To explore the protective function and mechanism of notoginsenoside Rb1 against hypoxia hypercapnia-induced pulmonary vasoconstriction (HHPV).The pulmonary artery smooth muscle cells of healthy male SD rats were primarily cultured and the second to the fifth subcultured cells were incubated with 8, 40, and 100 mg/L notoginsenoside Rb1 respectively under the hypoxia-hypercapnia condition (1% O2 and 6% CO2). The cells were harvested for 24 h. The phosphated extracellular signal-regulated kinase (p-ERK) protein expression of the cells was detected by Western blot. The mRNA expressions of ERK1 and ERK2 were detected using half quantitative reverse transcription polymerase chain reaction (RT-PCR).The expression of p-ERK protein, the mRNA expressions of ERK1 and ERK2 were weakly positive in the control group. Their expressions in the hypoxia-hypercapnia group were obviously enhanced (P < 0.01). After intervention of Rb1 at different concentrations, their expressions were obviously lowered (P < 0.05, P < 0.01) in a dose-dependent manner. The optimal effects were obtained at the dose of 100 mg/L. The expression of p-ERK protein was significantly positively correlated with mRNA expressions of ERK1 and ERK2 in notoginsenoside Rbl-treated groups (r = 0.500, P < 0.01; r = 0.977, P < 0.01).ERK1/2 pathway might play a role in the rat HHPV. Notoginsenoside Rb, could alleviate HHPV by inhibiting the ERK1/2 pathway.
Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.
Objective. We conducted a meticulous bioinformatics analysis leveraging expression data of 226 PANRGs obtained from previous studies, as well as clinical data from AML patients derived from the HOVON database. Methods. Through meticulous data analysis and manipulation, we were able to categorize AML cases into two distinct PANRG clusters and subsequently identify differentially expressed genes (PRDEGs) with prognostic significance. Furthermore, we organized the patient data into two corresponding gene clusters, allowing us to investigate the intricate relationship between the risk score, patient prognosis, and the immune landscape. Results. Our findings disclosed significant associations between the identified PANRGs, gene clusters, patient survival, immune system, and cancer-related biological processes and pathways. Importantly, we successfully constructed a prognostic signature comprising nineteen genes, enabling the stratification of patients into high-risk and low-risk groups based on individually calculated risk scores. Furthermore, we developed a robust and practical nomogram model, integrating the risk score and other pertinent clinical features, to facilitate accurate patient survival prediction. Our comprehensive analysis demonstrated that the high-risk group exhibited notably worse prognosis, with the risk score proving to be significantly correlated with infiltration of most immune cells. The qRT-PCR results revealed significant differential expression patterns of LGR5 and VSIG4 in normal and human leukemia cell lines (HL-60 and MV-4-11). Conclusions. Our findings underscore the potential utility of PANoptosis-based molecular clustering and prognostic signatures as predictive tools for assessing patient survival in AML.
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arteriolar resistance. Pulmonary vasoconstriction has been proved to play a significant role in PAH. We previously reported that Panax notoginseng saponins (PNS) might attenuate hypoxia and hypercapnia-induced pulmonary vasoconstriction (HHPV).In the present study, our specific objective was to investigate the role of ginsenoside Rg1, a major component of PNS, in this process and the possible underlying mechanism. The second order pulmonary rings isolated from the Sprague-Dawley rats were treated with different dosage of ginsenoside Rg1 at 8, 40, or 100 mg/L respectively, both before and during the conditions of hypoxia and hypercapnia. Contractile force changes of the rings were detected. Furthermore, SB203580, the selective inhibitor for p38 activation was applied to the rings. Pulmonary arterial smooth muscle cells (PASMCs) were cultured under hypoxic and hypercapnic conditions, and ginsenoside Rg1 was administered to detect the changes induced by p38.Under the hypoxic and hypercapnic conditions, we observed a biphasic pulmonary artery contractile response to the second pulmonary artery rings. It is hypothesized that the observed attenuation of vasoconstriction and the production of vasodilation could have been induced by ginsenoside Rg1. This effect was significantly reinforced by SB203580 (P<0.05 or P<0.01). The expression of p38 in the PASMCs under hypoxic and hypercapnic conditions was significantly activated (P<0.05 or P<0.01) and the observed activation was attenuated by ginsenoside Rg1 (P<0.05 or P<0.01).Our findings strongly support the significant role of ginsenoside Rg1 in the inhibition of hypoxia and hypercapnia-induced vasoconstriction by the p38 pathway.
