The role of short-chain fatty acids in immunity, inflammation and metabolism.

Short-chain fatty acids (SCFAs) are carboxylic acids with carbon atom numbers less than 6, which are important metabolites of gut microbiome. Existing research shows that SCFAs play a vital role in the health and disease of the host. First, SCFAs are the key energy source for colon and ileum cells, and affect the intestinal epithelial barrier and defense functions by regulating related gene expression. Second, SCFAs regulate the function of innate immune cells to participate in the immune system, such as macrophages, neutrophils and dendritic cells. Third, SCFAs can also regulate the differentiation of T cells and B cells and the antigen-specific adaptive immunity mediated by them. Besides, SCFAs are raw materials for sugar and lipid synthesis, which provides a theoretical basis for studying the potential role of SCFAs in regulating energy homeostasis and metabolism. There are also studies showing that SCFAs inhibit tumor cell proliferation and promote apoptosis. In this article, we summarized in detail the role of SCFAs in immunity, inflammation and metabolism, and briefly introduced the role of SCFAs in tumor cell survival. It provides a systematic theoretical basis for the study of SCFAs as potential drugs to promote human health.

Engineering of bioactive metal sulfide nanomaterials for cancer therapy.

Metal sulfide nanomaterials (MeSNs) are a novel class of metal-containing nanomaterials composed of metal ions and sulfur compounds. During the past decade, scientists found that the MeSNs engineered by specific approaches not only had high biocompatibility but also exhibited unique physicochemical properties for cancer therapy, such as Fenton catalysis, light conversion, radiation enhancement, and immune activation. To clarify the development and promote the clinical transformation of MeSNs, the first section of this paper describes the appropriate fabrication approaches of MeSNs for medical science and analyzes the features and limitations of each approach. Secondly, we sort out the mechanisms of functional MeSNs in cancer therapy, including drug delivery, phototherapy, radiotherapy, chemodynamic therapy, gas therapy, and immunotherapy. It is worth noting that the intact MeSNs and the degradation products of MeSNs can exert different types of anti-tumor activities. Thus, MeSNs usually exhibit synergistic antitumor properties. Finally, future expectations and challenges of MeSNs in the research of translational medicine are spotlighted.

Multifractal vector optical fields.

We introduce the concept of multifractal into vector optical fields (VOFs). We propose, design and generate new fractal VOFs-multifractal VOFs (MF-VOFs), in which multifractal structure and VOF act as the lattice and the base, respectively. We generate two kinds of MF-VOFs experimentally and explore their focusing behaviors. We also investigate the self-healing and information recovering abilities of MF-VOFs, comparing with those of single-fractal VOFs (SF-VOFs) when their lattices are composed of the same hierarchy of fractal geometries. The results show that MF-VOFs have better self-healing and information recovering abilities than that of traditional SF-VOFs, meaning that MF-VOFs have better ability to resist the information loss during the focusing and imaging processes. These properties may find potential applications in information transmission, optical communication, and so on.

Pseudo-topological property of Julia fractal vector optical fields.

Polarization singularities have topological properties, because they can maintain their features invariably during propagation. The topological property can be destroyed by shifting the polarization singularities away from the central axis, and this destruction originates from the space separation of spin angular momentum components. We find that paired centrosymmetric off-axis polarization singularities can recover the topological property in the Fourier plane (reciprocal space), which belongs to the pseudo-topological property. We reveal that the pseudo-topological property is related to the invisible redistribution of both spin and orbital angular momentum states. We experimentally generate a series of Julia fractal vector optical fields with the pseudo-topological property. They may have potential applications in optical encryption and quantum information.

Focusing behavior of the fractal vector optical fields designed by fractal lattice growth model.

