The Effect of Bifidobacterium animalis subsp. lactis MN-Gup on Glucose Metabolism, Gut Microbiota, and Their Metabolites in Type 2 Diabetic Mice.

Probiotics have garnered increasing attention as a potential therapeutic approach for type 2 diabetes mellitus (T2DM). Previous studies have confirmed that Bifidobacterium animalis subsp. lactis MN-Gup (MN-Gup) could stimulate the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells, but whether MN-Gup has a hypoglycemic effect on T2DM in vivo remains unclear. In this study, a T2DM mouse model was constructed, with a high-fat diet and streptozotocin in mice, to investigate the effect of MN-Gup on diabetes. Then, different doses of MN-Gup (2 × 109 CFU/kg, 1 × 1010 CFU/kg) were gavaged for 6 weeks to investigate the effect of MN-Gup on glucose metabolism and its potential mechanisms. The results showed that a high-dose of MN-Gup significantly reduced the fasting blood glucose (FBG) levels and homeostasis model assessment-insulin resistance (HOMA-IR) of T2DM mice compared to the other groups. In addition, there were significant increases in the short-chain fatty acids (SCFAs), especially acetate, and GLP-1 levels in the MN-Gup group. MN-Gup increased the relative abundance of Bifidobacterium and decreased the number of Escherichia-Shigella and Staphylococcus. Moreover, the correlation analysis revealed that Bifidobacterium demonstrated a significant positive correlation with GLP-1 and a negative correlation with the incremental AUC. In summary, this study demonstrates that Bifidobacterium animalis subsp. lactis MN-Gup has significant hypoglycemic effects in T2DM mice and can modulate the gut microbiota, promoting the secretion of SCFAs and GLP-1.

Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration.

AIMS: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.

Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

The exhaled breath represents an ideal matrix for non-invasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review we will specifically address volatile organic compounds in the breath, with a view towards fulfilling the promise of these as actionable biomarkers, in particular for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward, if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

Topography-driven microclimate gradients shape forest structure, diversity, and composition in a temperate refugial forest.

Macroclimate drives vegetation distributions, but fine-scale topographic variation can generate microclimate refugia for plant persistence in unsuitable areas. However, we lack quantitative descriptions of topography-driven microclimatic variation and how it shapes forest structure, diversity, and composition. We hypothesized that topographic variation and the presence of the forest overstory cause spatiotemporal microclimate variation affecting tree performance, causing forest structure, diversity, and composition to vary with topography and microclimate, and topography and the overstory to buffer microclimate. In a 20.2-ha inventory plot in the North American Great Plains, we censused woody stems ≥1 cm in diameter and collected detailed topographic and microclimatic data. Across 59-m of elevation, microclimate covaried with topography to create a sharp desiccation gradient, and topography and the overstory buffered understory microclimate. The magnitude of microclimatic variation mirrored that of regional-scale variation: with increasing elevation, there was a decrease in soil moisture corresponding to the difference across ~2.1° of longitude along the east-to-west aridity gradient and an increase in air temperature corresponding to the difference across ~2.7° of latitude along the north-to-south gradient. More complex forest structure and higher diversity occurred in moister, less-exposed habitats, and species occupied distinct topographic niches. Our study demonstrates how topographic and microclimatic gradients structure forests in putative climate-change refugia, by revealing ecological processes enabling populations to be maintained during periods of unfavorable macroclimate.

Histone methylation in Epstein-Barr virus-associated diseases.

Epstein-Barr virus (EBV) infection is linked to various human diseases, including both noncancerous conditions like infectious mononucleosis and cancerous diseases such as lymphoma and nasopharyngeal carcinoma. After the initial infection, EBV establishes a lifelong presence and remains latent in specific cells. This latent infection causes changes in the epigenetic marks known as histone methylation. Many studies have examined the role of histone methylation in different EBV-associated diseases, and understanding how EBV affects histone methylation can help us identify potential targets for epigenetic therapies. This review focuses on the research progress made in understanding histone methylation in well-studied EBV-associated diseases, intending to provide insights into potential strategies based on histone methylation to combat EBV-related ailments.

This review focuses on histone methylation in EBV-associated diseases, offering potential strategies to combat EBV-related ailments. #EBV #histonemethylation #epigenetics #medicalresearch.

