Mitochondrial dysfunction in diabetic nephropathy: insights and therapeutic avenues from traditional Chinese medicine.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. The progressive damage to glomeruli, tubules, and interstitium in the kidneys can lead to the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Most of the energy we need comes from mitochondria. Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. The pathogenesis of DN involves a variety of factors, such as altered haemodynamics, oxidative stress, and inflammation, and studies from animal models suggest that mitochondrial dysfunction plays an important role in the development of DN. Traditional Chinese medicine (TCM) has a history of more than 2,500 years and has rich experience and remarkable efficacy in the treatment of DN. Recent studies have found that TCM may have great potential in regulating mitochondrial dysfunction in the treatment of DN. This review will elucidate the main causes of mitochondrial dysfunction and the relationship with DN, and explore in depth the potential mechanisms of TCM to protect the kidney by improving mitochondrial dysfunction. Current pharmacological treatments for patients with DN do not prevent the inevitable progression to ESRD. With the rich variety of Chinese herbs, TCM is expected to be the most promising candidate for the treatment of DN as we continue to learn more about the mechanisms of DN and incorporate the current advances in extraction techniques.

[Analysis of the therapeutic effect of trochanteric flip osteotomy combined with Kocher-Langenbeck approach for high acetabular posterior wall fracture].

OBJECTIVE: Evaluation of the clinical efficacy of f trochanteric flip osteotomy combined with Kocher-Langenbeck approach for high acetabular posterior wall fracture. METHODS: Between January 2020 and December 2022, 20 patients with high acetabular posterior wall fractures were retrospectively analyzed, including 12 males and 8 females, aged 18 to 75 years old. They were divided into two groups according to the different surgical methods. Ten patients were treated with greater trochanteric osteotomy combined with Kocher-Langenbeck approach as the observation group, including 5 males and 5 females, aged from 18 to 75 years old. Ten patients were treated with Kocher-Langenbeck approach alone as the control group, including 7 males and 3 females, aged from 18 to 71 years old. Matta reduction criteria were used to evaluate the reduction quality of the two groups, and Harris score was used to compare the hip function of the two groups at the latest follow-up. The operation time, blood loss and postoperative complications of the two groups were analyzed. RESULTS: All patients were followed up for 10 to 24 months. According to the Matta fracture reduction quality evaluation criteria, the observation group achieved anatomical reduction in 6 cases, satisfactory reduction in 3 cases, and unsatisfactory reduction in 1 case, while the control group only achieved anatomical reduction in 3 cases, satisfactory reduction in 3 cases, and unsatisfactory reduction in 4 cases. At the final follow-up, the Harris hip score ranged from 71.4 to 96.6 in the observation group and 65.3 to 94.5 in the control group. According to the results of Harris score. The hip joint function of the observation group was excellent in 6 cases, good in 3 cases, and fair in 1 case. The hip joint function of the control group was excellent in 2 cases, good in 3 cases, fair in 3 cases, and poor in 2 cases. In the observation group, the intraoperative blood loss ranged from 300 to 700 ml, and the operation duration ranged from 120 to 180 min;in the control group, the intraoperative blood loss ranged from 300 to 650 ml, and the operation duration ranged from 100 to 180 min. Complications in the observation group included 1 case of traumatic arthritis and 1 case of heterotopic ossification, while complications in the control group included 3 cases of traumatic arthritis, 3 cases of heterotopic ossification and 1 case of hip abduction weakness. CONCLUSION: Trochanteric flip osteotomy combined with the Kocher-Langenbeck approach significantly improved anatomical fracture reduction rates, enhanced excellent and good hip joint function outcomes, and reduced surgical complication incidence compared to the Kocher-Langenbeck approach alone. Clinical application of this combined approach is promising, although larger studies are needed for further validation.

Quantum Criticality with Emergent Symmetry in the Extended Shastry-Sutherland Model.

