Prediction model of pressure injury occurrence in diabetic patients during ICU hospitalization--XGBoost machine learning model can be interpreted based on SHAP.

BACKGROUND: The occurrence of pressure injury in patients with diabetes during ICU hospitalization can result in severe complications, including infections and non-healing wounds. AIMS: The aim of this study was to predict the occurrence of pressure injury in ICU patients with diabetes using machine learning models. STUDY DESIGN: In this study, LASSO regression was used for feature screening, XGBoost was employed for machine learning model construction, ROC curve analysis, calibration curve analysis, clinical decision curve analysis, sensitivity, specificity, accuracy, and F1 score were used for evaluating the model's performance. RESULTS: Out of the 503 ICU patients with diabetes included in the study, pressure injury developed in 170 cases, resulting in an incidence rate of 33.8 %. The XGBoost model had a higher AUC for predicting pressure injury in patients with diabetes during ICU hospitalization (train: 0.896, 95 %CI: 0.863 to 0.929; test: 0.835, 95 % CI: 0.761-0.908). The importance of SHAP variables in the model from high to low was: 'Days in ICU', 'Mechanical Ventilation', 'Neutrophil Count', 'Consciousness', 'Glucose', and 'Warming Blanket'. CONCLUSION: The XGBoost machine learning model we constructed has shown high performance in predicting the occurrence of pressure injury in ICU patients with diabetes. Additionally, the SHAP method enables the interpretation of the results provided by the machine learning model. RELEVANCE TO CLINICAL PRACTICE: Improve the ability to predict the early occurrence of pressure injury in diabetic patients in the ICU. This will enable clinicians to intervene early and reduce the occurrence of complications.

Enhancing calvarial defects repair with PDGF-BB mimetic peptide hydrogels.

Addressing bone defects represents a significant challenge to public health. Localized delivery of growth factor has emerged as promising approach for bone regeneration. However, the clinical application of Platelet-Derived Growth Factor (PDGF) is hindered by its high cost and short half-life. In this work, we introduce the application of PDGF-mimicking peptide (PMP1) hydrogels for calvarial defect restoration, showcasing their remarkable effectiveness. Through osteogenic differentiation assays and q-PCR analyses, we demonstrate PMP1's substantial capacity to enhance osteogenic differentiation of bone marrow mesenchymal stem cell (BMSC), leading to increased expression of crucial osteogenic genes. Further molecular mechanistic investigations reveal PMP1's activation of the PI3K-AKT-mTOR signaling pathway, a key element of its osteogenic effect. In vivo experiments utilizing a rat calvaria critical-sized defect model underscore the hydrogels' exceptional ability to accelerate new bone formation, thereby significantly advancing the restoration of calvaria defects. This research provides a promising bioactive material for bone tissue regeneration.

Overexpression of ETV2 in BMSCs promoted wound healing in cutaneous wound mice by triggering the differentiation of BMSCs into endothelial cells and modulating the transformation of M1 phenotype macrophages to M2 phenotype macrophages.

This study aimed to investigate the effects of E26-transformation-specific variant-2 (ETV2) overexpression on wound healing in a cutaneous wound (CW) model and clarify associated mechanisms. pLVX-ETV2 lentivirus expressing ETV2 was constructed and infected into BMSCs to generate ETV2-overexpressed BMSCs (BMSCs+pLVX+ETV2). The RT-PCR assay was applied to amplify ETV2, VE-cadherin, vWF, ARG-1, IL-6, iNOS, TGF-ß, IL-10, TNF-α. Western blot was used to determine expression of VE-cadherin and vWF. ETV2 induced differentiation of BMSCs into ECs by increasing CDH5/CD31, triggering tube-like structures, inducing Dil-Ac-LDL positive BMSCs. ETV2 overexpression increased the gene transcription and expression of VE-cadherin and vWF (P<0.01). Transcription of M1 phenotype specific iNOS gene was lower and transcription of M2 phenotype specific ARG-1 gene was higher in the RAW264.7+BMSCs+ETV2 group compared to the RAW264.7+BMSCs+pLVX group (P<0.01). ETV2 overexpression (RAW264.7+BMSCs+ETV2) downregulated IL-6 and TNF-α, and upregulated IL-10 and TGF-ß gene transcription compared to RAW264.7+BMSCs+pLVX group (P<0.01). ETV2-overexpressed BMSCs promoted wound healing in CW mice and triggered the migration of BMSCs to the wound region and macrophage activation. ETV2-overexpressed BMSCs promoted collagen fibers and blood vessel formation in the wound region of CW mice. In conclusion, this study revealed a novel biofunction of ETV2 molecule in the wound healing process. ETV2 overexpression in BMSCs promoted wound healing in CW mice by triggering BMSCs differentiation into endothelial cells and modulating the transformation of M1 pro-inflammatory and M2 anti-inflammatory macrophages in vitro and in vivo.

