[Mechanism of bulleyaconitine A in inhibiting bone destruction of rheumatoid arthritis via Src/PI3K/Akt signaling pathway].

Based on the sarcoma receptor coactivator(Src)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway, the mechanism of action of bulleyaconitine A in the treatment of bone destruction of experimental rheumatoid arthritis(RA) was explored. Firstly, key targets of RA bone destruction were collected through GeneCards, PharmGKB, and OMIM databa-ses. Potential targets of bulleyaconitine A were collected using SwissTargetPrediction and PharmMapper databases. Next, intersection targets were obtained by the Venny 2.1.0 platform. Protein-protein interaction(PPI) network and topology analysis were managed by utilizing the STRING database and Cytoscape 3.8.0. Then, Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted in the DAVID database. AutoDock Vina was applied to predict the molecular docking and binding ability of bulleyaconitine A with key targets. Finally, a receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model was established in vitro. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect the mRNA expression levels of related targets, and immunofluorescence and Western blot were adopted to detect the protein expression level of key targets. It displayed that there was a total of 29 drug-disease targets, and Src was the core target of bulleyaconitine A in anti-RA bone destruction. Furthermore, KEGG enrichment analysis revealed that bulleyaconitine A may exert an anti-RA bone destruction effect by regulating the Src/PI3K/Akt signaling pathway. The molecular docking results showed that bulleyaconitine A had better bin-ding ability with Src, phosphatidylinositol-4,5-diphosphate 3-kinase(PIK3CA), and Akt1. The result of the experiment indicated that bulleyaconitine A not only dose-dependently inhibited the mRNA expression levels of osteoclast differentiation-related genes cathepsin K(CTSK) and matrix metalloproteinase-9(MMP-9)(P<0.01), but also significantly reduced the expression of p-c-Src, PI3K, as well as p-Akt in vitro osteoclasts(P<0.01). In summary, bulleyaconitine A may inhibit RA bone destruction by regulating the Src/PI3K/Akt signaling pathway. This study provides experimental support for the treatment of RA bone destruction with bulleyaconitine A and lays a foundation for the clinical application of bulleyaconitine A.

[Mechanism of Yuxuebi Tablets in treating synovial inflammation in rheumatoid arthritis based on transcriptomics].

This study investigated the mechanism of Yuxuebi Tablets(YXB) in the treatment of synovial inflammation in rheumatoid arthritis(RA) based on transcriptomic analysis. Transcriptome sequencing technology was employed to analyze the gene expression profiles of joint tissues from normal rats, collagen-induced arthritis(CIA) rats(an RA model), and YXB-treated rats. Common diffe-rentially expressed genes(DEGs) were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses. RA synovial inflammation-related target genes were retrieved from the OMIM and GeneCards databases. Venny 2.1 software was used to identify the intersection of YXB target genes and RA synovial inflammation-related target genes, and GO and KEGG enrichment analyses were performed on the intersecting target genes. Immunohistochemistry was used to assess the protein expression levels of the inflammatory factors interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in rat joint tissues. Western blot analysis was employed to measure the expression levels of key proteins in the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway. A total of 2 058 DEGs were identified by intersecting the genes from the normal group vs model group and the model group vs YXB treatment group. A search in OMIM and GeneCards databases yielded 1 102 RA synovial inflammation-related target genes. After intersecting with the DEGs in the YXB treatment group, 204 intersecting target genes were identified, primarily involving biological processes such as immune response, signal transduction, and inflammatory response; cellular components including plasma membrane, extracellular space, and extracellular region; molecular functions like protein binding, identical protein binding, and receptor binding. These target genes were mainly enriched in signaling pathways such as PI3K/Akt, cytokine-cytokine receptor interaction, and Janus kinase/signal transducer and activator of transcription(JAK/STAT). Western blot results showed that YXB at low, medium, and high doses could significantly inhibit the expression levels of key proteins in the PI3K/Akt signaling pathway in rat joint tissues in a dose-dependent manner. Immunohistochemistry further confirmed these findings, showing that YXB not only suppressed the protein expression levels of the inflammatory factors IL-1ß and TNF-α in the joint synovial tissues of CIA rats, but also inhibited p-Akt protein expression. In conclusion, this study used transcriptomic analysis to uncover the key mechanisms of YXB in inhibiting synovial inflammation and alleviating the progression of RA, with a focus on its role in suppressing the PI3K/Akt signaling pathway.