Motivated by the novel phenomena observed in the layered material SrCu_{2}(BO_{3})_{2}, the Shastry-Sutherland model (SSM) has been extensively studied as the minimal model for SrCu_{2}(BO_{3})_{2}. However, the nature of its quantum phase transition from the plaquette valence-bond solid to antiferromagnetic phase is under fierce debate, posing a challenge to understand the underlying quantum criticality. Via the state-of-the-art tensor network simulations, we study the ground state of the SSM on large-scale size up to 20×20 sites. We identify the continuous transition nature accompanied by an emergent O(4) symmetry between the plaquette valence-bond solid and antiferromagnetic phase, which strongly suggests a deconfined quantum critical point (DQCP). Furthermore, we map out the phase diagram of an extended SSM that can be continuously tuned to the SSM, which demonstrates the same DQCP phenomena along a whole critical line. Our results indicate a compelling scenario for understanding the origin of the proposed proximate DQCP in recent experiments of SrCu_{2}(BO_{3})_{2}.

Human umbilical cord mesenchymal stem cells derived-exosomes on VEGF-A in hypoxic-induced mice retinal astrocytes and mice model of retinopathy of prematurity.

AIM: To observe the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) secretions on the relevant factors in mouse retinal astrocytes, and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A (VEGF-A) and to observe the therapeutic effect on the mouse model of retinopathy of prematurity (ROP). METHODS: Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group. MTT assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect related indicators. Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored. At last, the efficacy of exosomes of UCMSCs in a mouse ROP model was explored. Graphpad6 was used to comprehensively process data information. RESULTS: The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation. Reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased, and the ROP cell model was established after 6h of hypoxia. The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α, the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent. Compared with the ROP cell model group, the expression of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signal pathway related factors in the hUCMSCs exocrine group is significantly decreased. The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1α in ROP model tissues. HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion. CONCLUSION: In a hypoxia induced mouse retinal astrocyte model, hUCMSCs exosomes are found to effectively reduce the expression of HIF-1α and VEGF-A, which are positively correlated with the concentration of hUCMSCs exosomes. HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1α and VEGF-A proteins in ROP mice, and are positively correlated with drug dosage. Besides, they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.

Different Contributions of embB and ubiA Mutations to Variable Level of Ethambutol Resistance in Mycobacterium tuberculosis Isolates.

Objective: To explore the association between the variant mutations within embB and ubiA, and the degree of ethambutol (EMB) resistance of Mycobacterium tuberculosis (M. tuberculosis) isolates. Methods: A total of 146 M. tuberculosis isolates were used to determine the minimum inhibitory concentrations (MICs) of EMB with a 96-well microplate-based assay. The mutations within embB and ubiA among these isolates were identified with DNA sequencing. Moreover, a multivariate regression model and a computer model were established to assess the effects of mutations on EMB resistance. Results: Our data showed that overall 100 isolates exhibited 28 mutated patterns within the sequenced embB and ubiA. Statistical analysis indicated that embB mutations Met306Val, Met306Ile, Gly406Ala, and Gln497Arg, were strongly associated with EMB resistance. Of these mutations, Met306Val and Gln497Arg were significantly associated with high-level EMB resistance. Almost all multiple mutations occurred in high-level EMB-resistant isolates. Although the mutation within ubiA accompanied with embB mutation presented exclusively in EMB-resistant isolates, four single ubiA mutations (Ala39Glu, Ser173Ala, Trp175Cys, and Val283Leu) leading to protein instability were observed in EMB-susceptible isolates. Conclusion: This study highlighted the complexity of EMB resistance. Some individual mutations and multiple mutations within embB and ubiA contributed to the different levels of EMB resistance.

Atorvastatin ameliorated myocardial fibrosis by inhibiting oxidative stress and modulating macrophage polarization in diabetic cardiomyopathy.

In this editorial, we commented on the article published in the recent issue of the World Journal of Diabetes. Diabetic cardiomyopathy (DCM) is characterized by myocardial fibrosis, ventricular hypertrophy and diastolic dysfunction in diabetic patients, which can cause heart failure and threaten the life of patients. The pathogenesis of DCM has not been fully clarified, and it may involve oxidative stress, inflammatory stimulation, apoptosis, and autophagy. There is lack of effective therapies for DCM in the clinical practice. Statins have been widely used in the clinical practice for years mainly to reduce cholesterol and stabilize arterial plaques, and exhibit definite cardiovascular protective effects. Studies have shown that statins also have anti-inflammatory and antioxidant effects. We were particularly concerned about the recent findings that atorvastatin alleviated myocardial fibrosis in db/db mice by regulating the antioxidant stress and anti-inflammatory effects of macrophage polarization on diabetic myocardium, and thereby improving DCM.

