Long-Term Effects of Ecological Restoration Projects on Ecosystem Services and Their Spatial Interactions: A Case Study of Hainan Tropical Forest Park in China.

Ecological restoration projects aim to comprehensively intervene in damaged or deteriorating ecosystems, restore them, improve the provision of ecosystem services, and achieve harmonious coexistence between humans and nature. Implementing ecological restoration projects leads to continuous changes in land use/land cover. Studying the long-term changes in land use/land cover and their impacts on ecosystem services, as well as the trade-off and synergy between these services, helps evaluate the long-term effectiveness of ecological restoration projects in restoring ecosystems. Therefore, this study analyzes the land use/land cover, and ecosystem services of the Hainan Tropical Forest Park in China to address this. Since 2000, the area has undergone multiple ecological restoration projects, divided roughly into two stages: 2003-2013 and 2013-2021. The InVEST model is used to quantify three essential ecosystem services in mountainous regions (water yield, carbon storage, and soil conservation), and redundancy analysis identifies the primary driving factors influencing their changes. We conducted spatial autocorrelation analysis to examine the interplay among ecosystem services under long-term land use/land cover change. The results indicate a decrease in the total supply of water yield (-5.14%) and carbon storage (-3.21%) in the first phase. However, the second phase shows an improvement in ecosystem services, with an increase in the total supply of water yield (11.45%), carbon storage (27.58%), and soil conservation (21.95%). The redundancy analysis results reveal that land use/land cover are the primary driving factors influencing the changes in ecosystem services. Furthermore, there is a shift in the trade-off and synergy between ecosystem services at different stages, with significant differences in spatial distribution. The findings of this study provide more spatially targeted suggestions for the restoration and management of tropical montane rainforests in the future.

Thalamocortical Mechanisms for Nostalgia-Induced Analgesia.

As a predominately positive emotion, nostalgia serves various adaptive functions, including a recently revealed analgesic effect. The current fMRI study aimed to explore the neural mechanisms underlying the nostalgia-induced analgesic effect on noxious thermal stimuli of different intensities. Human participants' (males and females) behavior results showed that the nostalgia paradigm significantly reduced participants' perception of pain, particularly at low pain intensities. fMRI analysis revealed that analgesia was related to decreased brain activity in pain-related brain regions, including the lingual and parahippocampal gyrus. Notably, anterior thalamic activation during the nostalgia stage predicted posterior parietal thalamus activation during the pain stage, suggesting that the thalamus might play a key role as a central functional linkage in the analgesic effect. Moreover, while thalamus-PAG functional connectivity was found to be related to nostalgic strength, periaqueductal gray-dorsolateral prefrontal cortex (PAG-dlPFC) functional connectivity was found to be associated with pain perception, suggesting possible analgesic modulatory pathways. These findings demonstrate the analgesic effect of nostalgia and, more importantly, shed light on its neural mechanism.SIGNIFICANCE STATEMENT Nostalgia is known to reduce individuals' perception of physical pain. The underlying brain mechanisms, however, are unclear. Our study found that the thalamus plays a key role as a functional linkage between nostalgia and pain, suggesting a possible analgesic modulatory mechanism of nostalgia. These findings have implications for the underlying brain mechanisms of psychological analgesia.

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl- and HCO3- secretion†.

