlapping the control. The lethal dose was reduced by 98.20%, indicating low persistence and potential food safety. The EOPH exhibited sublethal effects on S. zeamais populations, reducing both development rates and population growth. This reduction varied among the populations studied. Further research is encouraged to explore its effects on different insect populations and under broader environmental conditions. Full article

Nipah and Hendra viruses are lethal zoonotic pathogens with no approved vaccines or therapeutics. mRNA produced via in vitro transcription enables endogenous protein expression and cost reduction. Here, we systematically screened natural and artificial untranslated regions (UTRs) and identified an optimal combination for expressing henipavirus-neutralizing antibody 1E5. We generated mRNA-1E5 encapsulated in lipid nanoparticles (mRNA-1E5-LNPs). In vitro, mRNA-1E5-LNPs achieved functional antibody expression levels of >1500 ng/mL. In BALB/c mice, intravenous administration of mRNA-1E5-LNPs induced rapid antibody elevation (peak at day 3), without hepatic toxicity or tissue inflammation. We established two Hendra pseudovirus models in biosafety level 2 facilities to evaluate the efficacy of mRNA-1E5-LNPs. Low-dose prophylactic administration effectively blocked entry of the Hendra pseudovirus. Notably, a single 0.5 mg/kg dose of mRNA-1E5-LNPs, stored at 4 °C for two months and administered 7 days prior, provided good protection. Our findings provide a therapeutic strategy for henipaviral infections and a blueprint for the development of mRNA-based antibodies against emerging viruses. Full article

Klebsiella pneumoniae, a zoonotic pathogen of global concern, poses significant threats to both veterinary and public health. Here, a comparative study characterized 14 clinical isolates (7 avian-derived, 7 human-derived) from Jiangsu, China, through integrated genomic and phenotypic analyses. Firstly, multilocus sequence typing (MLST) revealed distinct epidemiological patterns: the same ST type in avian isolates was circulating between different species and different regions, whereas it was not found in human isolates. In addition, hypervirulent Klebsiella pneumoniae (hvKP) phenotypes confirmed by string test were exclusive to two human isolates (KP15, KP20). Secondly, biofilm detection demonstrated 78.6% (11/14) of isolates possessed biofilm-forming capacity, with cellulose but not curli as the predominant matrix component. Human-derived KP15 and KP20 had the strongest biofilm formation ability in all isolates. Antimicrobial susceptibility profiling identified serious multidrug resistance in both avian and human isolates. Virulence gene analysis revealed striking disparities, with human isolates harboring 10–20 virulence factors (median 15) versus 6–7 (median 6.5) in avian counterparts. Finally, functional pathogenesis assessments demonstrated human-derived strains exhibited stronger epithelial cell adhesion (2-fold higher) and invasion (1.97-fold higher) in Calu-3 cell models and paradoxically showed reduced macrophage phagocytosis (2.85-fold lower at 2 h) for immune escape. In vivo models confirmed dose-dependent mortality, with human isolates demonstrating higher lethality in both Galleria mellonella and mice. Virulence gene burden positively correlated with mortality outcomes. These findings delineate critical host adaptation differences in Klebsiella pneumoniae populations and provide empirical evidence for pathogen transmission dynamics at the human-animal interface. Full article

Background and Objectives: To evaluate the mRNA vaccine platform for blood-stage Plasmodium parasites, we completed a proof-of-concept study using the P. yoelii mouse model of malaria and two mRNA-based vaccines. Both encoded PyMSP1₁₉ fused to PyMSP8 (PyMSP1/8). One was designed for secretion of the encoded protein (PyMSP1/8-sec); the other encoded membrane-bound antigen (PyMSP1/8-mem). Methods: Secretion of PyMSP1/8-sec and membrane localization of PyMSP1/8-mem were verified in mRNA-transfected cells. As recombinant PyMSP1/8 (rPyMSP1/8) is known to protect mice against lethal P. yoelii 17XL infection, we first compared immunogenicity and efficacy of the PyMSP1/8-sec mRNA vaccine versus the recombinant formulation in outbred mice. Animals were immunized three times followed by challenge with a lethal dose of P. yoelii 17XL-parasitized RBCs (pRBCs). Similar immunization and challenge experiments were conducted to compare PyMSP1/8-sec versus PyMSP1/8-mem mRNA vaccines. Results: Immunogenicity of the PyMSP1/8-sec mRNA vaccine was superior to the recombinant formulation, inducing higher antibody titers against both vaccine components. Following challenge with P. yoelii 17XL pRBCs, all PyMSP1/8-sec-immunized animals survived, with 50% of these showing no detectible pRBCs in circulation (<0.01%). In addition, mean peak parasitemia in PyMSP1/8-sec mRNA-immunized mice was significantly lower than that in the rPyMSP1/8 vaccine group. Both PyMSP1/8-sec and PyMSP1/8-mem were protective against P. yoelii 17XL challenge, with PyMSP1/8-mem immunization providing a significantly higher level of protection than PyMSP1/8-sec immunization considering the number of animals with no detectable pRBCs in circulation and the mean peak parasitemia in animals with detectable parasitemia. Conclusions: mRNA vaccines were highly immunogenic and potently protective against blood-stage malaria, outperforming a similar recombinant-based vaccine. The membrane-bound antigen was more effective at inducing protective antibody responses, highlighting the need to consider antigen localization for mRNA vaccine design. Full article