We introduce a general fractal lattice growth model, significantly expanding the application scope of the fractal in the realm of optics. This model can be applied to construct various kinds of fractal "lattices" and then to achieve the design of a great diversity of fractal vector optical fields (F-VOFs) combinating with various "bases". We also experimentally generate the F-VOFs and explore their universal focusing behaviors. Multiple focal spots can be flexibly enginnered, and the optical tweezers experiment validates the simulated tight focusing fields, which means that this model allows the diversity of the focal patterns to flexibly trap and manipulate micrometer-sized particles. Furthermore, the recovery performance of the F-VOFs is also studied when the input fields and spatial frequency spectrum are obstructed, and the results confirm the robustness of the F-VOFs in both focusing and imaging processes, which is very useful in information transmission.

Inverse method to engineer uniform-intensity focal fields with arbitrary shape.

We present an inverse method to engineer uniform-intensity focal fields with arbitrary shape. Amplitude, phase, and polarization states, as adjustable parameters, are used to seek the desired focal fields in the non-iterative computational procedure. Our method can be applied to the cases with low and moderate numerical aperture (NA), in which case the feasibility and validity of our approach have been demonstrated in theory, simulation and experiment, respectively. For the case of higher NA, simulated results based on the Richards-Wolf diffraction integral are shown. We also made some discussions on the experiments with the higher NA. Our method should have wide applications in optical micro machining, optical trapping and so on.

Uncovering the differentiated impacts of carbon neutrality and clean air policies in multi-provinces of China.

Ambitious action plans have been launched to address climate change and air pollution. Through coupling the IMED|CGE, GAINS, and IMED|HEL models, this study investigate the impacts of implementing carbon neutrality and clean air policies on the energy-environment-health-economy chain in the Beijing-Tianjin-Hebei-Henan-Shandong-Shanxi region of China. Results show that Shandong holds the largest reduction in energy consumption and carbon emissions toward the 1.5°C target. Shandong, Henan, and Hebei are of particularly prominent pollutant reduction potential. Synergistic effects of carbon reduction on decreasing PM2.5 concentration will increase in the future, specifically in energy-intensive regions. Co-deployment of carbon reduction and end-of-pipe technologies are beneficial to decrease PM2.5-related mortalities and economic loss by 4.7-12.9% in 2050. Provincial carbon reduction cost will be higher than monetary health benefits after 2030, indicating that more zero-carbon technologies should be developed. Our findings provide scientific enlightenment on policymaking toward achieving carbon reduction and pollution mitigation from multiple perspectives.

Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics.

During the past decade, "membrane lipid therapy", which involves the regulation of the structure and function of tumor cell plasma membranes, has emerged as a new strategy for cancer treatment. Cholesterol is an important component of the tumor plasma membrane and serves an essential role in tumor initiation and progression. This review elucidates the role of cholesterol in tumorigenesis (including tumor cell proliferation, invasion/metastasis, drug resistance, and immunosuppressive microenvironment) and elaborates on the potential therapeutic targets for tumor treatment by regulating cholesterol. More meaningfully, this review provides an overview of cholesterol-integrated membrane lipid nanotherapeutics for cancer therapy through cholesterol regulation. These strategies include cholesterol biosynthesis interference, cholesterol uptake disruption, cholesterol metabolism regulation, cholesterol depletion, and cholesterol-based combination treatments. In summary, this review demonstrates the tumor nanotherapeutics based on cholesterol regulation, which will provide a reference for the further development of "membrane lipid therapy" for tumors.

Social-economic transitions and vulnerability to extreme temperature events from 1960 to 2020 in Chinese cities.

Climate change leads to more frequent and intense extreme temperature events, causing a significant number of excess deaths. Using an epidemiological approach, we analyze all-cause deaths related to heatwaves and cold spells in 2,852 Chinese counties from 1960 to 2020. Economic losses associated with these events are determined through the value of statistical life. Findings reveal that cold-related cumulative excess deaths (1,133 thousand) are approximately 2.5 times higher than heat-related deaths, despite an increase in heat-related fatalities in recent decades. Monetized mortality due to heat-related events is estimated at 1,284 billion CNY, while cold-related economic loss is 1,510 billion CNY. Notably, cities located in colder regions experience more heat-related excess deaths, and vice versa. Economic development does not significantly reduce mortality risks to heatwaves across China. This study provides insights into the spatial-temporal heterogeneity of heatwaves and cold spells mortality, essential for policymakers ensuring long-term climate adaptation and sustainability.