Synthesis of 2-benzyl N-substituted anilines via imine condensation-isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines.

A catalyst- and additive-free synthesis of 2-benzyl N-substituted anilines from (E)-2-arylidene-3-cyclohexenones and primary amines has been reported. The reaction proceeds smoothly through a sequential imine condensation-isoaromatization pathway, affording a series of synthetically useful aniline derivatives in acceptable to high yields. Mild reaction conditions, no requirement of metal catalysts, operational simplicity and the potential for scale-up production are some of the highlighted advantages of this transformation.

Effectiveness of different intrusion modes of maxillary anterior teeth with mini-implants in clear aligner treatment: a three-dimensional finite element analysis.

BACKGROUND: The intrusion of maxillary anterior teeth is often required and there are various intrusion modes with mini-implants in clear aligner treatment. The objective of this study was to evaluate the effectiveness of maxillary anterior teeth intrusion with different intrusion modes, aiming to provide references for precise and safe intrusion movements in clinical practice. METHODS: Cone-beam computed tomography and intraoral optical scanning data of a patient were collected. Finite element models of the maxilla, maxillary dentition, periodontal ligaments (PDLs), clear aligner (CA), attachments, and mini-implants were established. Different intrusion modes of the maxillary anterior teeth were simulated by changing the mini-implant site (between central incisors, between central and lateral incisor, between lateral incisor and canine), loading site (between central incisors, on central incisor, between central and lateral incisor, between lateral incisor and canine), and loading mode (labial loading and labiolingual loading). Ten conditions were generated and intrusive forces of 100 g were applied totally. Then displacement tendency of the maxillary anterior teeth and CA, and stress of the PDLs were analyzed. RESULTS: For the central incisor under condition L14 and for the canine under conditions L11, L13, L23, and L33, the intrusion amount was negative. Under other conditions, the intrusion amount was positive. The labiolingual angulation of maxillary anterior teeth exhibited positive changes under all conditions, with greater changes under linguoincisal loading. The mesiodistal angulation of canine exhibited positive changes under labial loading, while negative changes under linguoincisal loading except for condition L14. CONCLUSIONS: The intrusion amount, labiolingual and mesiodistal angulations of the maxillary anterior teeth were affected by the mini-implant site, loading site, and loading mode. Labial and linguoincisal loading may have opposite effects on the intrusion amount of maxillary anterior teeth and the mesiodistal angulation of canine. The labiolingual angulation of the maxillary incisors would increase under all intrusion modes, with greater increases under linguoincisal loading.

Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts.

Bench-stable 3,3-difluoroallyl sulfonium salts (DFASs), featuring tunable activity and their editable C-ß and gem-difluoroallyl group, proved to be versatile fluoroalkylating reagents for site-selective S-gem-difluoroallylation of cysteine residues in unprotected peptides. The reaction proceeds with high efficiency under mild conditions (ambient temperature and aqueous and weak basic conditions). Various protected/unprotected peptides, especially bioactive peptides, are site-selectively S-gem-difluoroallylated. The newly added gem-difluoroallyl group and other functional groups derived from C-ß of DFASs are poised for ligation with bio-functional groups through click and radical chemistry. This stepwise "doubly orthogonal" modification of peptides enables the construction of bioconjugates with enhanced complexity and functionality. This proof of principle is successfully applied to construct a peptide-saccharide-biotin chimeric bioconjugate, indicating its great potential application in medicinal chemistry and chemical biology.

Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Novel fluorescence probe for ClO- in living cells: Based on FRET mechanism.

