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The purpose of this experiment was to investigate the effects of Litsea cubeba essential oil (LCO) on the growth performance, blood antioxidation, immune function, apparent digestibility of nutrients, and fecal microflora in fattening pigs. A total of 120 pigs were randomly assigned to five groups, with six replicate pens per treatment and four pigs per pen, and they were fed basal diet, chlortetracycline (CTC), and low-, medium-, and high-concentration LCO. The results of the study showed that compared with the control treatment and CTC addition treatment of the basic diet, the catalase level in the serum of the pigs treated with 500 mg/kg LCO in the diet of finishing pigs was significantly increased (p < 0.05). The apparent digestibility of crude protein, crude ash, and calcium in pigs with different levels of LCO was significantly increased compared with the control treatments fed the basal diet (p < 0.05). In addition, compared with the control treatment fed the basal diet and the treatment with CTC, the apparent digestibility of ether extract in pigs treated with medium-dose LCO was significantly increased (p < 0.05), and the apparent digestibility of pigs was significantly increased after the addition of low-dose LCO (p < 0.05). Among the genera, the percentage abundance of SMB53 (p < 0.05) was decreased in the feces of the CTC group when compared to that in the medium-LCO group. At the same time, the relative abundance of L7A_E11 was markedly decreased in the feces of the control and medium- and high-concentration LCO group than that in the CTC group (p < 0.05). In conclusion, adding the level of 250 mg/kg LCO in the diet of pig could improve the growth performance and blood physiological and biochemical indicators of pigs, improve the antioxidant level of body and the efficiency of digestion and absorption of nutrients, and show the potential to replace CTC.

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit.Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N = 8, received saline only) or LPS (N = 60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 h by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only; LPS +5, 25, or 100 mg/kg intravenous STC3141 every 8 h (LPS + L, LPS + M, LPS + H, respectively); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 h for 56 h (LPS + D). The animals were observed for 72 h.Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS + H and +D groups had significantly lower circulating histone levels and lung wet-to-dry ratio, and the LPS + D group also had lower BALF histone concentrations; the blood neutrophils and platelets counts in LPS + D group did not change, meanwhile, the LPS + L, +M and +H groups had significantly lower neutrophil counts and higher platelet counts in the blood; the total number of BALF WBC, platelet counts, MPO and H3 were significantly lower in the LPS + L, +M, +H and +D groups than in the LPS only group; and the degree of inflammation was significantly less in the LPS + L, +M, +H and +D groups, moreover, inflammation in the LPS + L, +M and +H animals showed a dose-dependent response; finally, the LPS + L, +M, +H and +D groups had improved oxygenation compared to the LPS group, and there were no statistical differences in PCO2 or pH among groups. All animals survived.Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved acute lung injury and oxygenation.

Gliomas are difficult-to-treat brain tumors due to their aggressive nature, rapid proliferation, and high invasiveness (Zhang et al., J Cell Biochem, 2019, 120 (9), 15106–15118; Ge et al., Int J Biochem Cell Biol, 2021, 139, 106054). FOXD3-AS1 has been identified as an emerging potential target for tumor prediction and treatment in many studies (Qin et al., Front Oncol, 2021, 11, 688027). However, the utility of FOXD3-AS1 has not been reported in glioma patients (Li et al., Cancer Manag Res, 2021, 13, 9037–9048). The differential profiles of FOXD3-AS1 in TCGA–GBMLGG database were analyzed across clinical subgroups. The analysis of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) revealed that a high level of FOXD3-AS1 was associated with a poor prognosis and survival outcome. Based on the Cox regression analysis, FOXD3-AS1 was found to be a high-risk factor for glioma that affects prognosis outcomes independently. More importantly, because oxidative stress is closely linked to glioma prognosis, we focused on the potential mechanisms of six oxidative stress co-expressed genes with FOXD3-AS1. In addition, the predictive value of FOXD3-AS1 was determined for each clinical subgroup status. The ROC curve results showed that FOXD3-AS1 had a good predictive performance. A stratified clinicopathological subgroup analysis revealed that high expression of FOXD3-AS1 is associated with a poor prognosis. This also indicates a link between FOXD3-AS1 and tumorigenesis and prognosis, which has potential application value. Furthermore, the immune cell infiltration of FOXD3-AS1 and the signal marker correlation suggested that immune cell infiltration differed significantly between immune cell subsets. To the best of our knowledge, this is the first report to investigate FOXD3-AS1 in glioma and how it may modulate GBM and LGG immune microenvironments. Furthermore, FOXD3-AS1 was detected in tumor and paraneoplastic tissues using RT–qPCR. Transwell analysis verified the migration and invasion of the FOXD3-AS1 knockout group in vitro to a certain extent. In conclusion, FOXD3-AS1 can be used as a prognostic indicator for GBM and LGG, and it is closely related to immune infiltration and response to oxidative stress, which may contribute to the advancement of glioma immunotherapy research.