Auxin and carbohydrate control flower bud development in Anthurium andraeanum during early stage of sexual reproduction.

BACKGROUND: Flower buds of Anthurium andraeanum frequently cease to grow and abort during the early flowering stage, resulting in prolonged planting times and increased commercialization costs. Nevertheless, limited knowledge exists of the mechanism of flower development after initiation in A. andraeanum. RESULTS: In this study, the measurement of carbohydrate flow and intensity between leaves and flowers during different growth stages showed that tender leaves are strong sinks and their concomitant flowers are weak ones. This suggested that the tender leaves compete with their concomitant flower buds for carbohydrates during the early growth stages, potentially causing the abortion of the flower buds. The analysis of transcriptomic differentially expressed genes suggested that genes related to sucrose metabolism and auxin response play an important role during flower bud development. Particularly, co-expression network analysis found that AaSPL12 is a hub gene engaged in flower development by collaborating carbohydrate and auxin signals. Yeast Two Hybrid assays revealed that AaSPL12 can interact with AaARP, a protein that serves as an indicator of dormancy. Additionally, the application of exogenous IAA and sucrose can suppress the expression of AaARP, augment the transcriptional abundance of AaSPL12, and consequently expedite flower development in Anthurium andraeanum. CONCLUSIONS: Collectively, our findings indicated that the combination of auxin and sugar signals could potentially suppress the repression of AaARP protein to AaSPL12, thus advancing the development of flower buds in Anthurium andraeanum.

Asiatic acid prevents glucocorticoid-induced femoral head osteonecrosis via PI3K/AKT pathway.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) represents a predominant etiology of non-traumatic osteonecrosis, imposing substantial pain, restricting hip mobility, and diminishing overall quality of life for affected individuals. Centella asiatica (L.) Urb. (CA), an herbal remedy deeply rooted in traditional oriental medicine, has exhibited noteworthy therapeutic efficacy in addressing inflammation and facilitating wound healing. Drawing from CA's historical applications, its anti-inflammatory, anti-apoptotic, and antioxidant attributes may hold promise for managing GIONFH. Asiatic acid (AA), a primary constituent of CA, has been substantiated as a key contributor to its anti-apoptotic, antioxidant, and anti-inflammatory capabilities, showcasing a close association with orthopedic conditions. For the investigation of whether AA could alleviate GIONFH through suppressing oxidative stress, apoptosis, and to delve into its potential cellular and molecular mechanisms, the connection between AA and disease was analyzed through network pharmacology. DEX-induced apoptosis in rat osteoblasts and GIONFH in rat models, got utilized for the verification in vitro/vivo, on underlying mechanism of AA in GIONFH. Network pharmacology analysis reveals a robust correlation between AA and GIONFH in multiple target genes. AA has demonstrated the inhibition of DEX-induced osteoblast apoptosis by modulating apoptotic factors like BAX, BCL-2, Cleaved-caspase3, and cleaved-caspase9. Furthermore, it effectively diminishes the ROS overexpression and regulates oxidative stress through mitochondrial pathway. Mechanistic insights suggest that AA's therapeutic effects involve phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) pathway activation. Additionally, AA has exhibited its potential to ameliorate GIONFH progression in rat models. Our findings revealed that AA mitigated DEX-induced osteoblast apoptosis and oxidative stress through triggering PI3K/AKT pathway. Also, AA can effectively thwart GIONFH occurrence and development in rats.