Effect of soybean polysaccharide and soybean oil on gelatinization and retrogradation properties of corn starch.

This investigation stems from the wide interest in mitigating starch retrogradation, which profoundly impacts the quality of starch-based food, garnering significant attention in the contemporary food industry. Our study delves into the intricate dynamics of soluble soybean polysaccharide (SSPS) and soybean oil (SO) when added individually or in combination to native corn starch (NCS), offering insights into the gelatinization and retrogradation phenomena. We observed that SSPS (0.5 %, w/w) hindered starch swelling, leading to an elevated gelatinization enthalpy change (∆H) value, while SO (0.5 %, w/w) increased ∆H due to its hydrophobicity. Adding SSPS and/or SO concurrently reduced the viscosity and storage modulus (G') of starch matrix. For the starch gel (8 %, w/v) after refrigeration, SSPS magnified water-holding capacity (WHC) and decreased hardness through hydrogen bonding with starch, while SO increased hardness with limited water retention. Crucially, the combination of SSPS and SO maximized WHC, minimized hardness, and significantly inhibited starch retrogradation. The specific ratio of SSPS to SO was found to significantly influence the starch properties, with a 1:1 ratio resulting in the most desirable quality for application in starch-based foods. This study offers insights for utilizing polysaccharides and lipids in starch-based food products to extend shelf life.

Organoid forming potential as complementary parameter for accurate evaluation of breast cancer neoadjuvant therapeutic efficacy.

BACKGROUND: 13-15% of breast cancer/BC patients diagnosed as pathological complete response/pCR after neoadjuvant systemic therapy/NST suffer from recurrence. This study aims to estimate the rationality of organoid forming potential/OFP for more accurate evaluation of NST efficacy. METHODS: OFPs of post-NST residual disease/RD were checked and compared with clinical approaches to estimate the recurrence risk. The phenotypes of organoids were classified via HE staining and ER, PR, HER2, Ki67 and CD133 immuno-labeling. The active growing organoids were subjected to drug sensitivity tests. RESULTS: Of 62 post-NST BC specimens, 24 were classified as OFP-I with long-term active organoid growth, 19 as OFP-II with stable organoid growth within 3 weeks, and 19 as OFP-III without organoid formation. Residual tumors were overall correlated with OFP grades (P < 0.001), while 3 of the 18 patients (16.67%) pathologically diagnosed as tumor-free (ypT0N0M0) showed tumor derived-organoid formation. The disease-free survival/DFS of OFP-I cases was worse than other two groups (Log-rank P < 0.05). Organoids of OFP-I/-II groups well maintained the biological features of their parental tumors and were resistant to the drugs used in NST. CONCLUSIONS: The OFP would be a complementary parameter to improve the evaluation accuracy of NST efficacy of breast cancers.

Physical therapy for acute and sub-acute low back pain: A systematic review and expert consensus.

OBJECTIVE: To review the effectiveness of different physical therapies for acute and sub-acute low back pain supported by evidence, and create clinical recommendations and expert consensus for physiotherapists on clinical prescriptions. DATA SOURCES: A systematic search was conducted in PubMed and the Cochrane Library for studies published within the previous 15 years. REVIEW METHODS: Systematic review and meta-analysis, randomized controlled trials assessing patients with acute and sub-acute low back pain were included. Two reviewers independently screened relevant studies using the same inclusion criteria. The Physiotherapy Evidence Database and the Assessment of Multiple Systematic Reviews tool were used to grade the quality assessment of randomized controlled trials and systematic reviews, respectively. The final recommendation grades were based on the consensus discussion results of the Delphi of 22 international experts. RESULTS: Twenty-one systematic reviews and 21 randomized controlled trials were included. Spinal manipulative therapy and low-level laser therapy are recommended for acute low back pain. Core stability exercise/motor control, spinal manipulative therapy, and massage can be used to treat sub-acute low back pain. CONCLUSIONS: The consensus statements provided medical staff with appliable recommendations of physical therapy for acute and sub-acute low back pain. This consensus statement will require regular updates after 5-10 years.

