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Communications Biology Jun 2024Antimicrobial resistance (AMR) poses a serious threat to the clinical management of typhoid fever. AMR in Salmonella Typhi (S. Typhi) is commonly associated with the H58...
Antimicrobial resistance (AMR) poses a serious threat to the clinical management of typhoid fever. AMR in Salmonella Typhi (S. Typhi) is commonly associated with the H58 lineage, a lineage that arose comparatively recently before becoming globally disseminated. To better understand when and how H58 emerged and became dominant, we performed detailed phylogenetic analyses on contemporary genome sequences from S. Typhi isolated in the period spanning the emergence. Our dataset, which contains the earliest described H58 S. Typhi organism, indicates that ancestral H58 organisms were already multi-drug resistant (MDR). These organisms emerged spontaneously in India in 1987 and became radially distributed throughout South Asia and then globally in the ensuing years. These early organisms were associated with a single long branch, possessing mutations associated with increased bile tolerance, suggesting that the first H58 organism was generated during chronic carriage. The subsequent use of fluoroquinolones led to several independent mutations in gyrA. The ability of H58 to acquire and maintain AMR genes continues to pose a threat, as extensively drug-resistant (XDR; MDR plus resistance to ciprofloxacin and third generation cephalosporins) variants, have emerged recently in this lineage. Understanding where and how H58 S. Typhi originated and became successful is key to understand how AMR drives successful lineages of bacterial pathogens. Additionally, these data can inform optimal targeting of typhoid conjugate vaccines (TCVs) for reducing the potential for emergence and the impact of new drug-resistant variants. Emphasis should also be placed upon the prospective identification and treatment of chronic carriers to prevent the emergence of new drug resistant variants with the ability to spread efficiently.
Topics: Salmonella typhi; Typhoid Fever; Phylogeny; Humans; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Haplotypes; Mutation; Genome, Bacterial
PubMed: 38942806
DOI: 10.1038/s42003-024-06451-8 -
Biomedicine & Pharmacotherapy =... Jun 2024Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This...
Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca mobilization, and β-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 β cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on β-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.
PubMed: 38941892
DOI: 10.1016/j.biopha.2024.117044 -
Phytomedicine : International Journal... Jun 2024Effective control of postprandial blood glucose (PBG) level is essential for the prevention and treatment of diabetes and its complications. Several flavonoids have...
BACKGROUND
Effective control of postprandial blood glucose (PBG) level is essential for the prevention and treatment of diabetes and its complications. Several flavonoids have attracted much attention due to their significant PBG-lowering effects. However, there is still a certain gap in the in vivo hypoglycemic activity of most flavonoids compared to first-line drugs available on the market, and are still lack of the PBG-lowering effects of 8-hydroxyflavones and their structure-activity relationship.
PURPOSE
Evaluate hypoglycemic effects of 8-hydroxyflavones from Rhodiola crenulata in vitro and in vivo, especially comparatively analyze the relationship between hypoglycemic effects and flavonoid configuration and reveal the possible mechanism of 8-hydroxyflavones in lowering hyperglycemia.
METHODS
Starch, maltose, sucrose, and glucose tolerance tests in both diabetic and normal mice were used to evaluate and compare the hypoglycemic effects of 8-hydroxyflavones rhodiosin (RHS), rhodionin (RHN), and herbacetin (HBT). Molecular docking, enzyme kinetics, and immunofluorescence analysis were used to research the possible hypoglycemic mechanisms of 8-hydroxyflavones.
RESULTS
RHS (5 and 10 mg/kg) could efficiently decrease PBG levels in both normal and diabetes mice. Moreover, RHS, RHN, and HBT all had significant PBG-lowering effects in transgenic diabetes mice, and the effects were equivalent to or stronger than acarbose. Further mechanism research indicated that 8-hydroxyflavones achieved PBG-lowering effects by inhibiting both the activity and production of glycosidase. Notably, we have innovatively discovered that inhibiting the expression of glycosidases rather than just their activities may be a new target for hypoglycemic drugs.