Taxifolin-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long-term or excessive use of glucocorticoids (GCs). Taxifolin (TAX) is a natural antioxidant with various pharmacological effects, such as antioxidative stress and antiapoptotic properties. The purpose of this study was to explore whether TAX could regulate oxidative stress and apoptosis in GIONFH by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. We conducted qRT-PCR, Western blotting, TUNEL assays, flow cytometry, and other experiments in vitro. Microcomputed tomography analysis, hematoxylin-eosin staining, and immunohistochemical staining were performed to determine the therapeutic effect of TAX in vivo. TAX mitigated the overexpression of ROS and NOX gene expression induced by DEX, effectively reducing oxidative stress. Additionally, TAX could alleviate DEX-induced osteoblast apoptosis, as evidenced by qRT-PCR, Western blotting, and other experimental techniques. Our in vivo studies further demonstrated that TAX mitigates the progression of GIONFH in rats by combating oxidative stress and apoptosis. Mechanistic exploration revealed that TAX thwarts the progression of GIONFH through the activation of the Nrf2 pathway. Overall, our research herein reports that TAX-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of GIONFH.

Suppression of Overactive Insulin-Like Growth Factor 1 Attenuates Trauma-Induced Heterotopic Ossification in Mice.

Heterotopic ossification (HO) is the ectopic bone formation in soft tissues. Aside from hereditary HO, traumatic HO is common after orthopedic surgery, combat-related injuries, severe burns, or neurologic injuries. Recently, mammalian target of rapamycin (mTOR) was demonstrated to be involved in the chondrogenic and osteogenic processes of HO formation. However, its upstream signaling mechanism remains unknown. The current study used an Achilles tendon puncture-induced HO model to show that overactive insulin-like growth factor 1 (IGF-1) was involved in the progression of HO in mice. Micro-computed tomography imaging showed that IGF-1 not only accelerated the rate of osteogenesis and increased ectopic bone volume but also induced spontaneous ectopic bone formation in undamaged Achilles tendons. Blocking IGF-1 activity with IGF-1 antibody or IGF-1 receptor inhibitor picropodophyllin significantly inhibited HO formation. Mechanistically, IGF-1/IGF-1 receptor activates phosphatidylinositol 3-kinase (PI3K)/Akt signaling to promote the phosphorylation of mTOR, resulting in the chondrogenic and osteogenic differentiation of tendon-derived stem cells into chondrocytes and osteoblasts in vitro and in vivo. Inhibitors of PI3K (LY294002) and mTOR (rapamycin) both suppressed the IGF-1-stimulated mTOR signal and mitigated the formation of ectopic bones significantly. In conclusion, these results indicate that IGF-1 mediated the progression of traumatic HO through PI3K/Akt/mTOR signaling, and suppressing IGF-1 signaling cascades attenuated HO formation, providing a promising therapeutic strategy targeting HO.

Morroniside-mediated mitigation of stem cell and endothelial cell dysfunction for the therapy of glucocorticoid-induced osteonecrosis of the femoral head.

BACKGROUND: Prolonged use of glucocorticoids (GCs) potentially lead to a condition known as GCs-induced osteonecrosis of the femoral head (GIONFH). The primary mechanisms underlying this phenomenon lies in stem cells and endothelial cells dysfunctions. Morroniside, an iridoid glycoside sourced from Cornus officinalis, possesses numerous biological capabilities, including combating oxidative stress, preventing apoptosis, opposing ischemic effects, and promoting the regeneration of bone tissue. PURPOSE: This study aimed to analyze the impact of Morroniside on Dexamethasone (DEX)-induced dysfunction in stem cells and endothelial cells, and its potential as a therapeutic agent for GIONFH in rat models. METHODS: ROS assay, JC-1 assay, and TUNEL assay were used to detect oxidative stress and apoptosis levels in vitro. For the evaluation of the osteogenic capability of bone marrow-derived mesenchymal stem cells, we employed ALP and ARS staining. Additionally, the angiogenic ability of endothelial cells was assessed using tube formation assay and migration assay. Microcomputed tomography analysis, hematoxylin-eosin staining, and immunohistochemical staining were utilized to evaluate the in vivo therapeutic efficacy of Morroniside. RESULTS: Morroniside mitigates DEX-induced excessive ROS expression and cell apoptosis, effectively reducing oxidative stress and alleviating cell death. In terms of osteogenesis, Morroniside reverses DEX-induced osteogenic impairment, as evidenced by enhanced ALP and ARS staining, as well as increased osteogenic protein expression. In angiogenesis, Morroniside counteracts DEX-induced vascular dysfunction, demonstrated by an increase in tube-like structures in tube formation assays, a rise in the number of migrating cells, and elevated levels of angiogenic proteins. In vivo, our results further indicate that Morroniside alleviates the progression of GIONFH. CONCLUSION: The experimental findings suggest that Morroniside concurrently mitigates stem cell and endothelial cell dysfunction through the PI3K/AKT signaling pathway both in vitro and in vivo. These outcomes suggest that Morroniside serves as a potential therapeutic agent for GIONFH.