Hearing loss prevalence and burden of disease in China: Findings from provincial-level analysis.

BACKGROUND: Without timely and effective rehabilitation, hearing loss may profoundly affect human life quality. China has a large population of hearing-impaired individuals, which imposes a heavy health burden on society. Moreover, this population is projected to increase rapidly owing to China's aging society. METHODS: We used data from a population-representative epidemiological investigation of hearing loss and ear diseases in four Chinese provinces. We estimated the national prevalence using multiple linear regression of the age-group proportions and prevalence in 31 provinces with clustering analysis. We used years lived with disability (YLDs) to analyze the disease burden and forecasted the prevalence of hearing loss by 2060 in China. RESULTS: An estimated 115 million people had moderate-to-complete hearing loss in 2015 across the 31 provinces of China (8.4% of 1.37 billion people). Of these, 85.7% were older than age 50 years (99 million people) and 2.4% were younger than 20 years old (2.8 million people). Of all YLDs attributable to hearing loss, 68.9% were attributable to moderate-to-complete cases. By 2060, a projected 242 million people in China will have moderate-to-complete hearing loss, a 110.0% increase from 2015. CONCLUSIONS: The hearing loss prevalence in China is high. Population aging and socioeconomic factors substantially affect the prevalence and severity of hearing loss and the disease burden. The prevalence and severity of hearing loss are unevenly distributed across different provinces. Future public health policies should take these trends and regional variations into account.

Design, synthesis and cytotoxic activities of novel aliphatic amino-substituted flavonoids.

A series of flavonoids 9a-f, 13b, 13d, 13e and 14a-f bearing diverse aliphatic amino moieties were designed, synthesized and evaluated for their cytotoxic activities against the ECA-109, A-549, HL-60, and PC-3 cancer cell lines. Most of the compounds exhibited moderate to good activities. The structure-activity relationships were studied, revealing that the chalcone skeleton is the most preferable for cytotoxic activities. Chalcone 9d was the most promising compound due to its high potency against the examined cancer cell lines (its IC50 values against ECA-109, A549, HL-60 and PC-3 cells were 1.0, 1.5, 0.96 and 3.9 µM, respectively).

[Chemical constituents from leaves of Aglaia testicularis].

To study the chemical constituents from the leaves of Aglaia testicularis. The methanol extract was isolated and purified by silica gel, Sephadex LH-20 and preparative HPLC. Their chemical structures were elucidated by MS and spectral data (1H, 13C-NMR). Seven compounds were isolated from the leaves and identified as dasyclamide (1), aglamide A (2), aglamide B (3), aglamide C (4), aglamide D (5), aglaroxin A 1-O-acetate (6), and 3'-methoxyaglaroxin A 1-0-acetate (7). All compounds were isolated from this plant for the first time.

Circ-Plod2 destabilizes Mpo mRNA by binding to IGF2BP2 to promote osteogenic differentiation of bone marrow mesenchymal stem cells.

Osteogenic differentiation, proliferation, and/or apoptosis of bone marrow mesenchymal stem cells (BMSCs) are involved in the progression of postmenopausal osteoporosis (PMO). However, circular RNA (circRNA)-mediated changes in the cellular function of BMSCs in PMO are still unclear. This study revealed the excellent ability of circ-Plod2 to promote osteogenic differentiation of BMSCs and its molecular mechanisms. In this study, ovariectomized (OVX) rats and control (Sham) rats were used to simulate PMO. Initially, we found that the expression of circ-Plod2 in OVX BMSCs is down-regulated and the expression of the Mpo gene is up-regulated by sequencing and verification. Further, we confirmed that circ-Plod2 is located in the cytoplasm and belongs to exon-type circRNA. Interestingly, circ-Plod2 promotes Mpo-dependent osteogenic differentiation of BMSCs without affecting proliferation, apoptosis, adipogenic differentiation, or chondrogenic differentiation of BMSCs. Mechanistically, we demonstrated that circ-Plod2 specifically binds IGF2BP2 to form an RNA-protein complex that destabilizes Mpo mRNA. Overexpression of circ-Plod2 in the bone marrow cavity effectively alleviated osteoporosis in OVX rats and inhibited the expression of MPO in BMSCs. Together, this study reveals that circ-Plod2 destabilizes Mpo mRNA by binding to IGF2BP2 to promote osteogenic differentiation of BMSCs to alleviate osteoporosis. The findings of this study may provide biomarkers for the diagnosis of PMO, and may also provide potential strategies for the clinical treatment of PMO.