Aerobic exercises could improve the sperm motility of obese individuals. However, the underlying mechanism has not been fully elucidated, especially the possible involvement of the epididymis in which sperm acquire their fertilizing capacity. This study aims to investigate the benefit effect of aerobic exercises on the epididymal luminal milieu of obese rats. Sprague-Dawley male rats were fed on a normal or high-fat diet (HFD) for 10 weeks and then subjected to aerobic exercises for 12 weeks. We verified that TRPA1 was located in the epididymal epithelium. Notably, aerobic exercises reversed the downregulated TRPA1 in the epididymis of HFD-induced obese rats, thus improving sperm fertilizing capacity and Cl- concentration in epididymal milieu. Ussing chamber experiments showed that cinnamaldehyd (CIN), agonist of TRPA1, stimulated an increase of the short-circuit current (ISC) in rat cauda epididymal epithelium, which was subsequently abolished by removing the ambient Cl- and HCO3-. In vivo data revealed that aerobic exercises increased the CIN-stimulated Cl- secretion rate of epididymal epithelium in obese rats. Pharmacological experiments revealed that blocking cystic fibrosis transmembrane regulator (CFTR) and Ca2+-activated Cl- channel (CaCC) suppressed the CIN-stimulated anion secretion. Moreover, CIN application in rat cauda epididymal epithelial cells elevated intracellular Ca2+ level, and thus activate CACC. Interfering with the PGHS2-PGE2-EP2/EP4-cAMP pathway suppressed CFTR-mediated anion secretion. This study demonstrates that TRPA1 activation can stimulate anion secretion via CFTR and CaCC, which potentially forming an appropriate microenvironment essential for sperm maturation, and aerobic exercises can reverse the downregulation of TRPA1 in the epididymal epithelium of obese rats.

The Addition of an Ultra-Small Amount of Black Phosphorous Quantum Dots Endow Self-Healing Polyurethane with a Biomimetic Intelligent Response.

This study explores new applications of black phosphorus quantum dots (BPQDs) by adding them to self-healing material systems for the first time. Self-healing polyurethane with an ultra-small amount of BPQDs has biomimetic intelligent responsiveness and achieves balance between its mechanical and self-healing properties. By adding 0.0001 wt% BPQDs to self-healing polyurethane, the fracture strength of the material increases from 3.0 to 12.3 MPa, and the elongation at break also increases from 750% to 860%. Meanwhile, the self-healing efficiency remains at 98%. The addition of BPQDs significantly improves the deformation recovery ability of the composite materials and transforms the surface of self-healing polyurethane from hydrophilic to hydrophobic, making it suitable for applications in fields such as electronic skin and flexible wearable devices. This study provides a simple and feasible strategy for endowing self-healing materials with biomimetic intelligent responsiveness using a small amount of BPQDs.

A reduction in metabolism explains the tradeoffs associated with the long-term adaptation of phytoplankton to high CO2 concentrations.

Phytoplankton are responsible for nearly half of global primary productivity and play crucial roles in the Earth's biogeochemical cycles. However, the long-term adaptive responses of phytoplankton to rising CO2 remains unknown. Here we examine the physiological and proteomics responses of a marine diatom, Phaeodactylum tricornutum, following long-term (c. 900 generations) selection to high CO2 conditions. Our results show that this diatom responds to long-term high CO2 selection by downregulating proteins involved in energy production (Calvin cycle, tricarboxylic acid cycle, glycolysis, oxidative pentose phosphate pathway), with a subsequent decrease in photosynthesis and respiration. Nearly similar extents of downregulation of photosynthesis and respiration allow the high CO2 -adapted populations to allocate the same fraction of carbon to growth, thereby maintaining their fitness during the long-term high CO2 selection. These results indicate an important role of metabolism reduction under high CO2 and shed new light on the adaptive mechanisms of phytoplankton in response to climate change.

Early Detection of Cervical Cancer by Fluorescence Lifetime Imaging Microscopy Combined with Unsupervised Machine Learning.

Cervical cancer has high morbidity and mortality rates, affecting hundreds of thousands of women worldwide and requiring more accurate screening for early intervention and follow-up treatment. Cytology is the current dominant clinical screening approach, and though it has been used for decades, it has unsatisfactory sensitivity and specificity. In this work, fluorescence lifetime imaging microscopy (FLIM) was used for the imaging of exfoliated cervical cells in which an endogenous coenzyme involved in metabolism, namely, reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H], was detected to evaluate the metabolic status of cells. FLIM images from 71 participants were analyzed by the unsupervised machine learning method to build a prediction model for cervical cancer risk. The FLIM method combined with unsupervised machine learning (FLIM-ML) had a sensitivity and specificity of 90.9% and 100%, respectively, significantly higher than those of the cytology approach. One cancer recurrence case was predicted as high-risk several months earlier using this method as compared to using current clinical methods, implying that FLIM-ML may be very helpful for follow-up cancer care. This study illustrates the clinical applicability of FLIM-ML as a detection method for cervical cancer screening and a convenient tool for follow-up cancer care.

RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression.

Objective: Interleukin-17 (IL-17), produced by T helper (Th)-17 cells, is a potent regulator of bone homeostasis. Osteoblasts are key cells that orchestrate inflammatory bone destruction and bone remodeling. This study examines the effect of different concentrations of IL-17 on osteogenesis and receptor activator of nuclear factor-kappa B ligand (RANKL) expression of primary osteoblasts.Methods: First, the growth of primary osteoblasts was evaluated. Second, we assessed the effects of IL-17 on the level of autophagy and the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway. Next, osteogenic activity in different concentrations of IL-17 was tested. Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression.Results: Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner. Next, we showed that low levels of IL-17 promoted autophagy activity, whereas the opposite was observed at high levels of IL-17. Moreover, high levels of IL-17 activated the JAK2/STAT3 signaling pathway, although this effect was reversed by upregulation of autophagy. Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade.Conclusion: Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy-JAK2-STAT3 signaling pathway, thus affecting bone metabolism.

[Central neural mechanism of increased pain sensitivity induced by nicotine abstinence].

Nicotine is the main addictive component in cigarettes that motivates dependence on tobacco use for smokers and makes it difficult to quit through regulating a variety of neurotransmitter release and receptor activations in the brain. Even though nicotine has an analgesic effect, clinical studies demonstrated that nicotine abstinence reduces pain threshold and increases pain sensitivity in smoking individuals. The demand for opioid analgesics in nicotine abstinent patients undergoing surgery has greatly increased, which results in many side effects, such as nausea, vomiting, and respiratory depression, etc. In addition, these side effects would hinder patients' physical and psychological recovery. Therefore, identifying the neural mechanism of the increase of pain sensitivity induced by nicotine abstinence and deriving a way to cope with the increased demand for postoperative analgesics would have enormous basic and clinical implications. In this review, we first discussed different experimental pain stimuli (e.g., cold, heat, and mechanical pain)-induced pain sensitivity changes after a period of nicotine dependence/abstinence from both animal and human studies. Then, we summarized the effects of the brain neurotransmitter release (e.g., serotonin, norepinephrine, endogenous opioids, dopamine, and γ-aminobutyric acid) and their corresponding receptor activation changes after nicotine abstinence on pain sensitivity. Finally, we discussed the limits in recent studies. We proposed that more attention should be paid to human studies, especially studies among chronic pain patients, and functional magnetic resonance imaging might be a useful tool to reveal the mechanisms of abstinence-induced pain sensitivity changes. Besides, considering the influence of duration of nicotine dependence/abstinence and gender on pain sensitivity, we proposed that the effects of nicotine abstinence and individual differences (e.g., duration of abstinence from smoking, chronic/acute abstinence, and gender) on abstinence-induced pain sensitivity should be fully considered in formulating pain treatment protocols. In summary, this paper could deepen our understanding of nicotine abstinence-induced pain sensitivity changes and its underlying neural mechanism, and could also provide effective scientific theories to guide clinical pain diagnosis and treatment, which has important clinical significance.

TRAF6/ERK/p38 pathway is involved in interleukin-17-mediated autophagy to promote osteoclast precursor cell differentiation.

