Evolutionary insights and functional diversity of gasdermin family proteins and homologs in microorganisms.

The gasdermin protein family and its homologs in microorganisms have gained significant attention due to their roles in programmed cell death, immune defense, and microbial infection. This review summarizes the current research status of gasdermin proteins, their structural features, and functional roles in fungi, bacteria, and viruses. The review presents evolutionary parallels between mammalian and microbial defense systems, highlighting the conserved role of gasdermin proteins in regulating cell death processes and immunity. Additionally, the structural and functional characteristics of gasdermin homologs in microorganisms are summarized, shedding light on their potential as targets for therapeutic interventions. Future research directions in this field are also discussed to provide a roadmap for further investigation.

Picornavirus 2C proteins: structure-function relationships and interactions with host factors.

Picornaviruses, which are positive-stranded, non-enveloped RNA viruses, are known to infect people and animals with a broad spectrum of diseases. Among the nonstructural proteins in picornaviruses, 2C proteins are highly conserved and exhibit multiple structural domains, including amphipathic α-helices, an ATPase structural domain, and a zinc finger structural domain. This review offers a comprehensive overview of the functional structures of picornaviruses' 2C protein. We summarize the mechanisms by which the 2C protein enhances viral replication. 2C protein interacts with various host factors to form the replication complex, ultimately promoting viral replication. We review the mechanisms through which picornaviruses' 2C proteins interact with the NF-κB, RIG-I, MDA5, NOD2, and IFN pathways, contributing to the evasion of the antiviral innate immune response. Additionally, we provide an overview of broad-spectrum antiviral drugs for treating various enterovirus infections, such as guanidine hydrochloride, fluoxetine, and dibucaine derivatives. These drugs may exert their inhibitory effects on viral infections by targeting interactions with 2C proteins. The review underscores the need for further research to elucidate the precise mechanisms of action of 2C proteins and to identify additional host factors for potential therapeutic intervention. Overall, this review contributes to a deeper understanding of picornaviruses and offers insights into the antiviral strategies against these significant viral pathogens.

Delta radiomics analysis for prediction of intermediary- and high-risk factors for patients with locally advanced cervical cancer receiving neoadjuvant therapy.

This study aimed to assess the feasibility of using magnetic resonance imaging (MRI)-based Delta radiomics characteristics extrapolated from the Ax LAVA + C series to identify intermediary- and high-risk factors in patients with cervical cancer undergoing surgery following neoadjuvant chemoradiotherapy. A total of 157 patients were divided into two groups: those without any intermediary- or high-risk factors and those with one intermediary-risk factor (negative group; n = 75). Those with any high-risk factor or more than one intermediary-risk factor (positive group; n = 82). Radiomics characteristics were extracted using Ax-LAVA + C MRI sequences. The data was divided into training (n = 126) and test (n = 31) sets in an 8:2 ratio. The training set data features were selected using the Mann-Whitney U test and the Least Absolute Shrinkage and Selection Operator (LASSO) test. The best radiomics features were then analyzed to build a preoperative predictive radiomics model for predicting intermediary- and high-risk factors in cervical cancer. Three models-the clinical model, the radiomics model, and the combined clinic and radiomics model-were developed in this study utilizing the random forest Algorithm. The receiver operating characteristic (ROC) curve, decision curve analysis (DCA), accuracy, sensitivity, and specificity were used to assess the predictive efficacy and clinical benefits of each model. Three models were developed in this study to predict intermediary- and high-risk variables associated with postoperative pathology for patients who underwent surgery after receiving neoadjuvant radiation. In the training and test sets, the AUC values assessed using the clinical model, radiomics model, and combined clinical and radiomics models were 0.76 and 0.70, 0.88 and 0.86, and 0.91 and 0.89, respectively. The use of machine learning algorithms to analyze Delta Ax LAVA + C MRI radiomics features can aid in the prediction of intermediary- and high-risk factors in patients with cervical cancer receiving neoadjuvant therapy.

Lagopsis supina ameliorates myocardial ischemia injury by regulating angiogenesis, thrombosis, inflammation, and energy metabolism through VEGF, ROS and HMGB1 signaling pathways in rats.