Combining GC-MS/MS with a LLE-SPE sample pretreatment step to simultaneously analyse enrofloxacin and ofloxacin residues in chicken tissues and pork.

A widely applicable original gas chromatography-tandem mass spectrometry (GC-MS/MS) method was explored to qualitatively and quantitatively measure enrofloxacin and ofloxacin residues in chicken tissues and pork. The experimental samples were processed based on liquid-liquid extraction (LLE) and solid-phase extraction (SPE). Trimethylsilyl diazomethane (TMSD) was chosen to react derivatively with enrofloxacin and ofloxacin. In total, 78.25% âˆ¼ 90.56% enrofloxacin and 78.43% âˆ¼ 91.86% ofloxacin was recovered from the blank fortified samples. The limits of detection (LODs) were 0.7-1.0 µg/kg and 0.1-0.2 µg/kg, respectively. The limits of quantitation (LOQs) were 1.6-1.9 µg/kg and 0.3-0.4 µg/kg, respectively. It was verified that various experimental data met the requirements of the FAO & WHO (2014) for the detection of veterinary drug residues. Real samples obtained from local markets were analysed using the established method, and no residues of enrofloxacin or ofloxacin were detected in the samples.

Novel [68Ga/177Lu]Ga/Lu-AZ-093 as PSMA-Targeting Agent for Diagnosis and Radiotherapy.

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [68Ga]Ga-P16-093, containing a Ga(III) chelator, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [177Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [68Ga]GaCl3 or [177Lu]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [68Ga]Ga-1 or [177Lu]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [68Ga]Ga-P16-093 and [177Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 µM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [68Ga]Ga-1 and [177Lu]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [68Ga]Ga/[177Lu]Lu-1 (68Ga]Ga/[177Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.

Acute and Chronic Weight-Making Practice in Professional Mixed Martial Arts Athletes: An Analysis of 33 Athletes Across 80 Fights.

Mixed martial arts' popularity has increased in recent years, alongside descriptive research and evidence-based performance recommendations. Guidelines for (both chronic and acute) weight making exist; however, how these translate in real-life scenarios and detailed investigations on practices in larger groups deserve attention. The present study examined the body mass (BM) and composition of 33 professional mixed martial arts athletes preparing for 80 fights. Athletes were supported by on-site dietitians, who encouraged evidence-based practices. Fasted BM was measured throughout the last ∼10 days before all bouts (acute weight management phase). A subset of athletes had body composition assessed before and after the chronic weight loss phase for 40 fights. Most athletes engaged in chronic BM loss, and all engaged in acute weight loss. Many lost fat-free mass (FFM) during the chronic phase, with rates of BM loss <0.5% best preserving FFM. Regardless of losses, the present athletes possessed greater FFM than other combat sport athletes and engaged in greater acute weight loss. Dehydration in the 24-48 hr before the weigh-in was not reflective of weight regain after the weigh-in, rather BM 7-10 days before the weigh-in was most reflective. These findings suggest that many mixed martial arts athletes could increase FFM at the time of competition by maintaining leaner physiques outside of competition and/or allowing increased time to reduce BM chronically. Acutely, athletes can utilize evidence-based protocols, eliminating carbohydrates, fiber, sodium, and finally fluid in a staged approach, before the weigh-in, reducing the amount of sweating required, thus theoretically better protecting health and preserving performance.

Limosilactobacillus fermentum TY-S11 ameliorates hypercholesterolemia via promoting cholesterol excretion and regulating gut microbiota in high-cholesterol diet-fed apolipoprotein E-deficient mice.

Hypercholesterolemia is a metabolic disease characterized by elevated cholesterol level in the blood, which is a risk factor for many diseases. Probiotic intervention may be one of the ways to improve hypercholesterolemia. In this study, three strains with better cholesterol removal ability were selected from 60 strains of lactic acid bacteria, and were orally administered to apolipoprotein E-deficient mice on a high-cholesterol diet. Among the three strains, only Limosilactobacillus fermentum TY-S11, which was isolated from the intestine of a longevity person, significantly improved serum and liver lipid levels in hypercholesterolemic mice. Further study found that L. fermentum TY-S11 promoted the excretion of cholesterol in the feces and inhibited the absorption of cholesterol in the small intestine. As for gut microbiota, the results showed that L. fermentum TY-S11 not only prevented the reduction of diversity caused by high-cholesterol diet, but also increased the contents of short-chain fatty acids in feces. These results confirmed the ameliorative effect of L. fermentum TY-S11 on hypercholesterolemia.

