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Objective·To investigate the changes of adipose tissues in mice after high-fat diet before and during pregnancy and the potential effects on adipose tissues in their offspring.Methods·C57BL/6J female mice were randomly assigned to the normal diet (CON group, n=12) or the high-fat diet (HFD group, n=12) for 5 weeks. The two groups were further subdivided according to pregnancy: a normal diet non-pregnancy group (CON-UN group), a normal diet pregnancy group (CON-P group), a high-fat diet non-pregnancy group (HFD-UN group), and a high-fat diet pregnancy group (HFD-P group). The original diet was maintained during pregnancy and lactation. White adipose tissues (WAT) and brown adipose tissues (BAT) were collected from visceral and scapula of mice after 5 weeks of feeding or E18.5d. Offspring from both dietary groups were placed on a normal diet after weaning, and their adipose tissues were collected at the 11th week. H-E staining was used to observe the changes of adipocytes. Flow cytometry was employed to detect the proportions of CD4+T cells, CD8+T cells, total T cells, CD4+T/CD8+T and NK cells in WAT. RT-PCR was used to assess the expression of IL-6 and IL-1β mRNA in WAT.Results·After 5 weeks on a high-fat diet, the body weight of female mice in the HFD group was higher than that in the CON group (P

BaCe0.8Fe0.1Ni0.1O3−δ (BCFN) in a perovskite structure is impregnated consecutively by BCFN solution and BCFN suspension into a phase-inversion prepared NiO–Gd0.1Ce0.9O2−δ (GDC) scaffold as an anode for solid oxide fuel cells (SOFCs) with on-cell dry reforming of methane (DRM). The whole pore surface of the scaffold is covered by small BCFN particles formed by BCFN solution impregnation; the large pores near the scaffold surface are filled by BCFN aerogels with a high specific surface area produced by BCFN suspension impregnation, which act as a catalytic layer for on-cell DRM. After reduction, the anode consists of a Ni–GDC scaffold and BCFN particles with exsolved FeNi3 nanoparticles. This BCFN-impregnated Ni–GDC anode has higher electrical conductivity, electrochemical activity, and resistance to carbon deposition, with which the cell shows maximum power densities between 1.44 and 0.92 W·cm−2 when using H2 and between 1.09 and 0.50 W·cm−2 when using CO2–CH4 at temperatures ranging from 750 to 600 °C. A stable performance at 400 mA·cm−2 and 700 °C is achieved using 45% CO2–45% CH4–10% N2 for more than 400 h without carbon deposition, benefiting from the impregnated BCFN aerogel with a high specific surface area and water adsorbability.

The aim of this study was to investigate the global epidemiological trends in the incidence and deaths of acute respiratory infections (ARIs), encompassing both upper respiratory infections (URIs) and lower respiratory infections (LRIs), from 1990 to 2021. Using data from the Global Burden of Disease study 2021 (GBD 2021), we utilized the average annual percentage change (AAPC) to examine the trends in the age-standardized incidence rate and deaths rate (ASIR and ASDRs) of URIs and LRIs. In 2021, the global ASIR of URIs and LRIs were 166,770.73 (95 % UI: 148,098.16–189,487.93) per 100,000 and 4283.61 (95 % UI: 4057.03–4524.89) per 100,000, respectively. The highest ASIR of URIs occurred in high-sociodemographic index (SDI) regions (232744.64, 95 % UI: 206887.07–261694.81) per 100,000, whereas LRIs occurred in low-SDI regions (9261.1, 95 % UI: 8741.61–9820.86) per 100,000. In 2021, the global ASDRs of URIs and LRIs were 0.28 (95 % UI: 0.09–0.61) per 100,000 and 28.67 (95 % UI: 25.92–31.07) per 100,000, respectively. The highest ASDRs of both URIs and LRIs were observed in low-SDI regions, with 1.1 (95 % UI: 0.08–2.78) per 100,000 and 70.68 (95 % UI: 62.56–78.62) per 100,000, respectively. From 1990 to 2021, the global ASIR for URIs and LRIs decreased, with AAPCs of −0.17 % (95 % CI: 0.17 % to −0.16 %) and −1.28 % (95 % CI: −1.37 % to −1.22 %), respectively. The global ASDRs also decreased (−3.39 % for URIs; −2.46 % for LRIs). However, during the COVID-19 pandemic, the ASIR of URIs increased in many countries, especially in high-SDI regions (rate difference before and during the COVID-19 pandemic in ASIR was 2210.19 per 100,000.) and low-SDI regions (rate difference in ASIR: 111.26 per 100,000). The global incidence and deaths related to ARIs have decreased over the past 32 years. However, it remains a significant public health concern, particularly due to the notable incidence of URIs in high SDI regions and the deaths associated with both URIs and LRIs in low SDI regions. Furthermore, an increase in the incidence of URIs was observed in both high- and low-SDI regions during the COVID-19 pandemic, highlighting the need for increased attention.

