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Modern human society is burdened with the pandemic of cardiovascular and metabolic diseases. Metrnl is a widely distributed secreted protein in the body, involved in regulating glucose and lipid metabolism and maintaining cardiovascular system homeostasis. In this review, we present the predictive and therapeutic roles of Metrnl in various cardiovascular and metabolic diseases, including atherosclerosis, ischemic heart disease, cardiac remodeling, heart failure, hypertension, chemotherapy-induced myocardial injury, diabetes mellitus, and obesity.
Subject(s)
Biomarkers , Cardiovascular Diseases , Metabolic Diseases , Humans , Metabolic Diseases/metabolism , Metabolic Diseases/drug therapy , Cardiovascular Diseases/metabolism , Biomarkers/metabolism , AnimalsABSTRACT
OBJECTIVE: To explore the clinical efficacy of double beam double tunnel enhanced reconstruction technique in the treatment of knee anterior cruciate ligament(ACL) training injuries. METHODS: Twenty-nine cases of ACL injury of knee joint from January 2021 to December 2021 were retrospectively analyzed. All the cases were underwent ligament reconstruction surgery. Cases were grouped by surgical technique:there were 14 patients in conventional reconstruction group, including 13 males and 1 female, aged from 22 to 31 years old with an average of (27.07±7.28) years old, autogenous hamstring tendon was used for ligament reconstruction. There were 15 patients in the enhanced reconstruction group, including 13 males and 2 females, aged from 25 to 34 years old with an average of (29.06±4.23) years old, double tunnel ligament reconstruction, the autogenous hamstring muscle was used as the anteromedial bundle, and the posterolateral bundle was replaced by a high-strength line. The difference between knee tibial anterior distance, Lysholm score, International Knee Literature Committee (IKDC) subjective score, Tegner motor level score and visual analog scale (VAS) at 6th and 12th months after the surgery, limb symmetry index (LSI) were recorded at the last follow-up and surgery-related adverse effects during follow-up. RESULTS: All patients were followed up, ranged from 13 to 15 months with an average of (13.7±0.8) months. There were no serious adverse reactions related to surgery during the period. There was no statistical difference between the preoperative general data and the observation index of the two groups (P>0.05). The difference in tibial anterior distance at 6 and 12 months in the enhanced reconstruction group (1.45±0.62) mm and (1.74±0.78) mm which were lower those that in the conventional reconstruction group (2.42±0.60) mm and (2.51±0.63) mm(P<0.05). There was no significant difference in postoperative Lysholm score, Tegner motor level score, IKDC score, VAS, and limb symmetry index at the last follow-up(P>0.05). CONCLUSION: The enhanced reconstruction technique can more effectively maintain the stability of the knee joint and has no significant effect on the postoperative knee joint function compared with the traditional ligament reconstruction technique. The short-term curative effect is satisfactory, and it is suitable for the group with high sports demand.
Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Humans , Male , Female , Adult , Anterior Cruciate Ligament Reconstruction/methods , Anterior Cruciate Ligament Injuries/surgery , Young Adult , Retrospective Studies , Treatment OutcomeABSTRACT
The selection of internal fixation as the primary fixation modality for the patient is one of the challenges for the surgeon treating the patient in question. A model of the lateral tibial plateau fracture was established. Three different configurations of internal fixators namely L bone plate, T bone plate, and screw-washer were analyzed. Three stages after surgery were simulated to assess the displacement of bone plates, screws, washers, and the stress shielding ratio in the fracture area.At three stages after surgery, the T bone plate showed better stability for patients during rehabilitation compared with the remaining two schemes, and the screw-washer scheme was the least stable due to the larger internal fixation displacement and stress shielding ratio in the fracture area. In contrast, the L bone plate scheme showed better stability in the early stages after surgery but was second only to the screw-washer scheme in the middle and late stages after surgery. The T bone plate showed better stability and became a new selection for surgeons to treat related patients. At three stages after surgery, the T bone plate has better biomechanical stability compared to the L bone plate and screw-washer schemes.