As a member of the death-associated protein kinase (DAPK) family, DAP kinase-associated apoptosis-inducing kinase 2 (DRAK2) performs apoptosis-related functions. Compelling evidence suggests that DRAK2 is involved in regulating the activation of T lymphocytes as well as pancreatic β-cell apoptosis in type I diabetes. In addition, DRAK2 has been shown to be involved in the development of related tumor and non-tumor diseases through a variety of mechanisms, including exacerbation of alcoholic fatty liver disease (NAFLD) through SRSF6-associated RNA selective splicing mechanism, regulation of chronic lymphocytic leukemia and acute myeloid leukemia, and progression of colorectal cancer. This review focuses on the structure, function, and upstream pathways of DRAK2 and discusses the potential and challenges associated with the clinical application of DRAK2-based small-molecule inhibitors, with the aim of advancing DRAK2 research.

Metal compounds, especially gold complexes, have recently gained increasing attention as possible lung cancer therapeutics. Some gold complexes display not only excellent activity in cisplatin-sensitive lung cancer but also in cisplatin-resistant lung cancer, revealing promising prospects in the development of novel treatments for lung cancer. This review summarizes examples of anticancer gold(I) and gold (III) complexes for lung cancer treatment, including mechanisms of action and approaches adopted to improve their efficiency. Several excellent examples of gold complexes against lung cancer are highlighted.

Background: This study assessed the effects of esmolol injection in patients with in-hospital cardiac arrest (IHCA) with refractory ventricular fibrillation (VF)/pulseless ventricular tachycardia (pVT).Methods: From January 2018 to December 2021, 29 patients with IHCA with refractory shockable rhythm were retrospectively reviewed. Esmolol was administered after advanced cardiovascular life support (ACLS)-directed procedures, and outcomes were assessed.Results: Among the 29 cases, the rates of sustained return of spontaneous circulation (ROSC), 24-h ROSC, and 72-h ROSC were 79%, 62%, and 59%, respectively. Of those patients, 59% ultimately survived to discharge. Four patients with cardiac insufficiency died. The duration from CA to esmolol infusion was significantly shorter for patients in the survival group (SG) than for patients in the dead group (DG) (12 min, IQR: 8.5–19.5 vs. 23.5 min, IQR: 14.4–27 min; p = 0.013). Of those patients, 76% (22 of 29) started esmolol administration after the second dose of amiodarone. No significant difference was observed in the survival rate between this group and groups administered an esmolol bolus simultaneously or before the second dose of amiodarone (43% vs. 64%, p = 0.403). Of those patients, 31% (9 of 29) were administered an esmolol bolus for defibrillation attempts ≤ 5, while the remaining 69% of patients received an esmolol injection after the fifth defibrillation attempt. No significant differences were observed in the rates of ≥ 24-h ROSC (67% vs. 60%, p = 0.73), ≥ 72-h ROSC (67% vs. 55%, p = 0.56), and survival to hospital discharge (67% vs. 55%, p = 0.56) between the groups administered an esmolol bolus for defibrillation attempts ≤ 5 and defibrillation attempts > 5.Conclusion: IHCA patients with refractory shockable rhythms receiving esmolol bolus exhibited a high chance of sustained ROSC and survival to hospital discharge. Patients with end-stage heart failure tended to have attenuated benefits from beta-blockers. Further large-scale, prospective studies are necessary to determine the effects of esmolol in patients with IHCA with refractory shockable rhythms.