BACKGROUND: Lagopsis supina (Steph. ex. Willd.) Ikonn.-Gal. is an important traditional Chinese medicine used to treat various ailments. However, its impact on myocardial ischemia (MI) injury remains unknown. PURPOSE: This research aimed to reveal the therapeutic effect, potential mechanism, and metabolomics of L. supina against MI injury in rats. METHODS: The therapeutic effects of the ethanolic extract of L. supina (LS) and its four fractions (LSA∼D) on a left anterior descending (LAD) artery occlusion-induced MI model rat were explored. The pharmacodynamics including myocardial infraction area, myocardial tissue pathology and apoptosis, and serum biochemical parameters (CK, CK-MB, CTn-T, SOD, ET-1, NO, eNOS, VEGF, TXB2, 6-keto-PGF1α, TNF-α, IL-6, and CRP) were evaluated. The 24 related protein expressions were detected using western blotting assay. Simultaneously, the qualitative and quantitative analyses of microporous adsorption resin with 30% (LSC) and 60% (LSD) aqueous ethanol fractions were performed using UHPLC-MS and HPLC. Moreover, the serum metabolomics analysis of rats was profiled using UHPLC-MS. RESULTS: LS exerted remarkable alleviating effect on MI in rats. Importantly, LSC and LSD, two effective fractions of LS, significantly reduced myocardial infraction area, alleviated myocardial tissue pathology and apoptosis, regulated serum biochemical parameters. Furthermore, LSC and LSD markedly up-regulated the levels of VEGF-A, VEGFR-2, PKC, Bcl-2, Nrf2, HO-1, and thrombin, as well as prominently down-regulated the protein expression of Notch 1, p-PI3K, p-PI3K/PI3K, p-Akt, p-Akt/Akt, Bax, cleaved-caspase-3, cleaved-caspase-3/caspase-3, vWF, p-Erk, p-Erk/Erk, HMGB1, p-p38, p-p38/p38, p-p65, and p-p65/p65. A total of 26 candidate biomarkers were significantly regulated by LSC and LSD and they are mainly involved in amino acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. Finally, phenylethanols and flavonoids may be major bio-constituents of LSC and LSD against MI. CONCLUSIONS: This work, for the first time, demonstrated that L. supina had a significant therapeutic effect on MI in rats. Additionally, LSC and LSD, two bio-fractions from L. supina, exerted their potential to ameliorate MI injury by promoting angiogenesis, inhibiting thrombosis, blocking inflammation, and facilitating energy metabolism through promotion of VEGF pathway, as well as suppression of ROS and HMGB1 pathways in rats. These findings suggest that LSC and LSD hold promise as potential therapeutic agents for MI injury in clinical application.

Nomogram for prognosis of elderly patients with cervical cancer who receive combined radiotherapy.

This retrospective study identified prognostic factors to help guide the clinical treatment of elderly patients (≥ 65 years) with cervical cancer who had undergone radiotherapy. A personalized model to predict 3- and 5-years survival was developed. A review was conducted of 367 elderly women with cervical cancer (staged II-III) who had undergone radiotherapy in our hospital between January 2012 and December 2016. The Cox proportional hazards regression model was used for survival analysis that considered age, hemoglobin, squamous cell carcinoma antigen, pathologic type, stage, pelvic lymph node metastasis status, and others. A nomogram was constructed to predict the survival rates. The median follow-up time was 71 months (4-118 months). The 3- (5-) years overall, progression-free, local recurrence-free, and distant metastasis-free survival rates were, respectively, 91.0% (84.4%), 92.3% (85.9%), 99.18% (99.01%), and 99.18% (97.82%). The following were significant independent prognostic factors for overall survival: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The C-index of the line chart was 0.699 (95% CI 0.652-0.746). The areas under the receiver operating characteristic curves for 3- and 5-years survival were 0.751 and 0.724. The nomogram was in good concordance with the actual survival rates. The independent prognostic factors for overall survival in elderly patients with cervical cancer after radiotherapy were: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The novel prognostic nomogram based on these factors showed good concordance with the actual survival rates and can be used to guide personalized clinical treatment.

Revealing the Active Constituents and Mechanisms of Semiliquidambar cathayensis Chang Roots against Rheumatoid Arthritis through Network Pharmacology, Molecular Docking, and in Vivo Experiment.