To investigate the effects of interleukin (IL)-17-mediated autophagy on the TNF receptor associated factor (TRAF6)/extracellular signal-regulated kinase (ERK)/p38 pathway and osteoclast differentiation. Mouse bone marrow-derived macrophages (BMM) were cultured with a medium containing 30 ng/mL macrophage colony stimulating factor and 50 ng/mL receptor activator of nuclear factor-kappa B ligard (RANKL), and IL-17 (0.01, 0.1, 1.0, 10 ng/mL) was added for intervention (IL-17 group). Tartrate-resistant acid phosphatase (TRAP) staining was used to observe TRAP positive multinucleated cells; phalloidin fluorescent staining was used to detect actin ring circumference; toluidine blue staining was used to analyze bone resorption lacuna formation. To further examine the mechanism of the effect of IL-17-mediated autophagy on the differentiation of osteoclasts, the control group used RANKL medium to culture mouse macrophage RAW264.7 cells, while the IL-17 group was treated with IL-17 (0.01, 0.1, 1.0, /mL). Western blot was used to detect the expression of autophagy-related proteins Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) and osteoclast-related proteins c-fos and nuclear factor of activated T cell 1 (NFATc1) after treatment with different concentrations of IL-17. The expression of LC3, NFATc1, TRAF6/ERK/p38 signaling pathway related proteins were detected in IL-17 and autophagy inhibitor 3-MA group. The number of TRAP positive multinucleated cells, the circumference of the actin ring and the area of bone resorption lacuna in IL-17 group treated with IL-17 (0.01, 0.1, were significantly higher than those in the control group. In IL-17 treated RAW264.7 cells, the expression of c-fos, NFATc1, Beclin-1, LC3, TRAF6, p-ERK, and p-p38 was all significantly up-regulated (all 0.05). After treatment with the autophagy inhibitor 3-MA, the expression levels of LC3, NFATc1, TRAF6, p-ERK, and p-p38 all decreased significantly (all 0.05). IL-17 can promote the expression of autophagy proteins and enhance the differentiation ability of osteoclast precursor cells, and the TRAF6/ERK/p38 signaling pathway may be involved in this process.

Exploring the potential causal relationship between gut microbiota and heart failure: A two-sample mendelian randomization study combined with the geo database.

OBJECTIVE: In recent years, researchers have observed a potential association between alterations in gut microbiota and the onset and progression of heart failure. Nevertheless, the causal relationship between gut microbiota and heart failure remains a topic of controversy. This study employed a two-sample Mendelian randomization approach to investigate the causal link between gut microbiota and heart failure. METHOD: We extracted single nucleotide polymorphism (SNPs) data for heart failure (ebi-a-gcst009541) and gut microbiota from the publicly available genome-wide association analysis (GWAS) summary database. The primary analytical method employed was inverse variance weighting (IVW), complemented by validation using MR-PRESSO, weighted median, and MR pleiotropic residual methods. Additionally, gene pleiotropy (MR-Egger), heterogeneity testing, and a "leave-one-out" analysis were conducted to assess the robustness of the findings. Utilizing the limma package, differentially expressed genes (DEGs) from the Gut Microbiota datasets (GSE3586, GSE5406) and Heart Failure datasets (GSE47908, GSE87466) sourced from the Gene Expression Omnibus (GEO) were curated. Subsequent enrichment analysis was conducted using the Cluster Profiler and GO plot packages to validate the MR analysis outcomes. RESULTS: The results of our analysis revealed seven distinct bacterial groups in the intestines that exhibited associations.with.the.risk.of.heart.failure. These.included.class.negativicutes (P = 0.02,OR:1.11,95%CI:1.02,1.21), gene.eubacterium.eligensgroup (P = 0.02,OR:1.10,95%CI:1.01,1.20),gene.eubacteriummoxidoreducensgroup (P = 0.01,OR:1.10,95%CI:1.02,1.19),Order.selenium (P = 0.02,OR:1.11,95%CI:1.02,1.21), gene.familyxiiiucg001 (P = 0.03,OR=1.09.95%CI:1.01,1.19), gene.familyxiiiad3011group (P = 0.03,OR:0.92,95%CI:0.86,0.99), and.gene.anaerostipes (P = 0.00,OR:0.87,95%CI:0.80,0.94). Nevertheless, upon conducting reverse causal MR analysis, no evidence of a causal relationship between heart failure and the aforementioned seven gut microbiota groups was found.Bioinformatics analysis reveals shared DEGs between gut microbiota and heart failure. CONCLUSION: This Mendelian randomization study represents the first endeavor to explore the causal relationship between specific gut microbiota and heart failure. The findings suggest a significant correlation between these seven specific gut microbiota groups and the risk of heart failure, potentially offering valuable insights for heart failure prevention and control efforts.

Cellular mechanism underlying leptin-induced anion secretion of rat epididymal epithelial cells.