Integrative pharmacology reveals the mechanisms of Erzhi pills, A traditional Chinese formulation, stimulating melanogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Erzhi pills (EZP), a traditional Chinese medicine formula prescribed for the treatment of vitiligo, has shown promising efficacy. However, the oral bioactive components and mechanisms underlying the promotion of melanogenesis by EZP remain unclear. AIM OF THE STUDY: This study aimed to investigate the pharmacological basis and mechanism of EZP in promoting melanogenesis. MATERIALS AND METHODS: UHPLC-TOF-MS analysis was used to identify absorbed phytochemicals in serum after oral administration of EZP. Network pharmacology methods were used to predict potential targets and pathways involved in the melanogenic activity of EZP, resulting in the construction of a "compound-target-pathway" network. Zebrafish and B16F10 cells were used to evaluate the effects of EZP on tyrosinase activity and melanin content. Western blot and ELISA analyses were used to validate the effects of EZP on melanogenesis-related proteins, including MITF, TYR, CREB, p-CREB, and cAMP. RESULTS: UHPLC-TOF-MS analysis identified 36 compounds derived from EZP in serum samples. Network pharmacology predictions revealed 89 target proteins associated with the identified compounds and closely related to vitiligo. GO and KEGG analyses indicated the involvement of the cAMP/PKA signaling pathway in the promotion of melanogenesis by EZP. Experimental results showed that EZP increased tyrosinase activity and melanin content in zebrafish and B16F10 cells without inducing toxicity. Western blot and ELISA results suggested that the melanogenic effect of EZP may be related to the activation of the cAMP/PKA signaling pathway. These results confirm the feasibility of combining serum pharmacological and network pharmacological approaches. CONCLUSIONS: EZP have the potential to increase tyrosinase activity and melanin content in zebrafish and cells possibly through activation of the cAMP/PKA pathway.

Acupuncture for ventilator-dependent patients at a hospital-based respiratory care center: A randomized controlled trial.

Background: In intensive care units, mechanical ventilation is an important therapy to help patients with dyspnea. However, long-term ventilator dependence would consume huge medical resources and increase the risk of morbidity and mortality. The aim of the study was to examine the efficacy of the acupuncture combined with western medical care on ventilator parameters in ventilator-dependent patients. Methods: In this clinical trial, 80 ventilator-dependent patients aged 20 to 80 years old were randomly assigned to acupuncture group and control group in the respiratory care center (RCC) of Changhua Christian Hospital. Besides regular medical care and therapy, participants in the acupuncture group received acupuncture therapy at the same 17 acu-points for 20 minutes once a day, a total of 12 sessions. The ventilator parameters were recorded to evaluate the respiratory efficiency for all participants. The primary outcome was rapid shallow breathing index (RSBI), and secondary outcomes were respiratory rate (RR), tidal volume (TV) and ventilation per minute (MV). Results: Though there was no significant difference in the parameter between the acupuncture group and the control group, we found the trend of decreasing RSBI in the acupuncture group. In subgroup analyses, the mean of RSBI significantly decreased 16.02 (with the SD in 60.84) in acupuncture group, while it increased 17.84 (with the SD in 39.38) in control group (p=0.036) after 12 sessions. Conclusion: Acupuncture treatment can improve breathing ability of patients with respirator dependence in respiratory care center.

Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice.

Depression is a multifaceted psychiatric disorder that affects a significant number of individuals worldwide, and its pathophysiology encompasses a variety of mechanisms, including the induction of endoplasmic reticulum (ER) stress, which has been correlated with depressive-like behaviors in animal models. Yamogenin, a bioactive compound derived from traditional Chinese medicine Dioscorea species, possesses diverse pharmacological properties. This investigation aimed to explore the antidepressant-like effects of yamogenin and the underlying mechanisms involved. By utilizing a murine model of lipopolysaccharide (LPS)-induced depressive-like behavior, we demonstrated that yamogenin enhanced sucrose preference and reduced immobility time in the forced swimming test. These effects were observed alongside the attenuation of ER stress through modulation of the PERK/eIF2α/ATF4/CHOP signaling pathway in the prefrontal cortex. Moreover, yamogenin augmented the expression of the antiapoptotic protein Bcl-2 while diminishing the expression of the proapoptotic protein caspase-3. Additionally, yamogenin exhibited inhibitory effects on microglial activation but did not elicit the promotion of brain-derived neurotrophic factor (BDNF) signaling. Collectively, our findings propose that yamogenin exerts antidepressant-like effects in LPS-induced mice by inhibiting ER stress and microglial activation. This study contributes novel insights into the potential utilization of yamogenin as a natural antidepressant agent.