Summary: Background: Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30–70 years with an office blood pressure (BP) of

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors in the contemporary era, representing a significant global health concern. Early HCC patients have mild symptoms or are asymptomatic, which promotes the onset and progression of the disease. Moreover, advanced HCC is insensitive to chemotherapy, making traditional clinical treatment unable to block cancer development. Sorafenib (SFB) is a first-line targeted drug for advanced HCC patients with anti-angiogenesis and anti-tumor cell proliferation effects. However, the efficacy of SFB is constrained by its off-target distribution, rapid metabolism, and multi-drug resistance. In recent years, nanoparticles based on a variety of materials have been demonstrated to enhance the targeting and therapeutic efficacy of SFB against HCC. Concurrently, the advent of joint drug delivery systems has furnished crucial empirical evidence for reversing SFB resistance. This review will summarize the application of nanotechnology in the field of HCC treatment over the past five years. It will focus on the research progress of SFB delivery systems combined with multiple therapeutic modalities in HCC treatment.

Objective: To develop a model combining clinical and radiomics features from CT scans for a preoperative noninvasive evaluation of Huvos grading of neoadjuvant chemotherapy in patients with HOS. Methods: 183 patients from center A and 42 from center B were categorized into training and validation sets. Features derived from radiomics were obtained from unenhanced CT scans.Following dimensionality reduction, the most optimal features were selected and utilized in creating a radiomics model through logistic regression analysis. Integrating clinical features, a composite clinical radiomics model was developed, and a nomogram was constructed. Predictive performance of the model was evaluated using ROC curves and calibration curves. Additionally, decision curve analysis was conducted to assess practical utility of nomogram in clinical settings. Results: LASSO LR analysis was performed, and finally, three selected image omics features were obtained.Radiomics model yielded AUC values with a good diagnostic effect for both patient sets (AUCs: 0.69 and 0.68, respectively). Clinical models (including sex, age, pre-chemotherapy ALP and LDH levels, new lung metastases within 1 year after surgery, and incidence) performed well in terms of Huvos grade prediction, with an AUC of 0.74 for training set. The AUC for independent validation set stood at 0.70. Notably, the amalgamation of radiomics and clinical features exhibited commendable predictive prowess in training set, registering an AUC of 0.78. This robust performance was subsequently validated in the independent validation set, where the AUC remained high at 0.75. Calibration curves of nomogram showed that the predictions were in good agreement with actual observations. Conclusion: Combined model can be used for Huvos grading in patients with HOS after preoperative chemotherapy, which is helpful for adjuvant treatment decisions.

Abstract The unique structural features of hard carbon (HC) make it a promising anode candidate for sodium‐ion batteries (SIB). However, traditional methods of preparing HC require special equipment, long reaction times, and large energy consumption, resulting in low throughputs and efficiency. In our contribution, a novel synthesis method is proposed, involving the formation of HC nanosheets (NS‐CNs) within minutes by creating an anoxic environment through flame combustion and further introducing sulfur and nitrogen sources to achieve heteroatom doping. The effect of heterogeneous element doping on the microstructure of HC is quantitatively analyzed by high‐resolution transmission electron microscopy and image processing technology. Combined with density functional theory calculation, it is verified that the functionalized HC exhibits stronger Na+ adsorption ability, electron gain ability, and Na+ migration ability. As a result, NS‐CNs as SIB anodes provide an ultrahigh reversible capacity of 542.7 mAh g−1 at 0.1 A g−1, and excellent rate performance with a reversible capacity of 236.4 mAh g−1 at 2 A g−1 after 1200 cycles. Furthermore, full cell assembled with NS‐CNs as the can present 230 mAh g−1 at 0.5 A g−1 after 150 cycles. Finally, in/ex situ techniques confirm that the excellent sodium storage properties of NS‐CNs are due to the construction of abundant active sites based on the novel synthesis method for realizing the reversible adsorption of Na+. This work provides a novel strategy to develop novel carbons and gives deep insights for the further investigation of facile preparation methods to develop high‐performance carbon anodes for alkali‐ion batteries.