Comparative study of trimming and resection of diseased finger superficial flexor tendons in gouty carpal tunnel syndrome.

BACKGROUND: Hyperuricemia can lead to synovial hyperplasia in the wrist. In severe cases, it can lead to the deposition of gouty stone in the carpal tunnel, resulting in increased pressure in the carpal tunnel and compression of the median nerve to cause carpal tunnel syndrome (CTS), which is called gouty carpal tunnel syndrome (GCTS). As for the surgical treatment of gouty carpal tunnel syndrome, scholars have different opinions on whether it is necessary to remove the superficial flexor tendon. The purpose of this study was to compare the clinical efficacy of trimming and resection of the diseased superficial flexor tendon in the treatment of gouty carpal tunnel syndrome. METHODS: Clinical data were collected from May 2016 to July 2021 from 10 patients (13 affected wrists) diagnosed with gouty carpal tunnel syndrome and classified into two groups according to the surgical modality: the diseased portion of the gout-eroded superficial finger tendon was trimmed in 9 wrists, and the diseased superficial finger flexor tendon was excised in 4 wrists. Values related to flexion and extension functions, 2-PD, DASH, BCTQ, VAS and recurrence in the affected fingers were compared between the two groups as well as before and after surgery in each group. RESULTS: All affected limbs used were cleared of gouty stones, finger numbness improved, no skin necrosis occurred, and all incisions healed at stage I. At follow-up (13.58 ± 5.53 months), there was no significant difference between groups in flexion and extension function, 2-PD, DASH, BCTQ, and VAS with respect to the affected fingers, and patients in both groups improved significantly before and after surgery. Treatment of only one wrist involved trimming to remove lesion-affected portions of tendon, which reappeared 1 year after surgery, and there was one case of poor recovery from greater piriformis muscle atrophy in both procedures. CONCLUSION: Regarding surgical treatment of patients with gouty carpal tunnel syndrome in which the gouty stone has invaded the superficial flexor tendons of the fingers, the diseased superficial flexor tendons can be selectively excised, and the postoperative mobility of the affected fingers may not be impaired.

Real-World Systemic Treatment Patterns after Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma in the United States.

Real-world (RW) evidence is needed to evaluate atezolizumab plus bevacizumab (atezo + bev) utilization for hepatocellular carcinoma (HCC) in clinical practice. This retrospective cohort study used administrative claims databases to evaluate treatment patterns in individuals with HCC ≥18 years of age who were initiated on atezo + bev between June 2020 and June 2022. The endpoints of this study were the proportion of individuals who discontinued atezo + bev and received subsequent systemic therapies, time to discontinuation (TTD), and time to next treatment. Overall, 825 individuals were eligible (median age 67 years; 80% male). Over a median follow-up of 15.3 months, most (72%) discontinued atezo + bev, with a median TTD of 3.5 months. A minority (19%) received subsequent therapies, with the most common second-line agents being lenvatinib (6%), cabozantinib (4%), and nivolumab (4%). The median time from index to next treatment post-atezo + bev was 5.4 months. Further research is needed to identify the patients who are most likely to benefit from atezo + bev as well as later-line HCC therapies to optimize overall survival.

MiR-146b-5p enriched bioinspired exosomes derived from fucoidan-directed induction mesenchymal stem cells protect chondrocytes in osteoarthritis by targeting TRAF6.