CONCLUSION
We have firstly comprehensively and systematically clarified PBG-lowering effects of 8-hydroxyflavones from Rhodiola crenulata, and revealed their structure-activity relationships and hypoglycemic mechanisms. The study demonstrated that the substitution of 8-hydroxy groups in flavonoids could significantly enhance their hypoglycemic effects, which were equivalent to or stronger than commercially available drug acarbose. 8-Hydroxyflavones could be used as therapeutic or health drugs with significant potential to reduce postprandial hyperglycemia.
PubMed: 38941814
DOI: 10.1016/j.phymed.2024.155836 -
Protoplasma Jun 2024Salt-induced stress poses a significant barrier to agricultural productivity by impeding crop growth. Presently, environmentalists are dedicated to safeguarding food...
Salt-induced stress poses a significant barrier to agricultural productivity by impeding crop growth. Presently, environmentalists are dedicated to safeguarding food security by enhancing agricultural yields in challenging environments. Biostimulants play a crucial role in mitigating abiotic stresses in crop production, and among these, plant essential oils (EOs) stand out as organic substances with diverse biological effects on living organisms. Among the natural promoters of plant growth, Rosmarinus officinalis L. essential oil (RoEO) has gained considerable attention. Although the manifold effects of essential oils (EOs) on plant growth have been extensively demonstrated, their impact on salt stress tolerance in durum wheat seedlings remains unexplored. This investigation was undertaken to evaluate the biostimulatory capabilities of RoEO on the durum wheat cultivar "Mahmoudi." The effects of three RoEO concentrations (1, 2.5, and 5 ppm) on seed germination, growth establishment, and the induction of salt resistance under salinity conditions (150 mM NaCl) were tested. At 5 ppm, RoEO enhanced seedlings' tolerance to salinity by improving growth and reducing membrane deterioration and oxidative stress-induced damage. The expression profile analyses of seven stress-related genes (TdNHX1, TdSOS1, TdSOD, TdCAT, TdGA20-ox1, TdNRT2.1, and TdGS) using RT-qPCR showed enhancement of several important genes in durum wheat seedlings treated with 5 ppm RoEO, even under control conditions, which may be related to salt stress tolerance. The results indicate that the application of RoEO suggests a possible alternative strategy to increase salt tolerance in durum wheat seedlings towards better growth quality, thus increasing ROS scavenging and activation of antioxidant defense.
PubMed: 38940918
DOI: 10.1007/s00709-024-01965-8 -
Membrane protein Bcsdr2 mediates biofilm integrity, hyphal growth and virulence of Botrytis cinerea.Applied Microbiology and Biotechnology Jun 2024Grey mould caused by Botrytis cinerea is a devastating disease responsible for large losses to agricultural production, and B. cinerea is a necrotrophic model fungal...
Grey mould caused by Botrytis cinerea is a devastating disease responsible for large losses to agricultural production, and B. cinerea is a necrotrophic model fungal plant pathogen. Membrane proteins are important targets of fungicides and hotspots in the research and development of fungicide products. Wuyiencin affects the permeability and pathogenicity of B. cinerea, parallel reaction monitoring revealed the association of membrane protein Bcsdr2, and the bacteriostatic mechanism of wuyiencin was elucidated. In the present work, we generated and characterised ΔBcsdr2 deletion and complemented mutant B. cinerea strains. The ΔBcsdr2 deletion mutants exhibited biofilm loss and dissolution, and their functional activity was illustrated by reduced necrotic colonisation on strawberry and grape fruits. Targeted deletion of Bcsdr2 also blocked several phenotypic defects in aspects of mycelial growth, conidiation and virulence. All phenotypic defects were restored by targeted gene complementation. The roles of Bcsdr2 in biofilms and pathogenicity were also supported by quantitative real-time RT-PCR results showing that phosphatidylserine decarboxylase synthesis gene Bcpsd and chitin synthase gene BcCHSV II were downregulated in the early stages of infection for the ΔBcsdr2 strain. The results suggest that Bcsdr2 plays important roles in regulating various cellular processes in B. cinerea. KEY POINTS: • The mechanism of wuyiencin inhibits B. cinerea is closely associated with membrane proteins. • Wuyiencin can downregulate the expression of the membrane protein Bcsdr2 in B. cinerea. • Bcsdr2 is involved in regulating B. cinerea virulence, growth and development.