Primary liver cancer (PLC) is one of the most common solid malignancies. However, PLC drug development has been slow, and first-line treatments are still needed; thus, studies exploring and developing alternative strategies for effective PLC treatment are urgently needed. Chinese herbal medicine (CHM) has long been applied in the clinic due to its advantages of low toxicity and targeting of multiple factors and pathways, and it has great potential for the development of novel natural drugs against PLC.Purpose: This review aims to provide an update on the pharmacological mechanisms of Chinese patent medicines (CPMs) and the latest CHM-derived compounds for the treatment of PLC and relevant clinical evaluations.Materials and Methods: A systematic search of English literature databases, Chinese literature, the Clinical Trials Registry Platform, and the Chinese Clinical Trial Registry for studies of CHMs for PLC treatment was performed.Results: In this review, we summarize the clinical trials and mechanisms of CPMs for PLC treatment that have entered the clinic with the approval of the Chinese medicine regulatory authority. These CPMs included Huaier granules, Ganfule granules, Fufang Banmao capsules, Jinlong capsules, Brucea javanica oil emulsions, and compound kushen injections. We also summarize the latest in vivo, in vitro, and clinical studies of CHM-derived compounds against PLC: icaritin and ginsenoside Rg3. Dilemmas facing the development of CHMs, such as drug toxicity and low oral availability, and future developments are also discussed.Conclusion: This review provides a deeper the understanding of CHMs as PLC treatments and provides ideas for the development of new natural drugs against PLC.

Metformin is a first-line anti-diabetic agent with a powerful hypoglycemic effect. Several studies have reported that metformin can improve the prognosis of stroke patients and that this effect is independent of its hypoglycemic effect; however, the specific mechanism remains unclear. In this research, we explored the effect and specific mechanism of metformin in cerebral ischemia-reperfusion (I/R) injury by constructing a transient middle cerebral artery occlusion model in vivo and a glucose and oxygen deprivation/reoxygenation (OGD/R) model in vitro. The results of the in vivo experiments showed that acute treatment with low-dose metformin (10 mg/kg) ameliorated cerebral edema, reduced the cerebral infarction volume, improved the neurological deficit score, and ameliorated neuronal apoptosis in the ischemic penumbra. Moreover, metformin up-regulated the brain-derived neurotrophic factor (BDNF) expression and increased phosphorylation levels of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB) in the ischemia penumbra. Nevertheless, the above-mentioned effects of metformin were reversed by Compound C. The results of the in vitro experiments showed that low metformin concentrations (20 μM) could reduce apoptosis of human umbilical vein endothelial cells (HUVECs) under OGD/R conditions and promote cell proliferation. Moreover, metformin could further promote BDNF expression and release in HUVECs under OGD/R conditions via the AMPK/CREB pathway. The Transwell chamber assay showed that HUVECs treated with metformin could reduce apoptosis of SH-SY5Y cells under OGD/R conditions and this effect could be partially reversed by transfection of BDNF siRNA in HUVECs. In summary, our results suggest that metformin upregulates the level of BDNF in the cerebral ischemic penumbra via the AMPK/CREB pathway, thereby playing a protective effect in cerebral I/R injury.

Preliminary clinical and basic researches have proved that Qishen granule (QSG) is an effective prescription for treating heart failure (HF) in China, with a characteristic of regulating the ratio of M1/M2 macrophage in the myocardium. However, the regulative mechanism of monocytes targeting the cardio-splenic axis has not been fully elucidated. This study aimed to investigate the effects and mechanism of QSG inhibiting the release of splenic monocytes and the recruitment of myocardial tissue both in vivo and in vitro. Experiments in mice with acute myocardial infarction (AMI)-induced HF demonstrated that QSG could exert anti-inflammatory effects by inhibiting splenic monocytes release and phenotypic changes. Moreover, in vitro experiments indicated QSG could inhibit LPS-stimulated macrophage-conditioned medium (CM)-induced H9C2 cardiomyocyte injury by upregulating the key proteins in TLR4-MyD88-NF-κB p65 pathway. In addition, knockdown or overexpression of TLR4 in H9C2 cells further confirmed that QSG could attenuate inflammatory injury in cardiomyocytes via the TLR4-MyD88-NF-κB p65 pathway. Overall, these data suggested that QSG could improve cardiac function and reduce the inflammatory response in AMI-induced HF by inhibiting splenic monocytes release, and protecting myocardial function via the TLR4-MyD88-NF-κB pathway in heart failure mice.

Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway.Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining.Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor.Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.