Chemoprevention of lotus leaf ethanolic extract through epigenetic activation of the NRF2-mediated pathway in murine skin JB6 P+ cell neoplastic transformation.

Background and aim: Skin is one barrier protecting from environmental risk factors that can make skin cells cancerous through DNA damage and oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is an anti-stress defense system that can be regulated by DNA methylation and histone modification. Dietary phytochemicals have chemopreventive properties that can inhibit or delay carcinogenesis. The lotus leaf is a traditional medicinal plant containing many polyphenols whose extracts show many biological activities, including antioxidant, anti-obesity, and anti-cancer. This study aim to investigate the effect of lotus leaves on neoplastic transformation in murine skin JB6 P+ cells. Experimental procedure: Lotus leaves were extracted with water (LL-WE) and ethanol (LL-EE), and the LL-WE residues were further extracted with ethanol (LL-WREE). JB6 P+ cells were treated with different extracts. The chemoprotective effect would be evaluated by heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase (NQO1), and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression. Results and conclusion: LL-EE contained higher total phenolics and quercetin among extracts. In mouse skin JB6 P+ cells with 12-O-tetradecanoylphorbol-13-acetate treatment, LL-EE showed the greatest potential to suppress skin carcinogenesis. LL-EE activated the NRF2 pathway by upregulating antioxidant and detoxification enzymes upregulates antioxidant and detoxification enzymes, including HO-1, NQO1, and UGT1A1, and downregulates DNA methylation, which might be caused by lower DNA methyltransferase and histone deacetylase levels. Therefore, our results show that LL-EE reduces the neoplastic transformation of skin JB6 P+ cells, potentially by activating the NRF2 pathway and regulating epigenetic DNA methylation and histone acetylation.

Selenium modulates AR/IGF-1R/EGFR and TROP2 signaling pathways and improves anticancer efficacy in murine mammary carcinoma 4T1.

The micronutrient selenium (Se) has been shown to exert potential anticancer properties. This study aimed to evaluate the effects of Se (in Se yeast form) on the selenoproteins (SELENO), AR/IGF-1R/EGFR, PI3K/Akt/mTOR and Ras/Raf/ERK cascades, and immune checkpoint blockade in TNBC murine 4T1 cells. We also assessed the effects of combination treatment with chemotherapeutic doxorubicin and Se on trophoblast cell surface antigen 2 (TROP2) levels. Compared with the control groups, cells incubated with Se (0.25, 0.5, 0.75, 1.0, 1.5 µg Se/mL) have lower viability, raised intracellular Se concentrations and SELENO expression, and higher malondialdehyde products in a dose-dependent manner. Se induced the inactivation of AR/IGF-1R/EGFR and downregulation of the PI3K/Akt/mTOR and Ras/Raf/ERK signaling molecules. Se-treated cells also exhibited decreased mitochondrial membrane potential, reduced levels of the cell cycle regulatory protein cyclin D1, cancer stemness, metastatic and EMT-related markers, and increased apoptosis. Subsequently, Se treatment significantly suppressed PD-1/PD-L1 and CTLA-4 mRNA levels and proteins. Doxorubicin decreased 4T1 cell viability and TROP2 expression levels, but the addition of Se to doxorubicin contributed to further reductions. Similar responses to Se treatment were also observed in the human MDA-MB-231 and MCF-7 breast cancer cells. These results show that Se upregulates SELENO and anti-AR/IGF-1R/EGFR signaling in TNBC cells, thus inducing oxidative stress-dependent apoptosis and cell cycle arrest, stemness, EMT, and metastasis, as well as blocking the immune checkpoint molecules. TROP2 down-regulation with Se is also a potential anti-TNBC therapeutic target.

[Anti-depression mechanism of Zuojin Pills:based on UHPLC-TOF-MS, network pharmacology, and experimental verification].