Ghrelin Mitigates High-Glucose-Induced Oxidative Damage and Apoptosis in Lens Epithelial Cells.

Oxidative stress induced by high glucose (HG) plays an important role in the mechanism of diabetic cataract. Evidence has shown that effects from oxidative stress induced damage of lens or human lens epithelial (HLE) cells. Antioxidant supplementation is a plausible strategy to avoid oxidative stress and maintain the function of lens. Ghrelin have been used in treatment of many diseases. In this study, we found that ghrelin attenuated HG-induced loss of cell viability, reduced oxidative damage, and cell apoptosis in HLE cells. Ghrelin inhibited apoptosis through the downregulation of Bax and the upregulation of Bcl-2. Our results suggest that ghrelin could be considered as a promising therapeutic intervention for diabetic cataract. We also observed rat lens transparent in cultured media and examined lens histopathological changes. The results showed that ghrelin could inhibit the histopathological injury of lenses and ultrastructural changes induced by HG. In conclusion, ghrelin may play a role in the treatment of ocular diseases involving diabetic cataract.

Cell membrane-camouflaged PLGA biomimetic system for diverse biomedical application.

The emerging cell membrane (CM)-camouflaged poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) (CM@PLGA NPs) have witnessed tremendous developments since coming to the limelight. Donning a novel membrane coat on traditional PLGA carriers enables combining the strengths of PLGA with cell-like behavior, including inherently interacting with the surrounding environment. Thereby, the in vivo defects of PLGA (such as drug leakage and poor specific distribution) can be overcome, its therapeutic potential can be amplified, and additional novel functions beyond drug delivery can be conferred. To elucidate the development and promote the clinical transformation of CM@PLGA NPs, the commonly used anucleate and eukaryotic CMs have been described first. Then, CM engineering strategies, such as genetic and nongenetic engineering methods and hybrid membrane technology, have been discussed. The reviewed CM engineering technologies are expected to enrich the functions of CM@PLGA for diverse therapeutic purposes. Third, this article highlights the therapeutic and diagnostic applications and action mechanisms of PLGA biomimetic systems for cancer, cardiovascular diseases, virus infection, and eye diseases. Finally, future expectations and challenges are spotlighted in the concept of translational medicine.

Probabilistic Prediction of Nonadherence to Psychiatric Disorder Medication from Mental Health Forum Data: Developing and Validating Bayesian Machine Learning Classifiers.