Background This study comprehensively investigates the association between the expression of nicotinamide N-methyltransferase (NNMT) and clinical outcomes of urothelial bladder cancer (UBC), as well as the molecular mechanisms by which NNMT in cancer-associated fibroblast (CAF) modulates tumor progression and immunotherapy resistance in UBC.Methods Single-cell transcriptomic analyses, immunohistochemical and immunofluorescence assays were performed on bladder cancer samples to validate the relationship between NNMT expression and clinical outcomes. A series of experiments, including chromatin immunoprecipitation assay, liquid chromatography tandem mass spectrometry assay, and CRISPR‒Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9) knockout, together with in vivo models, have been established to determine the molecular functions of NNMT in CAFs in UBC.Results We demonstrated that elevated expression of the nicotinamide adenine dinucleotide (NAD+) metabolism enzyme NNMT in CAFs (NNMT+ CAFs) was significantly associated with non-response to programmed death-ligand 1 (PD-L1) blockade immunotherapy in patients with UBC and predicted the unfavorable prognosis of UBC in two independent large cohorts. Targeting NNMT using the inhibitor 5-Amino-1-methylquinolinium iodide significantly reduced tumor growth and enhanced the apoptotic effects of the anti-PD-L1 antibody in UBC mouse models. Mechanistically, NNMT+ CAFs recruit tumor-associated macrophages via epigenetic reprogramming of serum amyloid A (SAA) to drive tumor cell proliferation and confer resistance to programmed death-1/PD-L1 blockade immunotherapy.Conclusions NNMT+ CAFs were significantly associated with non-response to PD-L1 blockade immunotherapy in patients with UBC. Elevated NNMT, specifically in CAFs, upregulates SAA expression and enhances the recruitment and differentiation of macrophages in the tumor microenvironment, thereby directly or indirectly promoting tumor progression and conferring resistance to immunotherapies in bladder cancer.

BackgroundThe findings regarding the prognosis of prolonged disorders of consciousness (PDOC) vary widely among different studies. This study aims to investigate the mortality, consciousness recovery and disabilities of patients with PDOC after brain injury.MethodsA total of 204 patients with PDOC were included in a longitudinal cohort study, including 129 males and 75 females. There were 112 cases of traumatic brain injury (TBI), 62 cases of cerebral hemorrhage (CH), 13 cases of cerebral infarction (CI) and 17 cases of ischemic hypoxic encephalopathy (IHE). The status of consciousness at 1, 2, 3, 6, 12, 18, 24, 36, 48 months of the disease course was assessed or followed up using the Revised Coma Recovery Scale (CRS-R). If the patients were conscious, the disability Rating Scale (DRS) was also performed. The prognosis of different PDOC including coma, vegetative state (VS) and minimal conscious state (MCS) was analyzed. The survival patients were screened for variables and included in multivariate binary Logistic regression to screen the factors affecting the recovery of consciousness.ResultsThe mortality rates at 12, 24, 36, and 48 months were 10.7, 23.4, 38.9, and 68.4%, respectively. The median time of death was 18 months (8.75, 29). The probability of MCS regaining consciousness was higher than VS (p 0.05). The mortality rate of coma was higher than that of other PDOC (p 0.05). The probability of consciousness recovery after TBI was the highest and the mortality rate was the lowest. The possibility of consciousness recovery in IHE was the least, and the mortality rate of CI was the highest. The cause of brain injury and initial CRS-R score were the factors affecting the consciousness recovery of patients (p

Abstract The bioactivity of interferon-γ (IFN-γ) in cancer cells in the tumor microenvironment (TME) is not well understood in the current immunotherapy era. We found that IFN-γ has an immunosuppressive effect on colorectal cancer (CRC) cells. The tumor volume in immunocompetent mice was significantly increased after subcutaneous implantation of murine CRC cells followed by IFN-γ stimulation, and RNA sequencing showed high expression of B7 homologous protein 4 (B7H4) in these tumors. B7H4 promotes CRC cell growth by inhibiting the release of granzyme B (GzmB) from CD8+ T cells and accelerating apoptosis in CD8+ T cells. Furthermore, interferon regulatory factor 1 (IRF1), which binds to the B7H4 promoter, is positively associated with IFN-γ stimulation-induced expression of B7H4. The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.

Abstract Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.