Semiliquidambar cathayensis Chang roots (SC) are traditional Chinese medicine for treating rheumatoid arthritis (RA). However, the effect and potential mechanism of SC remain unclear. This study aims to reveal the anti-RA constituents and mechanisms of SC based on network pharmacology, molecular docking, and adjuvant-induced arthritis (AIA) model rat experiment. In this work, 9 potential active constituents, including kaempferol, quercetin, naringenin, paeoniflorin, catechin, fraxin, gentianin, hesperetin, and ellagic acid 3,3',4-trimethyl ether, in SC crossed 65 target genes of RA. In addition, 28 core targets were enriched in inflammation and others, among which interleukin-17 (IL-17) and tumor necrosis factor (TNF) were the major targets. The binding of bio-constituents with IL-17 and TNF were performed using molecular docking. Rat experiment demonstrated that the extract of SC restored body weight loss, reduced arthritis score and the indices of thymus and spleen, alleviated ankle joint histopathology, decreased the levels of rheumatoid factor (RF), C-reactive protein (CRP), IL-17, TNF-α, IL-1ß, IL-6, cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and matrix metalloproteinase-2 (MMP-2), whereas elevated the levels of IL-4 and IL-10. Collectively, it was the first time to comprehensively reveal the anti-RA efficacy and mechanism of SC via suppressing the inflammatory pathway based on network pharmacology, molecular docking, and experimental verification, which provide chemical and pharmacological evidences for the clinical application of SC.

The therapeutic effects of Lagopsis supina (Steph. ex Willd.) Ikonn.-Gal. fractions in trauma-induced blood stasis model rats.

Background: Lagopsis supina (Steph. ex Willd.) Ikonn.-Gal. has been a traditional Chinese medicine (TCM) for the treatment of blood stasis, inflammation, and diuresis. Moreover, Huo Xue Li Shui theory was an important TCM theory that used to treat many ailments. Nevertheless, the scientific connotation of this theory has not been clearly elucidated so far. Aim of the study: The aim of this study was to explore the scientific connotation of Huo Xue Li Shui with promoting blood circulation and removing blood stasis (PBCRBS), anti-inflammatory and diuretic effects in trauma-induced blood stasis model (TBSM) rats, taking microporous adsorption resin with water (LSB) and 30% ethanol (LSC) elution fractions from L. supina as a classical demonstration. Materials and methods: 48 rats were randomly assigned into six groups (n = 8/group): the control group, the model group, and model groups treatment with LSB or LSC. The biochemical parameters and protein expression were measured using kit method and Western blot assay, respectively. Results: Both LSB and LSC were effective in elevating body weight, food consumption, and water intake in model rats. In PBCRBS efficacy evaluation, LSB and LSC remarkably improved histopathological tissues. On the other hand, LSB and LSC prominently decreased the contents of plasma viscosity, platelet aggregation rate, thrombin time, prothrombin time, activated partial thromboplastin time (APTT), fibrinogen, thromboxane B2, thromboxane B2/6-keto-prostaglandin F1α, urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor-1(PAI-1), PAI-1/tissue-type plasminogen activator (t-PA), and PAI-1/u-PA, while significantly enhanced the contents of antithrombin III, 6-keto-prostaglandin F1α, and t-PA. In parallel, LSB and LSC obviously down-regulated the levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8, and remarkably up-regulated the level of IL-10. In determining diuretic activities, LSB and LSC prominently elevated urinary excretion volume and the level of atriopeptin, and remarkably reduced the levels of angiotensin II, anti-diuretic hormone, aldosterone, aquaporin 1 (AQP1), AQP2, and AQP3. In addition, LSB and LSC clearly suppressed protein expressions of AQP1, AQP2, and AQP3. Finally, LSB and LSC did not caused urinary pH, Na+, and Cl- electrolytes and had minor effects on K+ and Ca2+ concentrations. Conclusions: LSB and LSC exhibited prominent PBCRBS, anti-inflammatory, and diuretic effects in TBSM rats, thereby supported the traditional folk use of L. supina. This study successfully provided an experimental basis for the scientific connotation of Huo Xue Li Shui.

Natural phenylethanoid glycosides diuretics derived from Lagopsis supina: Biological activity, mechanism, molecular docking, and structure-activity relationship.