Background: Medication nonadherence represents a major burden on national health systems. According to the World Health Organization, increasing medication adherence may have a greater impact on public health than any improvement in specific medical treatments. More research is needed to better predict populations at risk of medication nonadherence. Objective: To develop clinically informative, easy-to-interpret machine learning classifiers to predict people with psychiatric disorders at risk of medication nonadherence based on the syntactic and structural features of written posts on health forums. Methods: All data were collected from posts between 2016 and 2021 on mental health forum, administered by Together 4 Change, a long-running not-for-profit organisation based in Oxford, UK. The original social media data were annotated using the Tool for the Automatic Analysis of Syntactic Sophistication and Complexity (TAASSC) system. Through applying multiple feature optimisation techniques, we developed a best-performing model using relevance vector machine (RVM) for the probabilistic prediction of medication nonadherence among online mental health forum discussants. Results: The best-performing RVM model reached a mean AUC of 0.762, accuracy of 0.763, sensitivity of 0.779, and specificity of 0.742 on the testing dataset. It outperformed competing classifiers with more complex feature sets with statistically significant improvement in sensitivity and specificity, after adjusting the alpha levels with Benjamini-Hochberg correction procedure. Discussion. We used the forest plot of multiple logistic regression to explore the association between written post features in the best-performing RVM model and the binary outcome of medication adherence among online post contributors with psychiatric disorders. We found that increased quantities of 3 syntactic complexity features were negatively associated with psychiatric medication adherence: "dobj_stdev" (standard deviation of dependents per direct object of nonpronouns) (OR, 1.486, 95% CI, 1.202-1.838, P < 0.001), "cl_av_deps" (dependents per clause) (OR, 1.597, 95% CI, 1.202-2.122, P, 0.001), and "VP_T" (verb phrases per T-unit) (OR, 2.23, 95% CI, 1.211-4.104, P, 0.010). Finally, we illustrated the clinical use of the classifier with Bayes' monograph which gives the posterior odds and their 95% CI of positive (nonadherence) versus negative (adherence) cases as predicted by the best-performing classifier. The odds ratio of the posterior probability of positive cases was 3.9, which means that around 10 in every 13 psychiatric patients with a positive result as predicted by our model were following their medication regime. The odds ratio of the posterior probability of true negative cases was 0.4, meaning that around 10 in every 14 psychiatric patients with a negative test result after screening by our classifier were not adhering to their medications. Conclusion: Psychiatric medication nonadherence is a large and increasing burden on national health systems. Using Bayesian machine learning techniques and publicly accessible online health forum data, our study illustrates the viability of developing cost-effective, informative decision aids to support the monitoring and prediction of patients at risk of medication nonadherence.

Short-chain fatty acids regulate B cells differentiation via the FFA2 receptor to alleviate rheumatoid arthritis.

BACKGROUND AND PURPOSE: Short-chain fatty acids (SCFAs) are metabolites from gut microbes involved in the host's inflammatory response and immunity. The aim of this study was to investigate the role of SCFAs in rheumatoid arthritis (RA) and possible mechanisms. EXPERIMENTAL APPROACH: Gut microbiota diversity in mice was analysed by 16S rDNA sequencing. SCFAs levels were analysed by gas chromatography mass spectrometry. T and B cells were analysed by flow cytometry. Bone damage was analysed by micro-CT and X-ray. Histopathological status was analysed by HE staining. Proteins in tissues were analysed by immunohistochemistry and PCR. Mice with CD19+ B cells deficient in FFA2 receptors were used to explore the molecular mechanisms involved. KEY RESULTS: Levels of acetate, propionate, butyrate, and valerate were decreased in RA patients, and the first three correlated positively with the frequency of Bregs but not Tregs in peripheral blood. Administration of the three SCFAs prior to the onset of collagen-induced arthritis in mice improved arthritic symptoms, increased the Bregs frequency, and decreased transitional B and follicular B cell frequency. However, the preceding phenomena could not be observed in mice with CD19+ B cells deficient in FFA2 receptors. The effects of the three SCFAs in RA were dependent on FFA2 receptors but were independent of the other five B cell receptors (FFA3 receptor, HCA2 receptor, PPARγ, Olfr-78, and AhR). CONCLUSIONS AND IMPLICATIONS: SCFAs regulate B cells differentiation via FFA2 receptors to alleviate RA. This provides new insights into the treatment of RA from an immunological and microbiological perspective.

PSTPIP2 regulates synovial macrophages polarization and dynamics via ERß in the joint microenvironment.