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Collaborative perception between a vehicle and the road has the potential to enhance the limited perception capability of autonomous driving technologies. With this background, self-powered vehicle-road integrated electronics (SVRIE) with a multilevel fractal structure is designed to play a dual role, including a SVRIE device integrated into vehicle tires and a SVRIE array embedded into a road surface. The pressure sensing capability and anti-crosstalk performance of the SVRIE array are characterized separately to validate the feasibility of applying the SVRIE in a cooperative vehicle-infrastructure system. It is demonstrated that the SVRIE based on the multi-layered fractal structure exhibits maximum performance in collaborative sensing and interaction between vehicles and road information, such as vehicle motion, road surface condition, and tire life cycle health monitoring. Traditional data analysis methods are often of questionable accuracy. Therefore, a convolutional neural network is used to classify the vehicle and road conditions with accuracy of at least 88.3%. The transfer learning model is constructed to enhance the road surface identification capabilities with 100% accuracy. The accuracies of the vehicle tire motion recognition and tire health monitoring are 97% and 99%, respectively. This work provides new ideas for collaborative perception between vehicles and roadsides.
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Solar thermal utilization has broad applications in a variety of fields. Currently, maximizing the photo-thermal conversion efficiency remains a research hotspot in this field. The exquisite plant structures in nature have greatly inspired human structural design across many domains. In this work, inspired by the photosynthesis of helical grass, a HM type solar absorber made in graphene-based composite sheets is used for solar thermal conversion. The unique design promoted more effective solar energy into thermal energy through multiple reflections and scattering of solar photons. Notably, the Helical Micropillar (HM) is fabricated using a one-step projection 3D printing process based on a special 3D helical beam. As a result, the solar absorber's absorbance value can reach 0.83 in the 400-2500 nm range, and the surface temperature increased by ≈128.3% relative to the original temperature. The temperature rise rate of the solar absorber reached 22.4 °C min-1, demonstrating the significant potential of the HM in practical applications of solar thermal energy collection and utilization.
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Visible-light photocatalysis has evolved as a powerful technique to enable controllable radical reactions. Exploring unique photocatalytic mode for obtaining new chemoselectivity and product diversity is of great significance. Herein, we present a photo-induced chemoselective 1,2-diheteroarylation of unactivated alkenes utilizing halopyridines and quinolines. The ring-fused azaarenes serve as not only substrate, but also potential precursors for halogen-atom abstraction for pyridyl radical generation in this photocatalysis. As a complement to metal catalysis, this photo-induced radical process with mild and redox neutral conditions assembles two different heteroaryl groups into alkenes regioselectively and contribute to broad substrates scope. The obtained products containing aza-arene units permit various further diversifications, demonstrating the synthetic utility of this protocol. We anticipate that this protocol will trigger the further advancement of photo-induced alkyl/aryl halides activation.
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The orientation map is one of the most well-studied functional maps of the visual cortex. However, results from the literature are of different qualities. Clear boundaries among different orientation domains and blurred uncertain distinctions were shown in different studies. These unclear imaging results will lead to an inaccuracy in depicting cortical structures, and the lack of consideration in experimental design will also lead to biased depictions of the cortical features. How we accurately define orientation domains will impact the entire field of research. In this study, we test how spatial frequency (SF), stimulus size, location, chromatic, and data processing methods affect the orientation functional maps (including a large area of dorsal V4, and parts of dorsal V1) acquired by intrinsic signal optical imaging. Our results indicate that, for large imaging fields, large grating stimuli with mixed SF components should be considered to acquire the orientation map. A diffusion model image enhancement based on the difference map could further improve the map quality. In addition, the similar outcomes of achromatic and chromatic gratings indicate two alternative types of afferents from LGN, pooling in V1 to generate cue-invariant orientation selectivity.
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Although highly appealing for rapid access of molecular complexity, multi-functionalization of alkenes that allows incorporation of more than two functional groups remains a prominent challenge. Herein, we report a novel strategy that merges dipolar cycloaddition with photoredox promoted radical ring-opening remote C(sp3)-H functionalization, thus enabling a smooth 1,2,5-trifunctionalization of unactivated alkenes. A highly regioselective [3+2] cycloaddition anchors a reaction trigger onto alkene substrates. The subsequent halogen atom transfer (XAT) selectively initiates ring-opening process, which is followed by a series of 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular fluorine atom transfer (FAT) events. With this method, site-selective introduction of three different functional groups is accomplished and a broad spectrum of valuable ß-hydroxyl-ε-fluoro-nitrile products are synthesized from readily available terminal alkenes.