Lung tissue is very sensitive to ischemia and reperfusion, and the injury mainly manifests as follows., increase in microvascular permeability resistance, with formation of and pulmonary capillary microthrombus and tissue edema, and disordered gas exchange. A number of studies showes that, apoptosis is involved in the pathophysiological mechanism of lung ischemia/reperfusion injury （LIRI）, and the intervention of apoptosis plays an obvious role in lung injury.
Key words:
lung; reperfusion injury; apoptosis; L-arginine
Acute myeloid leukemia (AML) is a common hematopoietic malignancy with invasive activity. Drug resistance greatly contributes to the poor efficacy of chemotherapy in AML treatment. Recent research indicates that long non-coding RNAs (LncRNAs) regulates chemotherapy resistance in malignancy. Microarray analysis was used to screen out AML related genes, and interaction between small nucleolar RNA host gene 5(SNHG5) and miR-32, as well as that between miR-32 and DNAJB9. Quantitative real-time PCR (qRT-PCR) and In situ hybridization(ISH) were used to determine the expression levels of SNHG5, miR-32 and DNAJB9 mRNA in AML cell lines and clinic samples. Western blot was performed to detect protein expression levels. After being treated with varying concentrations of Adriamycin(ADM), cell viability was evaluated using a cell counting kit-8(CCK8). We carried out a genome-wide LncRNA expression study and found SNHG5 aberrantly overexpressed in AML comparing to the donors. Knock-down of SNHG5 promoted sensitivity of AML cells to chemotherapy. In addition, miR-32 was identified as the downstream target of SNHG5 and miR-32 inhibitor abrogated the inhibiting effects of downregulated SNHG5 on AML cell viability. Furthermore, inhibited SNHG5 decreased DNAJB9 expression levels by sponging miR-32. The SNHG5/miR-32/DNAJB9 axis targeted autophagy to regulate chemotherapy resistance. SHNG5 regulates chemotherapy resistance by targeting the miR-32/DNAJB9 axis in acute myeloid leukemia, which provided a novel potential target for AML and revealed an important mechanism of chemotherapy resistance.
The aim of the present study was to investigate whether metallothionein was involved in the protection of lung ischemic preconditioning (IP) against lung ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were randomly divided into 3 groups based upon the intervention (n=8): control group (C), lung I/R group (I/R), lung I/R+IP group (IP). At the end of the experiment, the content of metallothionein was tested in lung tissue. Blood specimens collected from the arteria carotis were tested for the contents of malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and myeloperoxidase (MPO). The pneumocyte apoptosis index (AI) was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL). Ultrastructural changes of lung tissue were observed by using transmission electron microscope. The results showed that in I/R group, the content of metallothionein was decreased (P<0.05), the content of MDA and MPO activity were increased (P<0.01), and SOD activity was decreased (P<0.01), compared with those in control group. IP treatment significantly increased the content of metallothionein (P<0.01), attenuated the MDA level (P<0.05) and MPO activity (P<0.01), and improved SOD activity (P<0.01) in blood serum. The number of TUNEL-positive cells in IP group was significantly reduced compared with that in I/R group (P<0.01). There were abnormal ultrastructural changes in I/R group, which were markedly reversed in IP group. In conclusion, IP may protect lung against I/R injury by inducing the expression of metallothionein.
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