This study aims to explore the anti-depression mechanism of Zuojin Pills based on the plasma constituents, network pharmacology, and experimental verification. UHPLC-TOF-MS was used for qualitative analysis of Zuojin Pills-containing serum. Targets of the plasma constituents and the disease were retrieved from PharmMapper and GeneCards. Then the protein-protein interaction(PPI) network was constructed and core targets were screened for GO term enrichment and KEGG pathway enrichment. Cytoscape 3.7.2 was employed construct the "compound-target-pathway" network and the targets and signaling pathways of Zuojin Pills against depression were predicted. CUMS-induced depression mouse model was established to verify the key targets. The results showed that a total of 21 constituents migrating to blood of Zuojin Pills were identified, which were mainly alkaloids. A total of 155 common targets of the constituents and the disease and 67 core targets were screened out. KEGG enrichment and PPI network analysis showed that Zuojin Pills may play a role in the treatment of depression through AMPK/SIRT1, NLRP3, insulin and other targets and pathways. Furthermore, the results of animal experiments showed that Zuojin Pills could significantly improve the depression behaviors of depression, reduce the levels of IL-1ß, IL-6 and TNF-α in hippocampus and serum, activate AMPK/SIRT1 signaling, and reduce the protein expression of NLRP3. In conclusion, Zuojin Pills may play a role in the treatment of depression by activating AMPK/SIRT1 signaling pathway, and inhibiting NLRP3 activation and neuroinflammation in the hippocampus of mice.

Evaluation of You-Gui-Wan critical compounds inhibiting ALOX-5 and HDC gene expression in RBL-2H3 cells using a fractional factorial design.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) You-Gui-Wan (YGW) has been used to treat asthma for hundreds of years. AIM OF THE STUDY: YGW is composed of 10 types of medicinal materials. However, the immune mechanism of YGW in asthma treatment has not been elucidated. Therefore, this study investigated asthma symptoms attenuated by YGW and the underlying immune regulatory mechanism. MATERIALS AND METHODS: Intratracheal (i.t.) stimulation of BALB/c mice with Dermatophagoides pteronyssinus (Der p) was performed once per week (40 µL, 2.5 µg/µL). For six consecutive weeks, different doses of YGW (0.2 g/kg and 0.5 g/kg) were orally administered 30 min before stimulation with Der p. After the last stimulation, airway hyperreactivity, lung gene expression, and total immunoglobulin E (IgE) in blood were evaluated using a whole-body plethysmograph system, real-time PCR, and ELISA, respectively. In addition, DNP-IgE/DNP-BSA was added to stimulate mast cells (RBL-2H3), and YGW or various compound compositions (Trial) were added to RBL-2H3 cells for 30 min to evaluate the effects of the drug on mast cell degranulation and on gene expression. JMP 5.1 software was used to design and analyze YGW's critical compounds by which it inhibited ALOX-5 and HDC gene expression in RBL-2H3 cells. RESULTS: YGW significantly decreased serum total IgE levels and airway hyperresponsiveness in asthmatic mice. YGW also reduced the gene expression of IL-6, TNF-α, IL-4, IL-13, and COX-2 in the lungs of asthmatic mice and RBL-2H3 cells. YGW and the compound (Trial 21) present in YGW inhibited the gene expression of ALOX-5 and HDC in RBL-2H3 cells. CONCLUSION: The experimental results indicate that YGW exhibits anti-airway hyperresponsiveness and specific immunomodulatory effects. In addition, YGW synergistically inhibits ALOX-5 and HDC gene expression in mast cells through a combination of 21 compounds, including luteolin, quercetin, and ß-carotene.

Characteristics and Outcomes for Hospitalized Patients With Cutaneous T-Cell Lymphoma.