A structural variation in the promoter of the leucoanthocyanidin reductase gene AaLAR1 enhances freezing tolerance by modulating proanthocyanidin accumulation in kiwifruit (Actinidia arguta).

Proanthocyanidins (PAs) are important metabolites that enhance freezing tolerance of plants. Actinidia arguta, especially freezing-tolerant germplasms, accumulate abundant PAs in dormant shoots and thereby enhance freezing tolerance, but the underlying mechanism is unknown. In this study, we used two A. arguta with contrasting cold-resistant phenotypes, KL and RB, to explore the mechanisms in response to cold tolerance. We determined that a leucoanthocyanidin reductase gene (AaLAR1) was more highly expressed in freezing-tolerant KL than in freezing-sensitive RB. Moreover, overexpressing AaLAR1 in kiwifruit promoted PAs biosynthesis and enhanced cold tolerance. The AaLAR1 promoters of various A. arguta germplasms differ due to the presence of a 60-bp deletion in cold-tolerant genotypes that forms a functional binding site for MYC-type transcription factor. Yeast one-hybrid and two-hybrid, dual-luciferase reporter, bimolecular fluorescence complementation and coimmunoprecipitation assays indicated that the AaMYC2a binds to the MYC-core cis-element in the AaLAR1 promoter with the assistance of AaMYB5a, thereby promoting PAs accumulation in the shoots of cold-tolerant kiwifruit. We conclude that the variation in the AaLAR1 promoter and the AaMYC2a-AaMYB5a-AaLAR1 module shape freezing tolerance in A. arguta. The identification of a key structural variation in the AaLAR1 promoter offers a new target for resistance breeding of kiwifruit.

Case report: Isolated immunoglobulin G4-related sclerosing cholangitis misdiagnosed as hilar cholangiocarcinoma.

Background: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is frequently accompanied with type 1 autoimmune pancreatitis (AIP). Isolated IgG4-SC which is not accompanied with AIP is uncommon in clinical practice, and its manifestations are similar to those of hilar cholangiocarcinoma. Case presentation: A 55-year-old male presented with persistent aggravation of icteric sclera and skin. He was initially diagnosed with hilar cholangiocarcinoma and underwent surgery. However, positive IgG4 plasma cells were found in the surgical specimens. Thus, a pathological diagnosis of IgG4-SC was established. After that, steroid therapy was given and initially effective. But he was steroid dependent, and then received rituximab therapy twice. Unfortunately, the response to rituximab therapy was poor. Conclusion: It is crucial to differentiate isolated IgG4-SC from hilar cholangiocarcinoma to avoid unnecessary surgery. Future studies should further explore effective treatment strategy in patients who do not respond to steroids therapy. It is also required to develop novel and accurate diagnostic approaches to avoid unnecessary surgical procedures.

Expression of concern: A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma.

Expression of concern for 'A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma' by Yandong Xie, et al., Biomater. Sci., 2022, 10, 6791-6803, https://doi.org/10.1039/D2BM01145J.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Melatonin enhances resistance to Botryosphaeria dothidea in pear by promoting jasmonic acid and phlorizin biosynthesis.

Ring rot, caused by Botryosphaeria dothidea, is an important fungal disease of pear fruit during postharvest storage. Melatonin, as a plant growth regulator, plays an important role in enhancing the stress resistance of pear fruits. It enhances the resistance of pear fruits to ring rot by enhancing their antioxidant capacity. However, the underlying mechanism remains unclear. In this study, we examined the effect of melatonin on the growth of B. dothidea. Results showed that melatonin did not limit the growth of B. dothidea during in vitro culture. However, metabolomics and transcriptomics analyses of 'Whangkeumbae' pear (Pyrus pyrifolia) revealed that melatonin increased the activity of antioxidant enzymes, including peroxidase (POD), superoxide dismutase (SOD), and polyphenol oxidase (PPO), in the fruit and activated the phenylpropanoid metabolic pathway to improve fruit resistance. Furthermore, melatonin treatment significantly increased the contents of jasmonic acid and phlorizin in pear fruit, both of which could improve disease resistance. Jasmonic acid regulates melatonin synthesis and can also promote phlorizin synthesis, ultimately improving the resistance of pear fruit to ring rot. In summary, the interaction between melatonin and jasmonic acid and phlorizin enhances the antioxidant defense response and phenylpropanoid metabolism pathway of pear fruit, thereby enhancing the resistance of pear fruit to ring rot disease. Our results provide new insights into the application of melatonin in the resistance to pear fruit ring rot.