Excessive local movement and inflammation are common problems in the process of wound repair, which lead to failure of later repair. In order to solve this problem, inspired by the octopus sucker structure, we successfully developed a photocrosslinked hydrogel that can adsorb skin surface fascia. In addition, extracellular vesicles from human bone marrow mesenchymal stem cells are encapsulated in the octopus like sucker structure. The morphology and structure of extracellular vesicles in bone marrow mesenchymal stem cells were detected by scanning electron microscopy and particle size analysis. Through iTRAQ, we tested the expression of angiogenesis related proteins contained in extracellular vesicles. Design small interfering RNA to verify its impact on angiogenic related genes and proteins. Macrophage polarization was detected by immunofluorescence. The expression of new blood vessels was detected by constructing a skin defect model and injecting microfil contrast agent into the heart. When the sucker is firmly adsorbed on the damaged wound, the sucker will slowly degrade. Using its delivery system, it is observed that the extracellular vesicles are released in the wound. Through iTRAQ, it was found that the angiogenesis regulator (angiopoietin-like 4, angiopoietin-like 3 and aminopeptidase N) released in the extracellular vesicles regulates collagen deposition, angiogenesis, and inhibits macrophage aggregation. In addition, the slowly released extracellular vesicles will further inhibit the polarization of proinflammatory macrophages. This biological behavior can provide an adaptive microenvironment for skin regeneration at an early stage. This new bionic octopus sucker structure gel creates a good microenvironment for wound repair and shortens the wound healing time. Therefore, this hydrogel inspired by the octopus sucker structure may provide a good strategy and commercial value for promoting wound repair treatment in clinical practice.

Abstract Objective The aim of the study was to investigate the 3.0 Tesla magnetic resonance imaging (MRI) features of Madelung’s deformity. Materials and methods The wrist MRI scans of 19 patients clinically diagnosed with Madelung’s deformity and 20 patients without deformity were consecutively selected from Beijing Jishuitan Hospital between April 2019 and December 2022 for observation, in the case group and control group, respectively. Multiple linear regression was used to analyze the factors affecting tilting angle and width of central disc (CD, also termed as triangular fibrocartilage, the main component of triangular fibrocartilage complex), while the chi-square test was used to compare the occurrences of CD (radial) attachment displacement, VL, and RTL. p

Anticoagulant treatment is an important strategy for secondary stroke prevention in non⁃valvular atrial fibrillation and acute ischemic stroke patients. However, the optimal timing for anticoagulation initiation after acute ischemic stroke has remained uncertain. In recent years, new clinical evidence has identified the benefit of early anticoagulation initiation rather than delayed anticoagulation initiation after acute ischemic stroke. This article reviews the literature on the topic of anticoagulation initiation in non⁃valvular atrial fibrillation with acute ischemic stroke patients. It helps physicians making decision to initiate anticoagulation at a more reasonable time point after balancing the risk of stroke recurrence and hemorrhagic transformation.

Objectives The objective of this study was to quantify the morphology, composition, and asymmetry of the paravertebral extensor muscles (PSEMs) in patients with cervical ossification of the posterior longitudinal ligament (OPLL) who had different modified K‐line (mK‐line) and the minimum interval between the mK‐line and OPLL (INTmin) values and to investigate the relationship between PSEMs and symptoms and outcomes following laminoplasty. These original findings elucidated that the atrophy of PSEMs could predict decompression outcomes and provided a theoretical basis for paraspinal muscle rehabilitation. Methods A total of 94 consecutive patients who underwent laminoplasty for OPLL between January 2020 and January 2022 were enrolled in this retrospective study. The relative cross‐sectional areas (rCSA), functional cross‐sectional areas (rFCSA), and FCSA/CSA ratio of the multifidus (MF), semispinalis cervicalis (SSCe), semispinalis capitis (SSCa), and splenius capitis (SpCa) were measured at the C3–C7 segments on cervical magnetic resonance imaging (MRI). This study compared the differences between the mK‐line (+) group and the mK‐line (−) group, as well as between the INTmin

Artificial Intelligence (AI) has garnered considerable attention from educators, policymakers, and scholars within the realms of education and social sciences, achieving notable historical significance. Employing bibliometric analysis, this paper aims to provide a comprehensive analysis of the most noticeable trend of using AI in education. The corpus comprises a dataset of publications sourced from Web of Science (WoS) and Scopus-indexed journals. It concentrates on contemporary scientific research and innovative methodologies within the education sector, particularly relevant to the intersection of education and technology in the AI era. The results reveal a significant rise in AI-related technological research beginning in 2018, with citations reaching their zenith in 2019. Furthermore, collaborative metrics indicate that the United States and China are leading in publication volume. In addition, the study highlights a rising interest in AI applications within education and healthcare, particularly in the context of the COVID-19 pandemic.