BACKGROUND: A large number of studies have shown that leptin plays an important role in the regulation of fertility via the hypothalamus-pituitary-gonad axis. However, its peripheral function in epididymis was still elusive. OBJECTIVE: The purpose of this study was to determine the pro-secretion effect of leptin on the rat epididymal epithelium. MATERIALS AND METHODS: In the present study, real-time quantitative polymerase chain reaction, western blot, and immunohistochemical analysis were employed to detect the expression pattern of leptin receptors in rat epididymis. The pro-secretion effect of leptin on epididymal epithelial cells was measured by short-circuit current, and the prostaglandin E2 and cyclic adenosine monophosphate level was evaluated by enzyme-linked immunosorbent assay. RESULTS: We verified that the leptin receptor was located on the epididymal epithelium, with a relatively high expression level in corpus and cauda epididymis. Ussing chamber experiments showed that leptin stimulated a significant rise of the short-circuit current in rat epididymal epithelial cells, which could be abolished by the specific leptin receptor antagonist peptide Allo-aca, or by removing the ambient Cl- and HCO3 -. Furthermore, the leptin-stimulated short-circuit current response could be abrogated by blocking the apical cystic fibrosis transmembrane regulator or the basolateral Na+-K+-2Cl- cotransporter. Our pharmacological experiments manifested that interfering with the prostaglandin H synthase-2-prostaglandin E2-EP2/EP4-adenylate cyclase pathways could significantly blunt the cystic fibrosis transmembrane regulator-mediated anion secretion induced by leptin. The enzyme-linked immunosorbent assay demonstrated that leptin could induce a substantial increase in prostaglandin E2 release and cyclic adenosine monophosphate synthesis of primary cultured rat cauda epididymal epithelial cells. Our data also suggested that JAK2, ERK, and PI3K-dependent phosphorylation may be involved in the activation of prostaglandin H synthase-2 and the subsequent prostaglandin E2 production. CONCLUSIONS: The present study demonstrated the pro-secretion function of leptin in rat epididymal epithelium via the activation of cystic fibrosis transmembrane regulator and Na+-K+-2Cl- cotransporter, which was dependent on the paracrine/autocrine prostaglandin E2 stimulated EP2/EP4-adenylate cyclase pathways, and thus contributed to the formation of an appropriate microenvironment essential for sperm maturation.

Efficacy and safety of different traditional Chinese health exercises in patients with coronary heart disease combined with chronic heart failure: A network meta-analysis.

BACKGROUND: Non-pharmacological treatments, particularly TCM health exercises, have garnered attention for their affordability, ease of access, and potential health advantages. Despite this interest, systematic and direct comparative studies assessing the effectiveness and safety of these therapies in patients with CHD-CHF remain scarce. METHODS: This study aimed to compare the efficacy and safety of conventional treatment, conventional treatment integrated with aerobic endurance training, and various TCM health exercises in treating patients with CHD-CHF using NMA. The analysis was designed to provide a reference for developing treatment plans. To achieve this, literature databases were searched for RCTs on different TCM health exercises for CHD-CHF patients up to December 6, 2022. Major outcomes analyzed included NT-proBNP, LVEF, 6-minute walk test, MLHFQ, clinical effectiveness, and adverse event occurrence. The Cochrane risk of bias tool was employed to assess the risk of bias in the included RCT studies. Systematic review with NMA was conducted using RevMan 5.4 and Stata for cumulative ranking, and comparative adjustment funnel plot analysis. RESULTS: Traditional Chinese medicine gong methods included BaDuanJin (A) and TaiChiQuan (B). The NMA and SUCRA results revealed that: A + D and A + C + D were most likely to be the best interventions to improve NT-proBNP; B + D and A + C + D were most likely to be the best interventions to improve LVEF; A + D and A + C + D were the best interventions to improve 6WMT in CHD-CHF patients; B + C + D had the best effect on shrinking LVESD;A + D and B + C + D was likely the best interventions for contracting LVEDD;B + D and A + D were consistent in their capacity to improve MLHFQ in patients with CHD-CHF, but B + D had better efficacy. Unlike A + C + D, B + C + D was the best intervention to improve MLHFQ. In contrast with interventions, including Dand C + D, B + D was the most clinically effective intervention. Unlike interventions including B + C + D, C + D, and D, A + C + D was the most clinically efficient intervention. CONCLUSION: The findings of this NMA showed that traditional Chinese health exercises integrated with conventional treatment are more effective than conventional treatment (D) alone in patients with CHD-CHF, with A + D, B + D, B + C + D, and A + C + D considered potentially optimal treatment interventions.