Aquaporins (AQPs) and vasopressin type 2 receptor (V2R) play a crucial role in urine excretion and are widely used to explore novel diuretics. In this study, three phenylpropanoids including stachysoside A (L1), acteoside (L2), and glucopyranosyl (1 â†’ 6) martynoside (L3) were isolated from Lagopsis supina (Steph. ex Willd.) lk. -Gal. ex Knorr. Their diuretic activity, mechanism, molecular docking, and structure-activity relationships were explored. The results suggest that L1, L2, and L3 exhibit acute (6 h) and prolonged (6 d) activities including increased urinary excretion volume, diuretic action, and diuretic activity, without affecting the urinary pH and minor altering the electrolyte balance in saline-loaded rats. Further, L1, L2, and L3 significantly reduced the levels of angiotensin II (Ang II), anti-diuretic hormone (ADH), and aldosterone (ALD), AQPs 1-4 and 7, and V2R, and remarkably elevated the atriopeptin (ANP) level. Besides, L1, L2, and L3 obviously suppressed mRNA and protein levels of AQPs 1-4 and 7, and V2R. The hypothetical binding modes of L1, L2, and L3 with these proteins were determined by molecular docking, and a tight structure-activity relationship was also proposed. Collectively, L1, L2, and L3 represent three natively novel phenylethanoid glycoside diuretics, which inhibit AQP and V2R-mediated molecular mechanisms. They are superior to furosemide as long-term diuretics.

Kaempferol 3-O-(2G-glucosylrutinoside)-7-O-glucoside isolated from the flowers of Hosta plantaginea exerts anti-inflammatory activity via suppression of NF-κB, MAPKs and Akt pathways in RAW 264.7 cells.

Kaempferol 3-O-(2G-glucosylrutinoside)-7-O-glucoside (KGG) has isolated from Hosta plantaginea flowers and possessed an inhibitory effect on cyclooxygenase 2 (COX-2), could be effective in inhibiting inflammation. However, the anti-inflammatory activity and mechanism of KGG remain unknown. In this study, for the first time, the anti-inflammatory effect of KGG and its potential molecular mechanisms were explored in cells. KGG had no cytotoxicity at concentrations of 1.25, 2.5, 5, 10, 20, and 40 µM by Cell Counting kit-8 assay in RAW 264.7 cells. Besides, KGG concentration-dependently (1.25, 2.5, and 5 µM) inhibited secretions of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Western blot showed that the phosphorylation of nuclear factor kappa-B (NF-κB) p65, inhibitor of NF-κB (IκB), p38 MAPK, c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (Erk), and protein kinase B (Akt), together with inducible nitric oxide synthase (iNOS) and COX-2 were significantly attenuated by KGG (1.25, 2.5, and 5 µM) in a concentration-dependent relationship. Meanwhile, KGG remarkably enhanced the protein expression of IκB. Taken together, KGG may be one of bioactive phytochemicals from H. plantaginea flowers, and be an anti-inflammatory agent via inhibiting NF-κB, mitogen-activated protein kinases (MAPKs), and Akt signaling pathways.

Prognostic value of tumor measurement parameters and SCC-Ag changes in patients with locally-advanced cervical cancer.

OBJECTIVE: To investigate the prognostic relevance of specific measurement parameters such as tumor diameter, tumor volume, tumor volume reduction rate (TVRR), and changes in the squamous cell carcinoma antigen (SCC-Ag) level in patients with locally-advanced cervical cancer (LACC) undergoing concurrent radiotherapy and chemotherapy. METHODS: This was a retrospective study of 203 patients with stage IIA-IVA cervical squamous cell carcinoma who were newly diagnosed at our hospital between January 2011 and March 2015. Clinical data and pre-and post-treatment imaging information were collected and each parameter was calculated using 3DSlicer software. The pre/post-treatment tumor diameter (TDpre/post), tumor volume (TVpre/post), SCC-Ag (SCCpre/post), and TVRR, SCC-Ag reduction rate (SCCRR) were analyzed and their prognostic relevance evaluated. RESULTS: The median follow-up was 69 months. The 5-year overall survival (OS) and disease progression-free survival (PFS) rates were 69.5% and 64.5%, respectively. On univariate analysis, TDpre/post, TVpre/post, TVRR, SCCpre/post and SCCRR showed significant association with OS and PFS (P < 0.05). On multivariate analysis, TDpre [Hazard ratio (HR) = 0.373, P = 0.028], TDpost (HR = 0.376, P = 0.003) and SCCpost (HR = 0.374, P = 0.001) were independent predictors of OS. TVRR (HR = 2.998, P < 0.001), SCCpre (HR = 0.563, P = 0.041), and SCCpost (HR = 0.253, P < 0.001) were independent predictors of PFS. Tumor measurement parameters showed a positive correlation with SCC-Ag (P < 0.05). CONCLUSION: TDpre/post, TVpre/post, TVRR, SCCpre/post, and SCCRR were prognostic factors in LACC. TDpre/post and SCCpost showed the most significant prognostic value. TVRR and SCCpre/post were closely related to disease progression. Further studies should investigate the correlation between measurement parameters of tumor and SCC-Ag.