Hypochlorous acid (HClO) as a kind of reactive oxygen species (ROS) plays a vital role in many biological processes. Organic fluorescence probes have attracted great interests for the detection of HClO, due to their relatively high selectivity and sensitivity, satisfactory spatiotemporal resolution and good biocompatibility. Constructing fluorescence probes to detect HClO with advantages of large Stokes shift, wide emission gap, near infrared emission and good water solubility is still challenging. In this work, a new ratiometric fluorescence probe (named HCY) for HClO was developed. FRET-based HCY was constructed by bonding a coumarin and a flavone fluorophore. In absence of HClO, HCY exists FRET process, however, FRET is inhibited in the presence of HClO because the conjugated double bond broke. Due to the good match of the emission spectrum of the donor and the absorption spectrum of the acceptor, the FRET system appears favorable energy transfer efficiency. HCY showed high sensitivity and rapid response time. The linearity between the ratios of fluorescence intensity and concentration of HClO was established with a low limit of detection. What's more, HCY was also applied for fluorescence images of HClO in RAW264.7 cells.

Changes of intestinal barrier in the process of intestinal inflammation induced by Aeromonas hydrophila in snakehead (Channa argus).

Bacterial intestinal inflammation frequently occurs in cultured fish. Nevertheless, research on intestinal barrier dysfunction in the process of intestinal inflammation is deficient. In this study, we explored the changes of intestinal inflammation induced by Aeromonas hydrophila (A. hydrophila) in snakehead and the relationship between intestinal barrier and inflammation. Snakehead [(13.05 ± 2.39) g] were infected via anus with A. hydrophila. Specimens were collected for analysis at 0, 1, 3, 7 and 21 d post-injection. The results showed that with the increase of exposure time, the hindgut underwent stages of normal function, damage, damage deterioration, repair and recovery. Relative to 0 d, the levels of IL-1ß and TNF-α in serum, and the expression of nod1, tlr1, tlr5, nf-κb, tnf-α and il-1ß in intestine were significantly increased, and showed an upward then downward pattern over time. However, the expression of tlr2 and il-10 were markedly decreased, and showed the opposite trend. In addition, with the development of intestinal inflammation, the diversity and richness of species, and the levels of phylum and genus in intestine were obviously altered. The levels of trypsin, LPS, AMS, T-SOD, CAT, GPx, AKP, LZM and C3 in intestine were markedly reduced, and displayed a trend of first decreasing and then rebounding. The ultrastructure observation showed that the microvilli and tight junction structure of intestinal epithelial cells experienced normal function initially, then damage, and finally recovery over time. The expression of claudin-3 and zo-1 in intestine were significantly decreased, and showed a trend of first decreasing and then rebounding. Conversely, the expression of mhc-i, igm, igt and pigr in intestine were markedly increased, and displayed a trend of increasing first and then decreasing. The above results revealed the changes in intestinal barrier during the occurrence and development of intestinal inflammation, which provided a theoretical basis for explaining the relationship between the two.

Extracellular vesicle surface display enhances the therapeutic efficacy and safety profile of cancer immunotherapy.

Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released by cells, can be efficiently engineered via inverse electron demand Diels-Alder (iEDDA)-mediated conjugation to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands on the EV surface conferred substantial enhancements in signaling efficacy, particularly for tumor necrosis factor receptor superfamily (TNFRSF) agonists, where the EV surface display served as an alternative FcγR-independent approach to induce ligand multimerization and efficient receptor crosslinking. EVs displaying a complementary combination of immunotherapeutic ligands were able to shift the tumor immune milieu toward an anti-tumorigenic phenotype and significantly suppress tumor burden and increase survival in multiple models of metastatic cancer to a greater extent than an equivalent dose of free ligands. In summary, we present an EV-based delivery platform for cancer immunotherapeutic ligands that facilitates superior anti-tumor responses at significantly lower doses with fewer side effects than is possible with conventional delivery approaches.

MicroRNA-1205 promotes breast cancer cell metastasis by regulating epithelial-to-mesenchymal transition via targeting of CDK3.