Importance: Cutaneous T-cell lymphoma (CTCL) is a group of rare, complex cutaneous malignant neoplasms associated with significant disease burden on patients and the health care system. Currently, the population of patients with CTCL admitted to the hospital remains largely uncharacterized and poorly understood. Objective: To characterize the clinical characteristics, course of hospitalization, and mortality outcomes of an inpatient CTCL cohort. Design, Setting, and Participants: This multicenter retrospective cohort study reviewed medical records for adult patients (age ≥18 years) with a CTCL diagnosis per National Comprehensive Cancer Network guidelines admitted for inpatient hospitalization at 5 US academic medical centers with inpatient dermatology consult services and CTCL clinics between August 2016 and August 2020. Main Outcomes and Measures: Patient demographics, clinical history and findings, hospitalization courses, and mortality outcomes. Results: A total of 79 hospitalized patients with CTCL were identified, including 52 (70.3%) men and 22 (29.7%) women, with a median (IQR) age at hospitalization of 62.9 (27-92) years. The majority of admitted patients with CTCL were White (65 patients [82.3%]), had disease classified as mycosis fungoides (48 patients [61.5%]), and had advanced-stage disease (≥IIB, 70 patients [89.7%]). Most hospitalizations were complicated by infection (45 patients [57.0%]) and required intravenous antibiotic therapy (45 patients [57.0%]). In-hospital mortality occurred in 6 patients (7.6%) and was associated with higher body mass index (36.5 vs 25.3), history of thromboembolic disease (50.0% vs 12.3%), and diagnosis of sepsis on admission (66.7% vs 20.5%). At 1-year postdischarge, 36 patients (49.3%) patients had died, and mortality was associated with history of solid organ cancers (27.8% vs 10.8%), wound care as the reason for dermatology consultation (58.3% vs 24.3%), and presence of large cell transformation (58.3% vs 22.9%). Conclusions and Relevance: The findings of this cohort study improve the understanding of hospitalized patients with CTCL and lend valuable insight into identifying factors associated with both in-hospital and long-term mortality outcomes. This refined understanding of the inpatient CTCL population provides a foundation for larger, more robust studies to identify causal risk factors associated with mortality, development of prognostic scoring systems to estimate the probability of hospital mortality. Overall, the findings may prompt physicians caring for patients with CTCL to implement preventive strategies to diminish hospitalization and improve clinical management across this unique disease spectrum.

Beneficial Effects and Potential Mechanisms of Tai Chi on Lower Limb Osteoarthritis: A Biopsychosocial Perspective.

Lower limb osteoarthritis (OA) is a chronic, multifactorial disease characterized by impaired physical function, chronic pain, compromised psychological health and decreased social functioning. Chronic inflammation plays a critical role in the pathophysiology of OA. Tai Chi is a type of classical mind-body exercise derived from ancient Chinese martial arts. Evidence supports that Tai Chi has significant benefits for relieving lower limb OA symptoms. Using a biopsychosocial framework, this review aims to elucidate the beneficial effects of Tai Chi in lower limb OA and disentangle its potential mechanisms from the perspective of biology, psychology, and social factors. Complex biomechanical, biochemical, neurological, psychological, and social mechanisms, including strengthening of muscles, proprioception improvement, joint mechanical stress reduction, change of brain activation and sensitization, attenuation of inflammation, emotion modulation and social support, are discussed.

[Mechanism of Jiaotai Pills in treatment of depression based on quantitative proteomics].

This study aimed to investigate the effect of Jiaotai Pills on protein expression in the hippocampus of the rat model of chronic unpredictable mild stress(CUMS)-induced depression by quantitative proteomics and explore the anti-depression mechanism of Jiaotai Pills. The SD rats were randomized into control, model, Jiaotai Pills, and fluoxetine groups(n=8). Other groups except the control group were subjected to CUMS modeling for 4 weeks. After 4 weeks of continuous administration, the changes of behavior and pathological morphology of the hippocampal tissue were observed. Proteins were extracted from the hippocampal tissue, and bioinformatics analysis was performed for the differentially expressed proteins(DEPs) identified by quantitative proteomics. Western blot was employed to verify the key DEPs. The results showed that Jiaotai Pills significantly alleviated the depression behaviors and hippocampal histopathological changes in the rat model of CUMS-induced depression. A total of 5 412 proteins were identified in the hippocampus of rats, including 65 DEPs between the control group and the model group and 35 DEPs between the Jiaotai Pills group and the model group. There were 16 DEPs with the same trend in the Jiaotai Pills group and the control group, which were mainly involved in sphingolipid, AMPK, and dopaminergic synapse signaling pathways. The Western blot results of Ppp2r2b, Cers1, and Ndufv3 in the hippocampus were consistent with the results of proteomics. In conclusion, Jiaotai Pills may play an anti-depression role by modulating the levels of Ppp2r2b, Cers1, Ndufv3 and other proteins and regulating sphingolipid, AMPK, and dopaminergic synapse signaling pathways.

Targeting EGFR in Combination with Nutritional Supplements on Antitumor Efficacy in a Lung Cancer Mouse Model.