The nopal cactus, a plant from the Cactaceae family, holds significant economic and nutritional value for Mexico. This study aimed to enhance the genetic diversity and morphological traits of Opuntia velutina, a species cultivated as a vegetable nopal. A total of 1050 in vitro O. velutina explants were exposed to 15 different doses of gamma radiation from ⁶⁰Co gamma, ranging from 5 to 125 Gy. The lethal dose was above 50 Gy, with an LD₅₀ of 22.8 Gy for stimulating in vitro shoot growth. Shoots derived from doses between 5 and 50 Gy were subjected to in vitro shoot proliferation across four consecutive generations to stabilize morphological traits. Cluster analysis categorized the 178 irradiated shoots into 13 distinct morphological groups (CG1–CG13). Twenty-seven shoots exhibiting significant morphological improvements, such as a 50–100% increase in cladode length, up to a six-fold increase in shoot number, and up to a seven-fold increase in root number, were selected for molecular analysis of genetic diversity. Six primers were used with the Inter Simple Sequence Repeat (ISSR) molecular markers to examine genetic uniformity, yielding 54.5% polymorphic bands, indicating a high level of genetic variation. Both a UPGMA dendrogram and STRUCTURE-based Bayesian analysis confirmed the genetic divergence among the selected mutant lines. Overall, gamma irradiation effectively enhanced both phenotypic and genotypic diversity in O. velutina. This study corroborates that in vitro mutagenesis through gamma radiation is a viable strategy for generating novel genotypes with breeding potential within the Opuntia genus. Full article

Background: Rabbit hemorrhagic disease (RHD) is an acute, hemorrhagic and highly lethal infectious disease caused by rabbit hemorrhagic disease virus (RHDV), which causes huge economic losses to the rabbit breeding industry. Moreover, there is limited cross-protection between the two different serotypes of classic RHDV (GI.1) and RHDV2 (GI.2). The shortcomings of traditional inactivated vaccines have led to the development of novel subunit vaccines that can protect against both strains, and the VP60 capsid protein is the ideal antigenic protein. This study focused on developing a bivalent RHDV vaccine that can prevent infection with both GI.1 and GI.2 strains. Methodology: Baculovirus vectors containing classic RHDV and RHDV2 VP60 were co-transfected with linearized baculovirus into sf9 cells and transferred to baculovirus via homologous recombination of the VP60 gene. Infected sf9 cells were lysed, and after purification via Ni-NTA chromatography, VLPs were observed using transmission electron microscopy (TEM). In order to evaluate the immunogenicity of the chimeric RHDV VLP vaccine in rabbits, the RHDV VP60-specific antibody, IL-4, IFN-γ and neutralizing antibody titers were analyzed in serum using ELISA and HI. Results: The recombinant baculovirus system successfully expressed chimeric RHDV VLPs with a diameter of 32–40 nm. After immunization, it could produce specific antibodies, IL-4 and IFN-γ. Following the second immunization, neutralizing antibodies, determined using hemagglutination inhibition (HI) assays, were elicited. Conclusions: These data show that the chimeric RHDV VLP bivalent vaccine for immunized New Zealand rabbits can induce humoral immunity and cellular immunity in vivo, and the immunization effect of the high-dose group is similar to that of the current commercial vaccine. Full article