Effectiveness and safety of electroacupuncture combined with conventional drugs in the treatment of stable angina pectoris in coronary artery disease: A systematic evaluation and meta-analysis.

BACKGROUND: The objective of this study is to systematically evaluate the clinical effectiveness and safety of electroacupuncture combined with conventional drugs in the treatment of stable angina pectoris. METHODS: Computer searches of 3 Chinese literature databases (CNKI, VIP, WangFang) and 4 English literature databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science), all searched from the time of database construction to October 2022. Two researchers were selected to independently perform literature screening, data extraction, and risk of bias evaluation, and meta-analysis of the included studies was performed using RevMan 5.3 software. RESULTS: A total of 7 publications with a total of 1042 patients were included, and electroacupuncture combined with conventional drug therapy compared with drug therapy alone was effective in improving clinical symptoms of angina pectoris (relative risk [RR] = 1.19, 95% CI = [1.09, 1.31], P = .0002), clinical treatment efficiency of electrocardiography (RR = 1.34, 95% CI = [1.19, 1.50], P = .00001), visual analog score (VAS) (mean deviation = 0.07, 95% CI = [-0.11, 0.25], P = .44), and Seattle Angina Scale (mean deviation = 4.91, 95% CI = [2.91, 6.91], P < .00001) were better than conventional drug therapy, while the number of adverse events in the intervention group was lower than that in the control group. One of the outcome indicators with greater heterogeneity was tested by sensitivity analysis, and each outcome indicator was found to be more robust. The risk of bias evaluation of each outcome indicator using funnel plots suggested the possibility of publication bias. CONCLUSION: The current study results found that electroacupuncture combined with conventional drugs can significantly improve the clinical symptoms of patients with stable angina pectoris compared with conventional drug therapy, with a low incidence of adverse reactions, but the number of high-quality literature with rigorous study design protocols is currently low, which may cause bias in the results of this study, so the above conclusions need to be further verified through clinical trials.

MLP-Like Model With Convolution Complex Transformation for Auxiliary Diagnosis Through Medical Images.

Medical images such as facial and tongue images have been widely used for intelligence-assisted diagnosis, which can be regarded as the multi-label classification task for disease location (DL) and disease nature (DN) of biomedical images. Compared with complicated convolutional neural networks and Transformers for this task, recent MLP-like architectures are not only simple and less computationally expensive, but also have stronger generalization capabilities. However, MLP-like models require better input features from the image. Thus, this study proposes a novel convolution complex transformation MLP-like (CCT-MLP) model for the multi-label DL and DN recognition task for facial and tongue images. Notably, the convolutional Tokenizer and multiple convolutional layers are first used to extract the better shallow features from input biomedical images to make up for the loss of spatial information obtained by the simple MLP structure. Subsequently, the Channel-MLP architecture with complex transformations is used to extract deep-level contextual features. In this way, multi-channel features are extracted and mixed to perform the multi-label classification of the input biomedical images. Experimental results on our constructed multi-label facial and tongue image datasets demonstrate that our method outperforms existing methods in terms of both accuracy (Acc) and mean average precision (mAP).

Ferritin was involved in interleukin-17A enhanced osteogenesis through autophagy activation.