Selenium (Se) and fish oil (FO) exert anti-epidermal growth factor receptor (EGFR) action on tumors. This study aimed to compare the anti-cancer efficacy of EGFR inhibitors (gefitinib and erlotinib) alone and in combination with nutritional supplements of Se/FO in treating lung cancer. Lewis LLC1 tumor-bearing mice were treated with a vehicle or Se/FO, gefitinib or gefitinib plus Se/FO, and erlotinib or erlotinib plus Se/FO. The tumors were assessed for mRNA and protein expressions of relevant signaling molecules. Untreated tumor-bearing mice had the lowest body weight and highest tumor weight and volume of all the mice. Mice receiving the combination treatment with Se/FO and gefitinib or erlotinib had a lower tumor volume and weight and fewer metastases than did those treated with gefitinib or erlotinib alone. The combination treatment exhibited greater alterations in receptor signaling molecules (lower EGFR/TGF-ß/TßR/AXL/Wnt3a/Wnt5a/FZD7/ß-catenin; higher GSK-3ß) and immune checkpoint molecules (lower PD-1/PD-L1/CD80/CTLA-4/IL-6; higher NKp46/CD16/CD28/IL-2). These mouse tumors also had lower angiogenesis, cancer stemness, epithelial to mesenchymal transitions, metastases, and proliferation of Ki-67, as well as higher cell cycle arrest and apoptosis. These preliminary results showed the Se/FO treatment enhanced the therapeutic efficacies of gefitinib and erlotinib via modulating multiple signaling pathways in an LLC1-bearing mouse model.

Fish Oil and Selenium with Doxorubicin Modulates Expression of Fatty Acid Receptors and Selenoproteins, and Targets Multiple Anti-Cancer Signaling in Triple-negative Breast Cancer Tumors.

Omega-3 fatty acids from fish oil (FO) and selenium (Se) potentiate some conventional therapies and have anticancer immune potential. This study aims to determine whether FO/Se modulates G-protein-coupled polyunsaturated fatty acid receptors (GPR-40 and GPR-120) and selenoproteins (Sel-H, Sel-W, and GPx4), and increases the therapeutic effect of doxorubicin in a dose-dependent manner on triple-negative breast cancer (TNBC) mouse. Mice were randomized into 5 groups (n = 7/group) and treated with physiological saline (control), low-dose doxorubicin, and doxorubicin in combination with low, medium, or high doses of FO/Se. The expression of signaling molecules in tumors was determined by measuring either mRNA or protein expression. Compared with doxorubicin alone, combination treatment resulted in lower tumor sizes and fewer overall metastasis, lower GPR-40 mRNA levels, and higher expression of all selenoproteins. Doxorubicin-FO/Se combination treatment decreased expression of membrane EGFR and FGFR, down-regulated downstream PI3K/AKT/mTOR, MAPK/ERK, and JAK2/c-Src/STAT3 signaling, increased tumor suppressor PTEN/TSC1/TSC2 expression and P53 activation, and suppressed oncogenic transcription factor expression. Dose-dependent inhibition of proliferation index Ki-67, cell cycle, and stem-cell-related markers were observed. Decreased immune check-points PD-L1/CTLA-4/Foxp3/CD86 and increased PD-1/CD28/IL-2 expression was also found. These observations suggest that the nutritional supplements FO/Se increase the chemotherapeutic efficacy of doxorubicin against TNBC by modulating GPR-40 and selenoprotein and targeting multiple signaling pathways in tumor tissues.

Curcumin Alleviates Hyperandrogenism and Promotes Follicular Proliferation in Polycystic Ovary Syndrome Rats: Insights on IRS1/PI3K/GLUT4 and PTEN Modulations.