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degradation and inflammation. In recent years, mesenchymal stem cells (MSCs) derived exosomes (MSCs-Exo) have attracted widespread attention for their potential role in modulating OA pathology. However, the unpredictable therapeutic effects of exosomes have been a significant barrier to their extensive clinical application. In this study, we investigated whether fucoidan-pretreated MSC-derived exosomes (F-MSCs-Exo) could better protect chondrocytes in osteoarthritic joints and elucidate its underlying mechanisms. In order to evaluate the role of F-MSCs-Exo in osteoarthritis, both in vitro and in vivo studies were conducted. MiRNA sequencing was employed to analyze MSCs-Exo and F-MSCs-Exo, enabling the identification of differentially expressed genes and the exploration of the underlying mechanisms behind the protective effects of F-MSCs-Exo in osteoarthritis. Compared to MSCs-Exo, F-MSCs-Exo demonstrated superior effectiveness in inhibiting inflammatory responses and extracellular matrix degradation in rat chondrocytes. Moreover, F-MSCs-Exo exhibited enhanced activation of autophagy in chondrocytes. MiRNA sequencing of both MSCs-Exo and F-MSCs-Exo revealed that miR-146b-5p emerged as a promising candidate mediator for the chondroprotective function of F-MSCs-Exo, with TRAF6 identified as its downstream target. In conclusion, our research results demonstrate that miR-146b-5p encapsulated in F-MSCs-Exo effectively inhibits TRAF6 activation, thereby suppressing inflammatory responses and extracellular matrix degradation, while promoting chondrocyte autophagy for the protection of osteoarthritic cartilage cells. Consequently, the development of a therapeutic approach combining fucoidan with MSC-derived exosomes provides a promising strategy for the clinical treatment of osteoarthritis.

Single-Molecule Conductance of Intramolecular Hydrogen Bonding in Histamine on Gold.

We perform single-molecule conductance measurements and DFT calculations on histamine, a biogenic amine that contains a flexible aliphatic linker and several nitrogen moieties with a potential for hydrogen bonding. Our study determines that junctions containing the free-base form of histamine can bridge through a molecular structure containing an intramolecular hydrogen bond. Conductance of this structure is higher than that through the saturated aliphatic linker. Flicker noise analysis of junction conductance confirms that transport occurs through the hydrogen bond and establishes a benchmark for noise measurements in hydrogen-bonded junctions. Overall, our work provides insights into the formation and conduction of intramolecular hydrogen bonding in single-molecule conductance measurements and into the conformations of the neurotransmitter histamine on noble metal surfaces.

Manipulating Quantum Interference between σ and π Orbitals in Single-Molecule Junctions via Chemical Substitution and Environmental Control.

Understanding and manipulating quantum interference (QI) effects in single molecule junction conductance can enable the design of molecular-scale devices. Here we demonstrate QI between σ and π molecular orbitals in an ∼4 Å molecule, pyrazine, bridging source and drain electrodes. Using single molecule conductance measurements, first-principles analysis, and electronic transport calculations, we show that this phenomenon leads to distinct patterns of electron transport in nanoscale junctions, such as destructive interference through the para position of a six-membered ring. These QI effects can be tuned to allow conductance switching using environmental pH control. Our work lays out a conceptual framework for engineering QI features in short molecular systems through synthetic and external manipulation that tunes the energies and symmetries of the σ and π channels.

Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats.

Roxadustat (FG-4592) is a specific hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. We investigated the effects of FG-4592 pretreatment on survival and second choke vessels of multi-territory perforator flaps in rats. In total, 72 rats were divided into two groups (n = 36 each): the experimental (FG-4592) group and the control group. FG-4592 was administered orally as a single dose of 60 mg/kg every other day; the first drug solution was administered to the animals 7 days before the surgical procedure. On postoperative day 7, the surviving flap area was calculated. At 12 h post-surgery, in the second choke zone in the flaps, macrovascular hinges were compared by angiography and imaging, and microvascular changes were assessed by histology. Laser Doppler imaging was used to evaluate flap perfusion at the second choke zone at 12 h and 7 days after surgery. At 7 days after surgery, the flap survival area and perfusion were significantly greater in rats given FG-4592 compared with controls. At 12 h after surgery, the diameter of macrovascular and microvascular vessels, nitric oxide content, perfusion, and the protein levels of HIF-1α and inducible nitric oxide synthase were also significantly greater in FG-4592-treated rats than controls. In conclusion, pretreatment with roxadustat may improve initial flap survival and dilate the second choke zone vessels in a multi-territory perforator flap.