Periodontitis is a prevalent inflammatory immune disease that involves tissue inflammation and excessive bone loss. In murine periodontitis models and periodontitis patients, upregulated interleukin-17A (IL-17A) expression was observed, and its level seemed to correlate with the disease severity. In this study, we intended to investigate the specific role of ferritin, a critical iron storage protein, in IL-17A enhanced osteogenic differentiation as well as the underlying mechanism. Under osteogenic induction, IL-17A stimulation promoted differentiation and mineralization of murine calvarial osteoblasts. In addition, increased iron accumulation and ferritin expression were detected in osteoblasts treated with IL-17A, indicating an alteration in iron metabolism during osteogenesis. Administration of iron chelator deferoxamine (DFO) and transfection with small interfering RNA (siRNA) targeting ferritin heavy chain (FTH) further revealed that ferritin suppression consequently inhibited osteoblast differentiation. Autophagy activation was also found upon IL-17A stimulation, which played a positive role in osteogenic differentiation and was subsequently suppressed by DFO or siRNA targeting FTH. In conclusion, IL-17A induced ferritin expression in osteoblasts, which further enhanced osteogenic differentiation via autophagy activation. These findings may provide further insight into the role of IL-17A in osteoblast differentiation and demonstrate ferritin as a potential target in modulating alveolar bone homeostasis.

All-trans-retinoic acid inhibits hepatocellular carcinoma progression by targeting myeloid-derived suppressor cells and inhibiting angiogenesis.

Hepatocellular carcinoma is characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of maintaining the immunosuppressive tumor microenvironment. Therefore, targeting MDSCs will improve immunotherapies for cancers. It has been shown that all-trans retinoic acid (ATRA) can differentiate MDSCs into mature myeloid cells. However, whether ATRA suppression of MDSCs function could inhibit the growth of liver cancer remains unknown. Here we found that ATRA significantly inhibited hepatocellular carcinoma promotion, tumor cell proliferation, and angiogenesis markers. Moreover, ATRA decreased the number of mononuclear myeloid-derived suppressor cells (M-MDSCs), granulocytic myeloid-derived suppressor cells (G-MDSCs) and tumor-associated macrophages (TAMs) in spleens. In addition, ATRA significantly reduced the intratumoral infiltrating G-MDSCs and the expression of protumor immunosuppressive molecules (arginase 1, iNOS, IDO and S100A8 + A9), which was accompanied by increased cytotoxic T cell infiltration. Our study demonstrates that ATRA not only has direct intrinsic inhibitory effect on tumor angiogenesis and fibrosis, but also reeducates the tumor microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces ATRA as a potential druggable target for treatment of hepatocellular carcinoma.

Alcohol remodels the immunosuppressive tumor microenvironment by targeting myeloid-derived suppressor cells.

The tumor immunosuppressive microenvironment plays an important role in tumor progression. Alcohol is well-known as a regulator of the immune system and several studies have also reported that chronic alcohol intake can activate the immune system. However, it is unclear whether alcohol can affect liver cancer progression by regulating the immunosuppressive microenvironment. In this study, we investigated the effects of different alcohol concentrations on the growth of liver cancer and tumor immune microenvironment. We examined the growth of tumors in mice provided with water, or alcohol (for 2 weeks before tumor injection, and for 3 weeks after tumor injection). We found that alcohol consumption at 5% and 20% inhibited the growth of subcutaneous tumors in hepatocellular carcinoma-bearing mice, whereas 2% alcohol concentration did not significantly inhibit liver cancer growth. The ratio of myeloid-derived suppressor cells (MDSCs) in peripheral blood and spleen of mice treated with 5% or 20% alcohol for 2 weeks before tumor inoculation was downregulated. After tumor inoculation, the proportion of MDSCs in peripheral blood, spleen, and tumor of mice treated with 5% or 20% alcohol for another 3 weeks also decreased and the proportion of CD4+ T cells and CD8+ T cells increased. In addition, Alcohol consumption of 20% reduced levels of the inflammatory factor IL-6 by inhibiting JAK/STAT3 signaling. These results indicate that chronic alcohol consumption may inhibit the growth of liver cancer by regulating MDSCs.

Personalized Intelligent Syndrome Differentiation Guided By TCM Consultation Philosophy.