BACKGROUND: The cytoskeletal protein, PSTPIP2, is associated with inflammation and is predominantly expressed in macrophages. Previous data have shown that PSTPIP2 inhibits articular bone damage in arthritic rats. The aim of this study is to explore the molecular mechanism of PSTPIP2's resistance to bone erosion. METHODS: In the current study, peripheral blood and surgically excised synovial tissue from RA patients, DBA/1 mice, Pstpip2CreR26-ZsGreen reporter mice, and Esr2fl/fl/Adgre-Cre tool mice were used for in vivo studies. Adeno-associated viral vector was used to overexpress PSPTIP2 protein in vivo. RESULTS: We found that The level of PSTPIP2 in synovial macrophages is negatively correlated with RA disease activity, which is mediated by synovial macrophages polarization. PSTPIP2hi synovial macrophages form a tight immunological barrier in the lining layer. Notably, the ability of PSTPIP2 to regulate synovial macrophages polarization is dependent on ERß. Additionally, PSTPIP2 regulates the dynamics of synovial macrophages via ERß. CONCLUSIONS: Together, this study reveals that PSTPIP2 regulates synovial macrophages polarization and dynamics via ERß to form an immunological barrier (F4/80+PSTPIP2hi cell-enriched zone) for the joints. Thus, local modulation of PSTPIP2 expression in the joint microenvironment may be a potential strategy for controlling bone erosion in rheumatoid arthritis. PSTPIP2 regulates synovial macrophages polarization and dynamics via ERß to form F4/80+PSTPIP2hi cellular barrier in joint microenvironment.

Hyaluronic Acid-Modified Nanoplatforms as a Vector for Targeted Delivery of Autophagy-Related Gene to the Endometriotic Lesions in Mice.

This investigation probed endometriosis treatment using targeted nanoparticles (NPs) to modulate autophagic activity. To that end, a novel form of polymer-based NP gene delivery platform consisting of polyethyleneimine (PEI) conjugated to stearic acid (SA) and nucleotides (DNA/siRNAs) and enclosed by hyaluronic acid (HA) was prepared. CD44 is highly upregulated in cystic lesions, and HA-CD44 binding in this specific nanoplatform was used to achieve targeted drug delivery to CD44-expression endometriotic tissues. The expression of autophagy-related genes was modulated to explore the importance of this process in the development of endometriosis. By inducing autophagic activity, we were able to reduce the size of endometriotic cysts and suppress the development of ectopic endometrium. To further confirm the relationship between autophagic activity and this disease in humans and animals, numbers of autophagic vesicles and autophagic protein expression were assessed in lesion tissue samples from patients, revealing there may be consistency between animal and human data. Overall, these data revealed the ability of this (PEI-SA/DNA) HA gene delivery system to regulate autophagic activity and, thereby, aid in the treatment of endometriosis.

Construction of Degradable and Amphiphilic Triblock Polymer Carriers for Effective Delivery of siRNA.

The development of effective and safe delivery carriers is one of the prerequisites for the clinical translation of siRNA-based therapeutics. In this study, a library of 144 functional triblock polymers using ring-opening polymerization (ROP) and thiol-ene click reaction is constructed. These triblock polymers are composed of hydrophilic poly (ethylene oxide) (PEO), hydrophobic poly (ε-caprolactone) (PCL), and cationic amine blocks. Three effective carriers are discovered by high-throughput screening of these polymers for siRNA delivery to HeLa-Luc cells. In vitro evaluation shows that siLuc-loaded nanoparticles (NPs) fabricated with leading polymer carriers exhibit sufficient knockdown of luciferase genes and relatively low cytotoxicity. The chemical structure of polymers significantly affects the physicochemical properties of the resulting siRNA-loaded NPs, which leads to different cellular uptake of NPs and endosomal escape of loaded siRNA and thus the overall in vitro siRNA delivery efficacy. After systemic administration to mice with xenograft tumors, siRNA NPs based on P2-4.5A8 are substantially accumulated at tumor sites, suggesting that PEO and PCL blocks are beneficial for improving blood circulation and biodistribution of siRNA NPs. This functional triblock polymer platform may have great potential in the development of siRNA-based therapies for the treatment of cancers.