Metastasis poses a huge obstacle to the survival of breast cancer patients. The microRNA miR-1205 acts as a tumor suppressor in various cancers, but its roles in breast cancer and metastasis remain unclear. To elucidate its function in breast cancer progression, we analyzed miR-1205 expression in human tumor samples and carried out a series of functional studies in in vitro and in vivo. miR-1205 was expressed more highly in metastatic breast tumor samples than in non-metastatic samples and was associated with lymph node metastasis, clinical stage, and poor prognosis. Moreover, miR-1205 promoted breast cancer cell invasiveness in vitro and metastasis in mice by directly targeting CDK3 and reducing CDK3 protein levels. We also showed that CDK3 interacts with Snail protein, inducing Snail degradation via the ubiquitin-proteasome system and potentially affecting epithelial-to-mesenchymal transition. Furthermore, analysis of clinical tissue samples indicated that CDK3 and miR-1205 levels were inversely correlated in lymph node metastasis-positive primary tumors. This study demonstrated the pro-metastatic role of miR-1205 in breast cancer, mediated via a novel miR-1205/CDK3/Snail axis. Moreover, we identified miR-1205 and CDK3 as potential markers of invasion and progression in breast cancer.

[Melatonin alleviates autophagy in cortical neurons of neonatal rats with hypoxic- ischemic brain damage via the PI3K/AKT pathway]. / è¤ªé»‘ç´ é€šè¿‡PI3K/AKTé€šè·¯å‡è½»ç¼ºæ°§ç¼ºè¡€æ€§è„‘æŸä¼¤æ–°ç”Ÿå¤§é¼ å¤§è„‘çš®å±‚ç¥žç»ç»†èƒžè‡ªå™¬çš„ç ”ç©¶.

OBJECTIVES: To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the PI3K/AKT signaling pathway, aiming to provide a basis for the clinical application of melatonin. METHODS: Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group, an HIBD group, and a melatonin group (n=9 each). The neonatal rat HIBD model was established using the classic Rice-Vannucci method. Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining. Autophagy-related protein levels of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunofluorescence staining and Western blot analysis. Phosphorylated phosphoinositide 3-kinase (p-PI3K) and phosphorylated protein kinase B (p-AKT) protein expression levels were measured by immunohistochemistry and Western blot. The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis. RESULTS: Twenty-four hours post-modeling, neurons in the sham operation group displayed normal size and orderly arrangement. In contrast, neurons in the HIBD group showed swelling and disorderly arrangement, while those in the melatonin group had relatively normal morphology and more orderly arrangement. Nissl bodies were normal in the sham operation group but distorted in the HIBD group; however, they remained relatively intact in the melatonin group. The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group, but was reduced in the melatonin group compared to the HIBD group (P<0.05). The number of p-PI3K+ and p-AKT+ cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group (P<0.05). LC3 and Beclin-1 protein expression levels were higher, and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group (P<0.05); however, in the melatonin group, LC3 and Beclin-1 levels decreased, and p-PI3K and p-AKT increased compared to the HIBD group (P<0.05). The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K+ and p-AKT+ cells between the two groups (P<0.05). CONCLUSIONS: Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD, thereby alleviating HIBD. This mechanism is associated with the PI3K/AKT pathway.

4,4'-methylenediphenol reduces Aß-induced toxicity in a Caenorhabditis elegans model of Alzheimer's disease.

Introduction: Gastrodia elata Blume is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing Gastrodia elata are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of Gastrodia elata, and, in recent years, this herb has also been used in the treatment of Alzheimer's disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4'-methylenediphenol, a key active ingredient of Gastrodia elata, can mitigate amyloid-ß (Aß)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD. Methods: We investigated the effects of 4,4'-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4'-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action. Results: 4,4'-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4'-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aß protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4'-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4'-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aß toxicity; importantly, our results suggested that these effects of 4,4'-methylenediphenol were mediated, at least partly, via the activation of DAF-16. Conclusion: We have demonstrated that 4,4'-methylenediphenol can reduce Aß-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of Gastrodia elata and its active ingredients.

Historic dog Furs Unravel the Origin and Artificial Selection of Modern Nordic Lapphund and Elkhound dog Breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100 to 200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

Collagen/Curdlan composite sponge for rapid hemostasis and skin wound healing.