Pharmacological activation of the Nrf2 pathway by Taxifolin remodels articular cartilage microenvironment for the therapy of Osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a widely prevalent degenerative disease marked by extracellular matrix (ECM) degradation, inflammation, and apoptosis. Taxifolin (TAX) is a natural antioxidant possessing various pharmacological benefits, such as combating inflammation, oxidative stress, apoptosis, and serves as a potential chemopreventive agent by regulating genes through an antioxidant response element (ARE)-dependent mechanism. Currently, no studies have investigated the therapeutic impact and precise mechanism of TAX on OA. PURPOSE: The aim of this study is to examine the potential role and mechanism of TAX in reshaping the cartilage microenvironment, thereby offering a stronger theoretical foundation for pharmacologically activating the Nrf2 pathway to manage OA. STUDY DESIGN AND METHODS: The pharmacological effects of TAX were examined in chondrocytes through in vitro studies and in a destabilization of the medial meniscus (DMM) rat model for in vivo analysis. RESULTS: TAX suppresses IL-1ß triggered secretion of inflammatory agents, chondrocyte apoptosis, and ECM degradation, contributing to the remodeling of the cartilage microenvironment. In vivo experiment results demonstrated that TAX counteracted cartilage degeneration induced by DMM in rats. Mechanistic investigations revealed that TAX hinders OA development by reducing NF-κB activation and ROS production through the activation of the Nrf2/HO-1 axis. CONCLUSION: TAX reshapes the articular cartilage microenvironment by suppressing inflammation, mitigating apoptosis, and decreasing ECM degradation through the activation of the Nrf2 pathway. As a result, pharmacological activation of the Nrf2 pathway by TAX holds potential clinical significance in remodeling the joint microenvironment for OA treatment.

Cooperative Self-Assembly of Dimer Junctions Driven by π Stacking Leads to Conductance Enhancement.

We demonstrate enhanced electronic transport through dimer molecular junctions, which self-assemble between two gold electrodes in π-π stabilized binding configurations. Single molecule junction conductance measurements show that benzimidazole molecules assemble into dimer junctions with a per-molecule conductance that is higher than that in monomer junctions. Density functional theory calculations reveal that parallel stacking of two benzimidazoles between electrodes is the most energetically favorable due to the large π system. Imidazole is smaller and has greater conformational freedom to access different stacking angles. Transport calculations confirm that the conductance enhancement of benzimidazole dimers results from the changed binding geometry of dimers on gold, which is stabilized and made energetically accessible by intermolecular π stacking. We engineer imidazole derivatives with higher monomer conductance than benzimidazole and large intermolecular interaction that promote cooperative in situ assembly of more transparent dimer junctions and suggest at the potential of molecular devices based on self-assembled molecular layers.

Hierarchical metacommunity structure of fungal endophytes.

The ecological and evolutionary processes shaping community structure and functions of microbial symbionts are known to be scale-dependent. Nonetheless, understanding how the relative importance of these processes changes across spatial scales, and deciphering the hierarchical metacommunity structure of fungal endophytes has proven challenging. We investigated metacommunities of endophytic fungi within leaves of an invasive plant (Alternanthera philoxeroides) across wide latitudinal transects both in its native (Argentina) and introduced (China) ranges to test whether metacommunities of fungal endophytes were structured by different drivers at different spatial scales. We found Clementsian structures with seven discrete compartments (distinctive groups of fungal species with coincident distribution ranges), which coincided with the distribution of major watersheds. Metacommunity compartments were explicitly demarcated at three spatial scales, that is, the between-continent, between-compartment, and within-compartment scales. At larger spatial scales, local environmental conditions (climate, soil, and host plant traits) were replaced by other geographical factors as principal determinants of metacommunity structure of fungal endophytes and community diversity-function relationships. Our results reveal novel insights into the scale dependency of diversity and functions of fungal endophytes, which are likely similar for plant symbionts. These findings can potentially improve our understanding of the global patterns of fungal diversity.