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An improved Finite Element Model(FEM) is applied to compare the biomechanical stability of plates with three different options in the treatment of distal fibula fractures in this study. The Computed Tomography(CT) scan of the knee to ankle segment of a volunteer was performed. A 3D fibula FEM was reconstructed based on the CT data. Three different loads (uni-pedal standing, torsion, and twisting) were applied, the same as in the experiments in the literature. The stresses and strains of the three options were compared under the same loads, using a 4-hole locking plate (Option A), a 5-hole locking plate (Option B), and a 6-hole locking plate (Option C) in a standard plate for lateral internal fixation. The simulation results show that all three options showed a stress masking effect. Option C had the best overall biomechanical performance and could effectively distribute the transferred weight. This is because option C has greater torsional stiffness and better biomechanical stability than options A and B, and therefore, option C is the recommended internal fixation method for distal fibula fractures. The Finite Element Analysis(FEA) method developed in this work applies to the stress analysis of fracture treatment options in other body parts.
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Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating the Renalase (Rnls) gene. Here, we demonstrate that Rnls loss of function in beta cells shapes autoimmunity by mediating a regulatory natural killer (NK) cell phenotype important for the induction of tolerogenic antigen-presenting cells. Rnls-deficient beta cells mediate cell-cell contact-independent induction of hallmark anti-inflammatory cytokine Tgfß1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 is markedly elevated on beta cells deficient for Rnls. Altered glucose metabolism in Rnls mutant beta cells is involved in the upregulation of CD47 surface expression. These findings are crucial to better understand how genetically engineered beta cells shape autoimmunity, giving valuable insights for future therapeutic advancements to treat and cure T1D.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1 , Insulin-Secreting Cells , Killer Cells, Natural , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/metabolism , Mice , Diabetes Mellitus, Type 1/immunology , Humans , CD47 Antigen/metabolism , CD47 Antigen/genetics , CD47 Antigen/immunology , Transforming Growth Factor beta1/metabolism , Mice, Inbred NOD , Monoamine OxidaseABSTRACT
Death-associated protein-1 (DAP-1) plays a crucial role in cell growth, migration, autophagy, and apoptosis in mammals. However, its function in insects remains unclear. In the present study, we cloned and identified Nilaparvata lugens DAP-1 (NlDAP-1). NlDAP-1 was expressed during all developmental stages and in all tissues of N. lugens, being particularly higher in the ovaries of female adults. RNAi with double-stranded NlDAP-1 RNA significantly inhibited the expression of NlDAP-1, leading to premature death (dying seven days earlier), delayed ovarian development, and fewer offspring (76.7% reduction in eggs with 77.4% reduction in egg hatching rate). Additionally, an immunofluorescence experiment showed that NlDAP-1 was highly expressed when yeast-like symbionts (YLSs) entered N. lugens oocytes, and inhibiting the expression of NlDAP-1 disturbed the process; the RNAi of NlDAP-1 caused a 34.9% reduction in the YLSs that entered oocytes. These results indicate that NlDAP-1 plays a crucial role in the reproductive development of N. lugens and the transovarial transmission of its YLSs.
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Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD+ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.
Subject(s)
AMP-Activated Protein Kinases , Aging , Caenorhabditis elegans , Mechanistic Target of Rapamycin Complex 1 , Mitochondria , Pyrazines , Signal Transduction , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/drug effects , Mechanistic Target of Rapamycin Complex 1/metabolism , Pyrazines/pharmacology , Mitochondria/metabolism , Mitochondria/drug effects , Signal Transduction/drug effects , AMP-Activated Protein Kinases/metabolism , Aging/metabolism , Aging/drug effects , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Nitrogen Oxides/metabolismABSTRACT
Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo , and protects pancreatic ß cells against autoimmune killing, ER and oxidative stress in vitro . The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of ß cell mass and islet dysfunction in chronically stressed Akita mice in vivo . We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human ß cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress, in vitro . Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of ß cells can rewire metabolism to protect against diabetogenic stress.