Collagen's unique properties promise hemostatic potential, but its sponge form's stability and mechanics need improvement. In this study, we developed a series of homeostatic sponges by co-assembling collagen and curdlan at different ratios into hydrogels, followed by freeze-drying treatment. The incorporation of curdlan into collagen sponges has been found to significantly enhance the sponge's properties, including increased porosity, elevated water uptake, improved elasticity, and enhanced resistance to degradation. In vitro cytotoxicity and hemolysis assays have demonstrated the biocompatibility and nontoxicity of composite sponges. In mouse liver perforation and incision models, the composite sponges achieved rapid coagulation within 67 s and 75 s, respectively, outperforming gauze and gelatin sponge in reducing blood loss. Furthermore, composite sponges demonstrated superior wound healing potential in mice full-thickness skin defects model, with accelerated healing rates observed at days 3, 7, and 14 compared to the control group. Overall, collagen/curdlan composite sponge show promise for hemostasis and wound healing applications.

Screening of active components of Ganoderma lucidum and decipher its molecular mechanism to improve learning and memory disorders.

Learning and memory impairment (LMI), a common degenerative central nervous system disease. Recently, more and more studies have shown that Ganoderma lucidum (GL) can improve the symptoms of LMI. The active ingredients in GL and their corresponding targets were screened through TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and BATMAN-TCM (Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine) databases, and the potential LMI targets were searched for through GeneCard (GeneCards Human Gene Database) and DrugBank. Then, we construct a 'main active ingredient-target' network and a protein-protein interaction (PPI) network diagram.The GO (Gene Ontology) functional enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway annotation analysis were performed on the common targets through DAVID (Database for Annotation Visualization and Integrated Discovery) to clarify the potential molecular mechanism of action of active ingredients in GL. The tumor necrosis factor (TNF) protein was verified by Western blot; Twenty one active ingredients in GL and 142 corresponding targets were screened out, including 59 targets shared with LMI. The 448 biological processes shown by the GO functional annotation results and 55 signal pathways shown by KEGG enrichment analysis were related to the improvement of LMI by GL, among which the correlation of Alzheimer's disease pathway is the highest, and TNF was the most important protein; TNF can improve LMI. GL can improve LMI mainly by 10 active ingredients in it, and they may play a role by regulating Alzheimer's disease pathway and TNF protein.

P-hydroxybenzaldehyde protects Caenorhabditis elegans from oxidative stress and ß-amyloid toxicity.

Introduction: Gastrodia elata is the dried tuber of the orchid Gastrodia elata Bl. It is considered a food consisting of a source of precious medicinal herbs, whose chemical composition is relatively rich. Gastrodia elata and its extracted fractions have been shown to have neuroprotective effects. P-hydroxybenzaldehyde (p-HBA), as one of the main active components of Gastrodia elata, has anti-inflammatory, antioxidative stress, and cerebral protective effects, which has potential for the treatment of Alzheimer's disease (AD). The aim of this study was to verify the role of p-HBA in AD treatment and to investigate its mechanism of action in depth based using the Caenorhabditis elegans (C. elegans) model. Methods: In this study, we used paralysis, lifespan, behavioral and antistress experiments to investigate the effects of p-HBA on AD and aging. Furthermore, we performed reactive oxygen species (ROS) assay, thioflavin S staining, RNA-seq analysis, qPCR validation, PCR Array, and GFP reporter gene worm experiment to determine the anti-AD effects of p-HBA, as well as in-depth studies on its mechanisms. Results: p-HBA was able to delay paralysis, improve mobility and resistance to stress, and delay aging in the AD nematode model. Further mechanistic studies showed that ROS and lipofuscin levels, Aß aggregation, and toxicity were reduced after p-HBA treatment, suggesting that p-HBA ameliorated Aß-induced toxicity by enhancing antioxidant and anti-aging activity and inhibiting Aß aggregation. p-HBA had a therapeutic effect on AD by improving stress resistance, as indicated by the down-regulation of NLP-29 and UCR-11 expression and up-regulation of PQN-75 and LYS-3 expression. In addition, the gene microarray showed that p-HBA treatment played a positive role in genes related to AD, anti-aging, ribosomal protein pathway, and glucose metabolism, which were collectively involved in the anti-AD mechanism of p-HBA. Finally, we also found that p-HBA promoted nuclear localization of DAF-16 and increased the expression of SKN-1, SOD-3, and GST-4, which contributed significantly to inhibition of Aß toxicity and enhancement of antioxidative stress. Conclusion: Our work suggests that p-HBA has some antioxidant and anti-aging activities. It may be a viable candidate for the treatment and prevention of Alzheimer's disease.