Abstract Background Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. Methods Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. Results Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. Conclusions Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Abstract Due to the existence of the magnetic pole edge effect, the actual cogging torque of the existing segmented step skew motor does not reach the theoretical minimum. Thus, a method for suppressing cogging torque of permanent magnet synchronous motor considering the magnetic pole edge effect is proposed. The magnetic pole edge effect is creatively converted into the amplitude and phase offset of the cogging torque generated by each pole segment. On this basis, an optimization problem is constructed in which the fundamental component of cogging torque is zero and the total harmonics is minimum. The optimal magnetic pole length and skew angle parameters of each segment are obtained by solving the optimization problem quantitatively. The results can provide theoretical guidance for motor design, which can minimize the cogging torque of step skew structures. The effectiveness of the proposed method in weakening the cogging torque of the step skew motor is demonstrated by theoretical calculation, 3D finite element analysis, and experimental results.

Chemokines play a crucial role in the pathogenesis of patients with hepatocellular carcinoma (HCC). The expression levels of interferon-γ-induced protein-10 (CXCL10) and macrophage inflammatory protein-3α (MIP-3a) were investigated to clarify their clinical significance in HCC.The protein levels of CXCL10 and MIP-3a in the serum of 105 HBV-associated HCC patients, 50 patients with liver cirrhosis (LC), 50 patients with chronic hepatitis B (CHB) and 50 healthy donors (HC) were detected by liquid chip technology (Luminex) or ELISA. In addition, their mRNA levels were also determined in liver cancer and adjacent cancer tissue (paracancer; ParaCa) from 65 HCC patients. The online database UALCAN was used to analyze the association between CXCL10 and pathological manifestations of liver cancer. In addition, the diagnostic value of CXCL10/MIP-3a and AFP in HCC patients was determined by analyzing the Receiver Operating Characteristic Curve (ROC).The protein concentrations of CXCL10 and MIP-3a were significantly higher in the HCC group than in the LC, CHB and HC groups. CXCL10 in sera and liver cancer tissues is significantly positively correlated with ALT, but no significance between CXCL10 in ParaCa tissues and sera-ALT. Their mRNA is significantly higher in cancer tissues than in ParaCa tissues. The areas under the ROC curve of CXCL10, MIP-3a, CXCL10 and MIP-3a combined and AFP were 0.9169, 0.9261, 0.9299 and 0.7880, respectively. Elevated chemokines CXCL10 and MIP-3a in HCC patients may be associated with the clinical manifestation of HCC and could be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.

BackgroundPueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) and Schisandra sphenanthera Rehder & E.H. Wilson are traditional edible and medicinal hepatoprotective botanical drugs. Studies have shown that the combination of two botanical drugs enhanced the effects of treating acute liver injury (ALI), but the synergistic effect and its action mechanisms remain unclear. This study aimed to investigate the synergistic effect and its mechanism of the combination of Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) (PM) and Schisandra sphenanthera Rehder & E.H. Wilson (SS) in the treatment of ALI.MethodsHigh performance liquid chromatography (HPLC) were utilized to conduct the chemical interaction analysis. Then the synergistic effects of botanical hybrid preparation of PM-SS (BHP PM-SS) against ALI were comprehensively evaluated by the CCl4 induced ALI mice model. Afterwards, symptom-oriented network pharmacology, transcriptomics and metabolomics were applied to reveal the underlying mechanism of action. Finally, the key target genes were experimentally by RT-qPCR.ResultsChemical analysis and pharmacodynamic experiments revealed that BHP PM-SS was superior to the single botanical drug, especially at 2:3 ratio, with a better dissolution rate of active ingredients and synergistic anti-ALI effect. Integrated symptom-oriented network pharmacology combined with transcriptomics and metabolomics analyses showed that the active ingredients of BHP PM-SS could regulate Glutathione metabolism, Pyrimidine metabolism, Arginine biosynthesis and Amino acid sugar and nucleotide sugar metabolism, by acting on the targets of AKT1, TNF, EGFR, JUN, HSP90AA1 and STAT3, which could be responsible for the PI3K-AKT signaling pathway, MAPK signaling pathway and Pathway in cancer to against ALI.ConclusionOur study has provided compelling evidence for the synergistic effect and its mechanism of the combination of BHP PM-SS, and has contributed to the development and utilization of BHP PM-SS dietary supplements.

ABSTRACTSARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search of effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) has been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped CsA-suppressed nuclear factor of activated T cells (NFAT) signaling to drive the expression of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 (RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic antiviral effects when used in combination with nirmatrelvir. Our study delineated the molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the anti-SARS-CoV-2 action of calcineurin inhibitors.IMPORTANCECyclosporine A (CsA), commonly used to inhibit immune responses, is also known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in combination with Paxlovid.