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BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia with high morbidity and mortality implications. Several studies have described a paradoxical inverse relationship between serum cholesterol and the risk of AF, but it remains unknown whether remnant cholesterol (RC) is associated with AF incidence. OBJECTIVE: This study aims to prospectively investigate the association between RC and AF. METHODS: A total of 392,783 participants free of AF at baseline from the UK Biobank were included for the analysis. Cox proportional hazards model, subgroup analysis, and sensitivity analyses were used to evaluate the independent association between RC levels and the risk of new-onset AF. Furthermore, we performed a discordance analysis by using the median cutoff points of low-density lipoprotein cholesterol (LDL-C) and RC. RESULTS: After a median follow-up of 12.8 years (interquartile range 12.0-13.6 years), a total of 23,558 participants experienced incident AF. Compared with the highest RC level, the lower RC level was associated with an increased risk of AF incidence (quartile 1 vs quartile 4: hazard ratio 1.396; 95% confidence interval [CI] 1.343-1.452). The results remained robust across a series of sensitivity analyses. In the discordance analyses, a significantly higher risk of AF was observed in participants with discordant low RC/high LDL-C levels than in those with concordant high RC/LDL-C levels. In the low LDL-C group, RC reduction even contributed to an additional 15.8% increased rate of incident AF (low RC/low LDL-C: hazard ratio 1.303; 95% CI 1.260-1.348 vs high RC/low LDL-C: hazard ratio 1.125; 95% CI 1.079-1.172). CONCLUSION: Low RC levels were associated with an increased risk of incident AF independent of traditional cardiovascular risk factors.
Subject(s)
Atrial Fibrillation , Cholesterol , Humans , Atrial Fibrillation/epidemiology , Atrial Fibrillation/blood , Male , Female , Prospective Studies , Middle Aged , Incidence , Cholesterol/blood , Risk Factors , United Kingdom/epidemiology , Follow-Up Studies , Cholesterol, LDL/blood , Aged , Risk Assessment/methods , Biomarkers/bloodABSTRACT
Exploring the impact factors associated with biodiversity and the relationship between them has always been a concerned issue in recent years. However, the previous research mostly focus on theoretical layer. Accordingly, the relationship between landscape pattern and biodiversity is to be analyzed in this research. The landscape pattern determines the function and ecological process of the landscape, and affects the species flow, information flow and energy flow in the landscape. Land use patterns has inevitably left an impact on the landscape pattern. Landscape pattern determines the function and ecological process of landscape and thus plays a significant role in biodiversity. East Dongting Lake National Nature Reserve is taken as the research object of the paper, and the remote sensing image data of three different time periods are collected, including 2000, 2010 and 2020. With an interpretation of the vegetation landscape pattern changes inside the protected area to collect and analyze the vegetation coverage. By comparing landscape patterns and the dynamic changes of land use in different periods of time, the correlation between landscape pattern characteristics and regional biodiversity is to be analyzed. Research shows: (1) From 2000 to 2020, the vegetation coverage of East Dongting Lake increased, but the landscape shape, scale, diversity and uniformity index decreased to varying degrees. (2) At the class level of landscape type, the relationship between landscape index and biodiversity is different. A complex relationship between farmland landscape and biodiversity. There is a significant positive correlation between the index of grassland landscape type and the index of regional biodiversity. (3) The correlation analysis results at the landscape level show that the landscape characteristic index is positively correlated with the regional biodiversity index. The grassland landscape in the area is the main habitat of biological species. At the same time, as the main grain producing area, the impact of farmland landscape cannot be ignored. This study has certain theoretical guiding significance for the protection and management of biodiversity in the region in terms of maintaining landscape pattern in particular the grassland landscape area and increasing vegetation coverage in the process of land use.
Subject(s)
Biodiversity , Conservation of Natural Resources , Lakes , Plants , Wetlands , Lakes/chemistry , China , Environmental Monitoring/methods , EcosystemABSTRACT
A novel actinobacterium strain, designated HUAS 2-6 T, was isolated from the rhizosphere soil of Camellia oleifera Abel collected from Taoyuan County, Northwestern Hunan Province, South China. This strain was subjected to a polyphasic taxonomic study. Strain HUAS 2-6 T is characterized by morphology typical of members of the genus Streptomyces, with deep purplish vinaceous aerial mycelia and deep dull lavender substrate mycelia. Strain HUAS 2-6 T, based on the full-length 16S rRNA gene sequence analysis, exhibited the highest similarities to S. puniciscabiei S77T (99.31%), S. filipinensis NBRC 12860 T (99.10%), S. yaanensis CGMCC 4.7035 T (99.09%), S. fodineus TW1S1T (99.08%), S. broussonetiae CICC 24819 T (98.76%), S. achromogenes JCM 4121 T (98.69%), S. barringtoniae JA03T (98.69%), and less than 98.70% with other validly species. In phylogenomic tree, strain HUAS 2-6 T was clustered together with S. broussonetiae CICC 24819 T, suggesting that they were closely related to each other. However, average nucleotide identity (ANI) and digital DNA-DNA hybridisation (dDDH) between them were much less than the species cutoff values (ANI 96.7% and dDDH 70%). Moreover, in phenotypic and chemotaxonomic characteristics, strain HUAS 2-6 T is distinct from S. broussonetiae CICC 24819 T. On the basis of the polyphasic data, strain HUAS 2-6 T is proposed to represent a novel species, Streptomyces camelliae sp. nov. (= MCCC 1K04729T = JCM 35918 T).