Extracts of Oldenlandia diffusa protects chondrocytes via inhibiting apoptosis and associated inflammatory response in osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoarthritis (OA) is a type of joint disorder that is marked by the gradual breakdown of cartilage and persistent inflammation of the synovial membrane, and is a leading cause of disability among elderly people worldwide. Oldenlandia diffusa (OD) is a member of the Rubiaceae family, and various researches have revealed that it possesses antioxidant, anti-inflammatory, and anti-tumor properties. Extracts of Oldenlandia diffusa is commonly used in traditional oriental medicine to treat various illnesses, including inflammation and cancer. AIM OF THE STUDY: This study is aimed at investigating the anti-inflammatory and anti-apoptosis effects of OD and its potential mechanisms on IL-1ß-induced mouse chondrocytes, as well as its characteristics in a mouse osteoarthritis model. MATERIALS AND METHODS: In this study, the key targets and potential pathways of OD were determined through network pharmacology analysis and molecular docking. The potential mechanism of OD in osteoarthritis was verified by in vitro and in vivo studies. RESULTS: The results of network pharmacology showed that Bax, Bcl2, CASP3, and JUN are key candidate targets of OD for the treatment of osteoarthritis. There is a strong correlation between apoptosis and both OA and OD. Additionally, molecular docking results show that ß-sitosterol in OD can strongly bind with CASP3 and PTGS2. In vitro experiments showed that OD pretreatment inhibited the expression of pro-inflammatory factors induced by IL-1ß, such as COX2, iNOS, IL-6, TNF-α, and PGE2. Furthermore, OD reversed IL-1ß-mediated degradation of collagen II and aggrecan within the extracellular matrix (ECM). The protective effect of OD can be attributed to its inhibition of the MAPK pathway and inhibition of chondrocyte apoptosis. Additionally, it was found that OD can alleviate cartilage degradation in a mouse model of knee osteoarthritis. CONCLUSION: Our study showed that ß-sitosterol, one of the active components of OD, could alleviate the inflammation and cartilage degeneration of OA by inhibiting chondrocyte apoptosis and MAPK pathway.

Stevioside targets the NF-κB and MAPK pathways for inhibiting inflammation and apoptosis of chondrocytes and ameliorates osteoarthritis in vivo.

Osteoarthritis (OA) is a joint disease that is characterized by articular cartilage degeneration and destruction. Stevioside (SVS) is a diterpenoid glycoside extracted from Stevia rebaudiana Bertoni with some specific effects against inflammatory and apoptotic, whereas it is still unclear what function SVS has in osteoarthritis. This study focuses on the anti-inflammatory and anti-apoptosis functions of SVS on chondrocytes induced by interleukin (IL)-1beta, and the role of SVS in an osteoarthritis model for mice. We can detect the production of inflammatory factors such as nitric oxide (NO) and prostaglandin E2 (PGE2) using real-time quantitative polymerase chain reaction (RT-qPCR), the Griess reaction, and enzyme linked immunosorbent assay (ELISA). On the basis of Western blot, we have observed the protein expressions of cartilage matrix metabolism, inflammatory factors, and apoptosis of chondrocytes. Simultaneously, the pharmacological effects of SVS in mice were evaluated by hematoxylin and eosin (HE), toluidine blue, Safranin O, and immunohistochemical staining. The results show that SVS slows extracellular matrix degradation and chondrocyte apoptosis. In addition, SVS mediates its cellular effect by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways. Meanwhile, molecular docking studies revealed that SVS has excellent binding capabilities to p65, extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The study suggests that SVS can be developed as a potential osteoarthritis treatment.

Plantamajoside suppresses the activation of NF-κB and MAPK and ameliorates the development of osteoarthritis.

Osteoarthritis (OA) is a common degenerative bone and joint disorder characterized by progressive cartilage degeneration and secondary synovial inflammation. It is a common chronic joint disorder that affects people of all ages (especially the old). Plantamajoside is a phenylpropanoside derived from plantain. It has a variety of biological properties, including antioxidant, anti-malignant cell proliferation, and anti-inflammatory properties. In this study, the latent mechanism of plantamajoside was explored by slowing the in-vivo and in-vitro progression of osteoarthritis. The results revealed that plantamajoside pre-conditioning inhibited IL-1ß induced pro-inflammatory factors like COX-2, iNOS, IL-6, and TNF-α. Moreover, plantamajoside also reversed the IL-1 ß mediated type II collagen and aggrecan degradation within the extracellular matrix (ECM). The protective effects of plantamajoside have been attributed to the inhibition of both MAPK and NF-κB pathways. Furthermore, our in-vivo research found that plantamajoside could slow the progression of OA in mice. Finally, all findings point to plantamajoside as a potential anti-OA therapeutic candidate.