Chagas disease (ChD) caused by Trypanosoma cruzi remains a major public health concern, affecting approximately 8 million people worldwide. However, the number of undiagnosed cases is likely much higher. Existing treatments rely on benznidazole and nifurtimox which, despite their efficacy during the acute phase of infection, are often associated with severe side effects that can be life-threatening. As a promising alternative, actinomycetes—which are renowned for producing pharmacologically and industrially relevant metabolites—have demonstrated potent antimicrobial properties; however, their antiparasitic potential remains largely unexplored. This study evaluated the anti-trypanocidal activities of extracellular metabolites produced by Streptomyces thermocarboxydus strain Chi-43 (ST-C43) and Streptomyces sp. strain Chi-104 (S-C104) against epimastigote, trypomastigote, and amastigote forms of T. cruzi. The strains were cultured in ISP2 broth, and their extracellular metabolites were assessed via antiparasitic diffusion assays in microplates. The 50% lethal concentration (LC₅₀) values ranged from 102 to 116 μg/mL against epimastigotes and trypomastigotes. The antiparasitic activity was confirmed through 3-(4,5-dimetiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based spectrophotometric assays and optical microscopy. Toxicity assays revealed that the extracellular metabolites were non-toxic to Artemia salina, non-cytotoxic to Huvecs, and non-hemolytic to human erythrocytes. Dose–response regression analysis showed statistically significant differences (p ≤ 0.05). LC-MS/MS analysis identified amphomycin and K-252c aglycone staurosporine as the active antiparasitic compounds. These findings highlight the potential of Streptomyces-derived extracellular metabolites as novel, selective, and safe anti-T. cruzi agents. Nevertheless, further studies in murine or preclinical models are needed to validate their efficacy and support future clinical applications for the treatment of ChD. Full article

The progressive commercial deployment of multi-walled carbon nanotubes (MWCNTs) raises concerns about their terrestrial ecotoxicity. We exposed adult Cornu aspersum (150 snails; five replicates of three animals per time-point) to 50 mg L⁻¹ MWCNT-dosed Lactuca sativa for 30 days and quantified five mechanistic biomarkers alongside survival. Hemocyte spread-cell area increased by 48% (from 243 ± 22 µm² at day 0 to 360 ± 18 µm² at day 14, p < 0.001). Lysosomal membrane stability (neutral red retention) fell twofold within 72 h and to 10 min by day 30 (controls ≈ 60 min), indicating early, persistent destabilization. Micronucleus frequency rose above the ecogenotoxic threshold of 5‰ after 7 days, peaking at 8.3 ± 0.7‰ on day 14 (p < 0.01). Hepatopancreas metallothionein concentrations doubled by day 3 (2.1 ± 0.3 vs. 1.0 ± 0.2 µg g⁻¹ ww in controls) and remained >150% of control throughout exposure, consistent with metal impurity mobilization. Acetylcholinesterase activity in cephalic tissue declined by 50% after 7 days and by 73% after 30 days, revealing sustained neurotoxicity. Despite these pronounced sub-individual disturbances, cumulative mortality reached only 19% at day 30, suggesting substantial, but finite, physiological compensation. Collectively, the data demonstrate that a 50 mg L⁻¹ dietary load of MWCNTs elicits rapid cytotoxic, genotoxic, and neurotoxic responses in C. aspersum that precede overt lethality, underscoring the utility of this gastropod and the chosen biomarker suite for monitoring nanotube contamination in agro-ecosystems and food-grade snail farming. Full article

Background/Objective: Platelet concentrates (PCs) are used in transfusion medicine to treat bleeding disorders. Staphylococcus aureus, a predominant PC contaminant, has been implicated in several adverse transfusion reactions. The aim of this study was to investigate the impact of PC storage on S. aureus resistance to quinolones, which are commonly used to treat S. aureus infections. Methods/Results: Four transfusion-relevant S. aureus strains (TRSs) were subjected to comparative transcriptome analyses when grown in PCs vs. trypticase soy broth (TSB). Results of these analyses revealed differentially expressed genes involved in antibiotic resistance. Of interest, the norB gene (encodes for the NorB efflux pump, which is implicated in quinolone resistance and is negatively regulated by MgrA) was upregulated (1.2–4.7-fold increase) in all PC-grown TRS compared to TSB cultures. Minimal Bactericidal Concentration (MBC) of ciprofloxacin and norfloxacin in PC-grown TRS compared to TSB showed increased resistance to both quinolones in PC cultures. Complementary studies with non-transfusion-relevant strains S. aureus RN6390 and its norB and mgrA deletion mutants were conducted. MBC of ciprofloxacin and norfloxacin and RT-qPCR assays of these strains showed that not only norB, but also norA and norC may be involved in enhanced quinolone resistance in PC-grown S. aureus. The role of norB in S. aureus virulence was also tested using the silkworm Bombyx mori animal model; lethal dose 50 (LD₅₀) assays revealed slightly higher virulence in larvae infected with the wild-type strain compared to the norB mutant. Conclusions: The PC storage environment enhances quinolone resistance in S. aureus and induces differential expression of efflux pump nor genes. Furthermore, our preliminary data of the involvement of NorB in virulence of S. aureus using a silkworm model merit further investigation with other systems such as a mammal animal model. Our results provide mechanistic insights to aid clinicians in the selection of antimicrobial treatment of patients receiving transfusions of S. aureus-contaminated PCs. Full article