Subject(s)
Camellia , DNA, Bacterial , Phylogeny , RNA, Ribosomal, 16S , Rhizosphere , Soil Microbiology , Streptomyces , Streptomyces/isolation & purification , Streptomyces/genetics , Streptomyces/classification , Camellia/microbiology , RNA, Ribosomal, 16S/genetics , DNA, Bacterial/genetics , China , Fatty Acids/analysis , Bacterial Typing Techniques , Sequence Analysis, DNA , Base CompositionABSTRACT
The design of siderophore-antibiotic conjugates is a promising strategy to overcome drug resistance in negative bacteria. However, accumulating studies have shown that only those antibiotics acting on the cell wall or cell membrane multiply their antibacterial effects when coupled with siderophores, while antibiotics acting on targets in the cytoplasm of bacteria do not show an obvious enhancement of their antibacterial effects when coupled with siderophores. To explore the causes of this phenomenon, we synthesized several conjugate probes using 3-hydroxypyridin-4(1H)-ones as siderophores and replacing the antibiotic cargo with 5-carboxyfluorescein (5-FAM) or malachite green (MG) cargo. By monitoring changes in the fluorescence intensity of FAM conjugate 20 in bacteria, the translocation of the conjugate across the outer membranes of Gram-negative pathogens was confirmed. Further, the use of the fluorogen activating protein(FAP)/MG system revealed that 3-hydroxypyridin-4(1H)-one-MG conjugate 26 was ultimately distributed mainly in the periplasm rather than being translocated into the cytosol of Escherichia coli and Pseudomonas aeruginosa PAO1. Additional mechanistic studies suggested that the uptake of the conjugate involved the siderophore-dependent iron transport pathway and the 3-hydroxypyridin-4(1H)-ones siderophore receptor-dependent mechanism. Meanwhile, we demonstrated that the conjugation of 3-hydroxypyridin-4(1H)-ones to the fluorescein 5-FAM can reduce the possibility of the conjugates crossing the membrane layers of mammalian Vero cells by passive diffusion, and the advantages of the mono-3-hydroxypyridin-4(1H)-ones as a delivery vehicle in the design of conjugates compared to the tri-3-hydroxypyridin-4(1H)-ones. Overall, this work reveals the localization rules of 3-hydroxypyridin-4(1H)-ones as siderophores to deliver the cargo into Gram-negative bacteria. It provides a theoretical basis for the subsequent design of siderophore-antibiotic conjugates, especially based on 3-hydroxypyridin-4(1H)-ones as siderophores.
Subject(s)
Anti-Bacterial Agents , Pseudomonas aeruginosa , Siderophores , Siderophores/chemistry , Siderophores/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/metabolism , Gram-Negative Bacteria/drug effects , Fluorescent Dyes/chemistry , Escherichia coli/drug effects , Escherichia coli/metabolism , Pyridones/pharmacology , Pyridones/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Animals , Fluorescein/chemistry , Biological Transport , Microbial Sensitivity TestsABSTRACT
Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cells regeneration is achieved predominantly by self-replication especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into beta cells. How pancreatic duct cells undergo transdifferentiated and whether we could manipulate the transdifferentiation to replenish beta cell mass is not well understood. Using a genome-wide CRISPR screen, we discovered that loss-of-function of ALDH3B2 is sufficient to transdifferentiate human pancreatic duct cells into functional beta-like cells. The transdifferentiated cells have significant increase in beta cell marker genes expression, secrete insulin in response to glucose, and reduce blood glucose when transplanted into diabetic mice. Our study identifies a novel gene that could potentially be targeted in human pancreatic duct cells to replenish beta cell mass for diabetes therapy.
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The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins' bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively.
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Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.