Traditional Chinese Medicine (TCM) is one of the oldest medical systems in the world, and inquiry is an essential part of TCM diagnosis. The development of artificial intelligence has led to the proposal of several computational TCM diagnostic methods. However, there are few research studies among them, and they have the following flaws: (1) insufficient engagement with the patient, (2) barren TCM consultation philosophy, and (3) inadequate validation of the method. As TCM inquiry knowledge is abstract and there are few relevant datasets, we devise a novel knowledge representation technique. The mapping of symptoms and syndromes is constructed based on the diagnostics of traditional Chinese medicine. As a guide, the inquiry knowledge base is constructed utilizing the "Ten Brief Inquiries," TCM's domain knowledge. Subsequently, a corresponding assessment approach is proposed for an intelligent consultation model for syndrome differentiation. We establish three criteria: the quality of the generated question-answer pairs, the accuracy of model identification, and the average number of questions. Three TCM specialists are asked to undertake a manual evaluation of the model separately. The results reveal that our approach is capable of pretty accurate syndrome differentiation. Furthermore, the model's question and answer pairs for simulated consultations are relevant, accurate, and efficient.

Interleukin-17 promotes osteoclastogenesis and periodontal damage via autophagy in vitro and in vivo.

OBJECTIVE: Because of its potent pro-inflammatory properties, interleukin-17 (IL-17) contributes to the pathogenesis of various inflammatory diseases. This study explored the effects of IL-17 on osteoclastogenesis in an osteoclast monoculture and osteoblast-osteoclast co-culture system, as tools to investigate the molecular mechanisms underlying the interactions between osteoclastogenesis and autophagy. METHODS: Various ratios of calvarial osteoblasts (OB) and osteoclast precursor cells (mouse macrophage cell line RAW264.7, hereinafter referred to as OC) were tested. Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the optimum osteoblasts:osteoclasts ratio. IL-17 was added to the co-culture system to test its effects on multinucleated osteoclast formation and osteoclast-related proteins. We assessed the effects of IL-17 on receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, and determined if IL-17 alone could modulate osteoclast formation in an osteoclast monoculture. Administration of exogenous RANKL combined with IL-17 was employed to stimulate RAW264.7 cells osteoclastogenesis and to determine production of osteoclasts and autophagy-related proteins. We knocked down Beclin1 expression in RAW264.7 cells and examined the expression of autophagy-related and osteoclast-related proteins in RAW264.7 cells and the co-culture system, and the TAK1-binding protein 3 (TAB3)/ extracellular signal regulated kinase (ERK) pathway. RESULTS: A ratio of 20 OB : 1 OC yielded the highest rate of osteoclast formation. Low IL-17 concentrations increased osteoclastogenesis in co-cultures significantly, but high levels of IL-17 had the opposite effect. IL-17 alone could not induce formation of TRAP+ multinucleated cells in RAW264.7 cells. Low IL-17 concentrations promoted osteoclast differentiation and autophagy in RAW264.7 cells induced by exogenous RANKL, but high IL-17 concentrations inhibited this process. Knockdown of Beclin1 reversed the enhanced effects of 0.1 ng/mL IL-17 on osteoclastogenesis and autophagy in RAW264.7 cells. The TAB3/ERK pathway was also blocked after autophagy inhibition. CONCLUSION: In the co-culture model used in this study, a ratio of 20 OB:1 OC proved to be the optimal ratio to facilitate osteoclast formation. IL-17 regulated RANKL-induced osteoclastogenesis via autophagy. The Beclin1/TAB3/ERK pathway was involved in osteoclast autophagy.

The analgesic effect of nostalgia elicited by idiographic and nomothetic approaches on thermal stimulus.

Nostalgia is shown to relieve an individual's perception of pain evoked by cold water, pressure, and thermal stimuli. However, there is no direct evidence to show the analgesic effects of different nostalgia-inducing methods on various stimulus intensities. We conducted two studies to examine the analgesic effect, at different pain intensities, after inducing nostalgia either idiographically or nomothetically. Study 1 (N = 118) induced nostalgia through an idiographic approach (i.e., event reflection task) and found that nostalgia relieved both high and low thermal pain. Study 2 (N = 66) induced nostalgia through a nomothetic approach (i.e., viewing nostalgic pictures) and found that nostalgia relieved low but not high thermal pain. The findings verify the analgesic effect of nostalgia on thermal pain and suggest the potential moderating role of the nostalgia induction approach and pain intensity. Practically, these findings have implications for using nostalgia as a nonpharmacological treatment for pain.