Aim: Inflammation and fibrosis have been shown to be critical factors in heart failure (HF) progression. Calycosin (Cal) is the major active component of Astragalus mongholicus Bunge and has been reported to have therapeutic effects on the cardiac dysfunction after myocardial infarction. However, whether Cal could ameliorate myocardial infarction (MI)-induced inflammation and fibrosis and precise mechanisms remain uncertain. The aim of this study is to explore the role of Cal in HF and to clarify the underlying mechanisms.Methods: For in vivo experiments, rats underwent left anterior descending artery ligation for heart failure model, and the cardioprotective effects of Cal were measured by echocardiographic assessment and histological examination. RNA-seq approach was applied to explore potential differential genes and pathways. For further mechanistic study, proinflammatory-conditioned media (conditioned media)-induced H9C2 cell injury model and TGFβ-stimulated cardiac fibroblast model were applied to determine the regulatory mechanisms of Cal.Results: In the in vivo experiments, echocardiography results showed that Cal significantly improved heart function. GO and reactome enrichment revealed that inflammation and fibrosis pathways are involved in the Cal-treated group. KEGG enrichment indicated that the PI3K–AKT pathway is enriched in the Cal-treated group. Further experiments proved that Cal alleviated cardiomyocyte inflammatory responses evidenced by downregulating the expressions of phosphorylated IκB kinase α/β (p-IKKα/β), phosphorylated nuclear factor kapa B (p-NFκB), and tumor necrosis factor α (TNFα). Besides, Cal effectively attenuated cardiac fibrosis through the inhibitions of expressions and depositions of collagen I and collagen III. In the in vitro experiments, the phosphatidylinositol three kinase (PI3K) inhibitor LY294002 could abrogate the anti-inflammation and antifibrosis therapeutic effects of Cal, demonstrating that the cardioprotective effects of Cal were mediated through upregulations of PI3K and serine/threonine kinase (AKT).Conclusion: Cal inhibited inflammation and fibrosis via activation of the PI3K–AKT pathway in H9C2 cells, fibroblasts, and heart failure in postacute myocardial infarction rats.

Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, has life-threatening cardiotoxicity. Therefore, searching cardioprotective drugs for DOX-induced cardiotoxicity (DIC) is urgently needed.Objectives: This study aimed to explore cardioprotective effect and specific mechanism by which Ferruginol (FGL) attenuated DIC in vivo and in vitro.Methods: We evaluated the cardioprotection of FGL and performed high-throughput RNA-Seq on a DIC mouse. Whereafter, multiple methods, including western blot, RT-qPCR, a transmission electron microscope, CO-IP, immunofluorescence, and other staining methods, and antagonist of SIRT1 and PGC-1α were utilized to confirm the cardioprotection and molecular mechanism of FGL.Results: FGL-exerted cardioprotection manifested as enhanced cardiac function and reduced structural damage and apoptosis. The transcriptome and other results revealed that FGL facilitated PGC-1α-mediated mitochondrial biogenesis and fatty acid oxidation (MB and FAO) by increasing the expression of PGC-1α and concurrently promoting the expression of SIRT1-enhancing deacetylase SIRT1 deacetylating and activating PGC-1α.Conclusions: These results documented that FGL exerted cardioprotective effects restoring MB&FAO via the SIRT1–PGC-1α axis.

The tumor-associated macrophage (TAM) serves as an immunosuppressive agent in the malignant tumor microenvironment, facilitating the development and metastasis of lung cancer. The photodynamic effect destabilizes cellular homeostasis owing to the generation of reactive oxygen species (ROS), resulting in the enhanced pro-inflammatory function of immunocytes. In our previous study, the Ce6-mediated photodynamic effect was found to have kept the viability of macrophages and to remodel them into the M1 phenotype. However, the mechanism remains unrevealed. The present study now explores the mechanism of photodynamic therapy (PDT)-mediated reprogramming of macrophages. As expected, Ce6-mediated PDT was capable of generating reactive oxygen species, which was continuously degraded, causing “low intensity” damage to DNA and thereby triggering subsequent DNA damage response in macrophages. The autophagy was thus observed in Ce6-treated macrophages and was shown to protect cells from being photodynamically apoptotic. More importantly, Ce6 PDT could activate the stimulator of interferon genes (STING) molecule, a sensor of DNA damage, which could activate the downstream nuclear factor kappa-B (NF-κB) upon activation, mediating the polarization of macrophages towards the M1 phenotype thereupon. In addition, inhibition of ROS induced by PDT attenuated the DNA damage, STING activation, and M1-phenotype reprogramming. Furthermore, the silence of the STING weakened Ce6 treatment-mediated M1 remodeling of macrophages as well. Altogether, these findings indicate the Ce6-induced photodynamic effect polarizes macrophages into an M1 phenotype through oxidative DNA damage and subsequent activation of the STING. This work reveals the crucial mechanism by which photodynamic therapy regulates the macrophage phenotype and also provides a novel intervenable signaling target for remodeling macrophages into the M1 phenotype.