Optical-Helicity-Dependent Orbital and Spin Dynamics in Two-Dimensional Ferromagnets.

Disentangling orbital (OAM) and spin (SAM) angular momenta in the ultrafast spin dynamics of two-dimensional (2D) ferromagnets on subfemtoseconds is a challenge in the field of ultrafast magnetism. Herein, we employed a non-collinear spin version of real-time time-dependent density functional theory to investigate the orbital and spin dynamics of the 2D ferromagnets Fe3GeTe2 (FGT) induced by circularly polarized light. Our results show that the demagnetization of the Fe sublattice in FGT is accompanied by helicity-dependent precession of the OAM and SAM excited by circularly polarized lasers. We further identify that precession of the OAM and SAM in FGT is faster than demagnetization within a few femtoseconds. Remarkably, circularly polarized lasers can significantly induce a periodic transverse linear response of the OAM and SAM on very ultrafast time scales of ∼600 attoseconds. Our finding suggests a powerful new route for attosecond regimes of the angular momentum manipulation to coherently control helicity-dependent orbital and spin dynamics in 2D ferromagnets.

Tetraniliprole risk assessment: Unveiling a hidden threat for managing a generalist herbivore.

Insecticide resistance poses a significant challenge in managing generalist herbivores such as the tobacco cutworm (TCW), Spodoptera litura. This study investigates the potential risks associated with using the novel diamide insecticide tetraniliprole to control TCW. A tetraniliprole-resistant strain was developed through twelve generations of laboratory selection, indicating an intermediate risk of resistance development. Field monitoring in China revealed a significant incidence of resistance, particularly in the Nanchang (NC) population (>100-fold). Tetraniliprole showed moderate to high cross-resistance to multiple insecticides and was autosomally inherited with incomplete dominance, controlled by multiple genes, some of which belong to the cytochrome P450 family associated with enhanced detoxification. Life table studies indicated transgenerational hormesis, stimulating TCW female fecundity and increasing population net reproduction rates (R0). These findings suggest a potential for pest resurgence under tetraniliprole use. The integrated risk assessment provides a basis for the sustainable management of TCW using tetraniliprole.

Pyrrole-containing hybrids as potential anticancer agents: An insight into current developments and structure-activity relationships.

Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side effects. Pyrrole and its derivatives are privileged heterocyclic compounds with significant diverse pharmacological effects. These compounds can target various aspects of cancer cells and have been applied in clinical settings or are undergoing clinical trials. As a result, pyrrole has emerged as a promising drug scaffold and has been further probed to get novel entities for the treatment of cancer. This article reviews recent research progress on anti-cancer drugs containing pyrrole. It focuses on the mechanism of action, biological activity, and structure-activity relationships of pyrrole derivatives, aiming to assist in designing and synthesizing innovative pyrrole-based anti-cancer compounds.

Systemic Thrombolysis for Isolated Splenic Vein Thrombosis Secondary to Oral Contraceptives: A Case Report.

Isolated splenic vein thrombosis (ISVT) is a very rare venous thromboembolism in the absence of pancreatic diseases, which can cause acute abdominal pain and chronic left-side portal hypertension. Herein, we reported a 40-year-old female patient who developed ISVT after taking oral contraceptives. Anticoagulation with oral rivaroxaban was the first-line choice of therapy in this case. Since then, abdominal pain alleviated, but she did not achieve vessel recanalization. Thus, a 7-day systemic thrombolysis with urokinase was given. Abdominal pain disappeared, but ISVT was not significantly improved. During follow-up period, long-term anticoagulation with oral rivaroxaban was given. Collectively, this case indicates the possibility of oral contraceptives as a risk factor of ISVT as well as anticoagulation combined with systemic thrombolysis as a choice of treatment for ISVT. Certainly, long-term follow-up is necessary in this case.