Topics: Botrytis; Biofilms; Virulence; Hyphae; Plant Diseases; Fragaria; Fungal Proteins; Membrane Proteins; Vitis; Spores, Fungal; Gene Deletion
PubMed: 38940906
DOI: 10.1007/s00253-024-13238-8 -
Alternative Therapies in Health and... Jun 2024Non-suicidal self-injury (NSSI) refers to direct and deliberate suicidal actions that damage the body but are not recognized by society and culture. Adolescence is the...
BACKGROUND
Non-suicidal self-injury (NSSI) refers to direct and deliberate suicidal actions that damage the body but are not recognized by society and culture. Adolescence is the transition period when children change into adult roles. At this time, teenagers are in the critical development period of physical and mental intelligence, and all aspects of their development have not yet been fully developed, so there are fierce inner conflicts. If the psychological problems of teenagers do not get timely counseling, it is very likely to choose self-injury suicide behavior, in such an extreme way to vent their bad emotions. The prevalence rate of NSSI among adolescents is much higher than that of other age groups. Studies have shown that psychological nursing is safe and effective, which can alleviate patients' negative emotions and avoid NSSI.
OBJECTIVE
To explore the impact of group psychological nursing with guardian participation on reducing NSSI behaviors and improving psychological well-being among adolescents.
DESIGN
This was a retrospective study.
SETTING
This study was performed in the Departments of the Third Psychiatry, Hangzhou Seventh People's Hospital.
PARTICIPANTS
132 adolescent patients with NSSI admitted to our center from August 2020 to July 2022 were selected as subjects and divided into 2 groups according to the time of admission, with 66 patients in each group.
INTERVENTIONS
Patients in the control group (CG) received drug therapy and commonly used cognitive behavioral therapy. Patients in the observation group (OG) received group psychological nursing with guardian participation. The participation of the guardian strengthens the level of understanding, tolerance and support of both parties, and helps to enhance the strength of family support, which in turn relives negative emotions.
PRIMARY OUTCOME MEASURES
(1) Ottawa self-injury inventory (OSI) scores were used to assess NSSI behavior severity; (2) Self-rating Anxiety Scale (SAS) and self-rating Depression Scale (SDS) scores were used to assess anxiety and depression; (3) General Self-efficacy Scale (GSES) scores were used to assess self-efficacy; (4) Trait Coping Style Questionnaire (TCSQ) scores were used to assess the quality of life; (5) social function Assessment Scale (SSPI) scores were used to assess social function; (6) Adolescent Life Events Scale (ASLEC) scores were used to evaluate the stress intensity of coping with life events; (7) multidimensional sub-health questionnaire assessment (MSQA) scores were used to assess adolescents' physical and psychological sub-health.
RESULTS
Before intervention, there were no significant differences in OSI, SAS, SDS, GSES, TCSO, SSPI ASLEC, and MSQA scores in both groups (P > .05). Compared to before intervention, the scores of OSI, SAS, SDS, GSES, TCSO, SSPI ASLEC and MSQA in both groups were improved after intervention (P < .05). The observation group showed significant improvements across all measures compared to the control group, indicating a reduction in NSSI behaviors and improvements in mental health.
CONCLUSION
Application of group psychological nursing with guardian participation in adolescent patients with NSSI behavior can better reduce NSSI behavior and improve physical and mental health, underline the importance of family support in treating NSSI, which also highlights the importance of family support in the treatment of NSSI.
PubMed: 38940803
DOI: No ID Found -
Angewandte Chemie (International Ed. in... Jun 2024Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a...
A Renal Clearable Nano-Assembly with Förster Resonance Energy Transfer Amplified Superoxide Radical and Heat Generation to Overcome Hypoxia Resistance in Phototherapeutics.
Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a challenge. Herein, we present a smart molecular design strategy based on the Förster resonance energy transfer (FRET) mechanism to develop a type I photodynamic therapy (PDT) agent with an encouraging amplification effect for accurate hypoxic tumor therapy. Of note, benefiting from the FRET effect, the obtained nanostructured type I PDT agent (NanoPcSZ) with boosted light-harvesting ability not only amplifies superoxide radical (O2•-) production but also promotes heat generation upon near-infrared light irradiation. These features facilitate NanoPcSZ to realize excellent phototherapeutic response under both normal and hypoxic environments. As a result, both in vitro and in vivo experiments achieved a remarkable improvement in therapeutic efficacy via the combined effect of photothermal action and type I photoreaction. Notably, NanoPcSZ can be eliminated from organs (including the liver, lung, spleen, and kidney) apart from the tumor site and excreted through urine within 24 h of its systemic administration. In this way, the potential biotoxicity of drug accumulation can be avoided and the biosafety can be further enhanced.
PubMed: 38940633
DOI: 10.1002/anie.202411514 -
ACS Infectious Diseases Jun 2024The ability of pathogenic bacteria to evade antibiotic treatment is an intricate and multifaceted phenomenon. Over the years, treatment failure among patients due to... (Review)
Review
The ability of pathogenic bacteria to evade antibiotic treatment is an intricate and multifaceted phenomenon. Over the years, treatment failure among patients due to determinants of antimicrobial resistance (AMR) has been the focal point for the research and development of new therapeutic agents. However, the survival of bacteria by persisting under antibiotic stress has largely been overlooked. Bacterial persisters are a subpopulation of sensitive bacterial cells exhibiting a noninheritable drug-tolerant phenotype. They are linked to the recalcitrance of infections in healthcare settings, in turn giving rise to AMR variants. The importance of bacterial persistence in recurring infections has been firmly recognized. Fundamental work over the past decade has highlighted numerous unique tolerance factors contributing to the persister phenotype in many clinically relevant pathogens. This review summarizes contributing factors that could aid in developing new strategies against bacterial antibiotic persisters.
PubMed: 38940498
DOI: 10.1021/acsinfecdis.4c00270 -
Biological Reviews of the Cambridge... Jun 2024New technologies have resulted in a better understanding of blood and lymphatic vascular heterogeneity at the cellular and molecular levels. However, we still need to...
New technologies have resulted in a better understanding of blood and lymphatic vascular heterogeneity at the cellular and molecular levels. However, we still need to learn more about the heterogeneity of the cardiovascular and lymphatic systems among different species at the anatomical and functional levels. Even the deceptively simple question of the functions of fish lymphatic vessels has yet to be conclusively answered. The most common interpretation assumes a similar dual setup of the vasculature in zebrafish and mammals: a cardiovascular circulatory system, and a lymphatic vascular system (LVS), in which the unidirectional flow is derived from surplus interstitial fluid and returned into the cardiovascular system. A competing interpretation questions the identity of the lymphatic vessels in fish as at least some of them receive their flow from arteries via specialised anastomoses, neither requiring an interstitial source for the lymphatic flow nor stipulating unidirectionality. In this alternative view, the 'fish lymphatics' are a specialised subcompartment of the cardiovascular system, called the secondary vascular system (SVS). Many of the contradictions found in the literature appear to stem from the fact that the SVS develops in part or completely from an embryonic LVS by transdifferentiation. Future research needs to establish the extent of embryonic transdifferentiation of lymphatics into SVS blood vessels. Similarly, more insight is needed into the molecular regulation of vascular development in fish. Most fish possess more than the five vascular endothelial growth factor (VEGF) genes and three VEGF receptor genes that we know from mice or humans, and the relative tolerance of fish to whole-genome and gene duplications could underlie the evolutionary diversification of the vasculature. This review discusses the key elements of the fish lymphatics versus the SVS and attempts to draw a picture coherent with the existing data, including phylogenetic knowledge.
PubMed: 38940420
DOI: 10.1111/brv.13114 -
International Journal of Molecular... Aug 2024Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second...
Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel HO stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to HO, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. , through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, HO‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.
Topics: Animals; Humans; Micelles; Osteosarcoma; Hydrogen Peroxide; Cell Line, Tumor; Dextrans; Mice; Lauric Acids; Apoptosis; Polymers; Xenograft Model Antitumor Assays; Bone Neoplasms; Mice, Nude; Antineoplastic Agents; Mice, Inbred BALB C; Male; TOR Serine-Threonine Kinases
PubMed: 38940336
DOI: 10.3892/ijmm.2024.5393