OBJECTIVE: To explore the effect of curcumin on the insulin receptor substrate 1 (IRS1)/phosphatidylinositol-3-kinase (PI3K)/endometrial expression of glucose 4 (GLUT4) signalling pathway and its regulator, phosphatase and tensin homolog (PTEN), in a rat model of polycystic ovarian syndrome (PCOS). METHODS: PCOS model was induced by letrozole intragastric administration. Sprague-Dawley rats were randomized into 4 groups according to a random number table: (1) control group; (2) PCOS group, which was subjected to PCOS and received vehicle; (3) curcumin group, which was subjected to PCOS and treated with curcumin (200 mg/kg for 2 weeks); and (4) curcumin+LY294002 group, which was subjected to PCOS, and treated with curcumin and LY294002 (a specific PI3K inhibitor). Serum hormone levels (17 ß-estradiol, follicle stimulating hormone, luteinizing hormone, progesterone, and testosterone) were measured by enzyme linked immunosorbent assay, and insulin resistance (IR) was assessed using the homeostasis model assessment of IR. Ovarian tissues were stained with haematoxylin and eosin for pathological and apoptosis examination. Expression levels of key transcriptional regulators and downstream targets, including IRS1, PI3K, protein kinase B (AKT), GLUT4, and PTEN, were measured via reverse transcription polymerase chain reaction and Western blot, respectively. RESULTS: The PCOS group showed impaired ovarian morphology and function. Compared with the PCOS group, curcumin treatment exerted ovarioprotective effects, down-regulated serum testosterone, restored IR, inhibited inflammatory cell infiltration in ovarian tissues, decreased IRS1, PI3K, and AKT expressions, and up-regulated GLUT4 and PTEN expressions in PCOS rats (P<0.05 or P<0.01). In contrast, IRS1, PI3K, AKT, and PTEN expression levels were not significantly different between PCOS and curcumin+LY294002 groups (P>0.05). CONCLUSION: The beneficial effects of curcumin on PCOS rats included the alteration of serum hormone levels and recovery of morphological ovarian lesions, in which, PTEN, a new target, may play a role in regulating the IRS1/PI3K/GLUT4 pathway.

Habitual fish oil supplementation and incident chronic obstructive pulmonary disease: Data from a prospective cohort study.

BACKGROUND: Fish oil is one of the most popular supplements in the UK and other developed countries. However, the relationship between fish oil use and chronic obstructive pulmonary disease (COPD) is unclear. OBJECTIVE: To prospectively examine the association of habitual fish oil supplementation with incident COPD risk and to evaluate potential effect modification by genetic predisposition. METHODS: This study included 484,414 participants (mean and standard deviation [SD] age: 56.5 [8.1] years) from the UK Biobank who completed a touchscreen questionnaire on habitual fish oil supplement use between 2006 and 2010 and were followed up through 2018. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) with adjustment for sociodemographic and lifestyle behaviours, health conditions, and other potential confounding factors. A weighted genetic risk score (GRS) for COPD was derived from 112 validated single nucleotide polymorphisms. RESULTS: During a median follow-up of 9.0 years, 8860 incident COPD events were recorded. A total of 31.4% (152,230) of the study participants reported habitual fish oil supplementation at baseline. Habitual fish oil supplementation was significantly associated with a lower risk of incident COPD (adjusted HR: 0.88; 95% CI: 0.84-0.93). The association with COPD did not differ by GRS strata (P for interaction = 0.880). The results from subgroup and sensitivity analyses supported the robustness of our findings. CONCLUSIONS: Our findings suggest that habitual fish oil supplementation is associated with a lower risk of incident COPD, irrespective of genetic predisposition.

The Effect of Massage Force on Relieving Nonspecific Low Back Pain: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of force applied during massage on relieving nonspecific low back pain (LBP). METHODS: This single-blinded, randomized controlled trial enrolled 56 female patients with nonspecific LBP at a single medical center. For each participant, the therapist performed a 30 min massage session (20 min general massage and 10 min focal massage) using a special instrument with a force sensor inserted, for a total of six sessions in 3 weeks. During the 10 min focal massage, HF and LF groups received high force (HF, ≥2 kg) and low force (LF, ≤1 kg) massage, respectively. The primary outcome was pain intensity (i.e., visual analog scale (VAS), 0-10), and secondary outcomes comprised pain pressure threshold, trunk mobility, LBP-associated disability, and quality of life. RESULTS: No significant between-group differences were observed in baseline characteristics. The HF group exhibited significantly lower VAS than did the LF group, with a mean difference of -1.33 points (95% CI: -2.17 to -0.5) at the end of the intervention, but no significant difference was noted at the end of the follow-up. A significant time effect (p < 0.05) was detected in all secondary outcomes except the pain pressure threshold and trunk mobility. A significant time × group interaction (p < 0.05) was found only for the VAS and pain pressure threshold. CONCLUSIONS: Compared with LF massage, HF massage exerted superior effects on pain relief in female patients with nonspecific LBP at the end of intervention. Applying different levels of force showed no effects on LBP-associated disabilities and quality of life.