Clinical features and outcomes of patients with acute myeloid leukemia: the single-center experience of 668 patients in China.

OBJECTIVE: To investigate efficacy and prognostic factors in the treatment of adult newly-diagnosed acute myeloid leukemia (AML) with or without allogeneic hematopoietic stem cell transplantation (Allo-HSCT). METHODS: We retrospectively analyzed 668 patients with newly-diagnosed AML (non-M3 type) in the Department of Hematology at Shanghai Changhai Hospital from January 2012 to December 2021. Based on different induction chemotherapy regimens, patients were categorized into an IA (idarubicin, IDA + cytarabine, Ara-C) (3 + 7, regimen) group (n = 303) and a DA (daunorubicin, DNR + cytarabine, Ara-C) (3 + 7, regimen) group (n = 365) with or without allo-HSCT. Minimal residual disease (MRD), complete response (CR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse effects (AE) were analyzed and compared. Characteristics significantly associated with overall or progression-free survival (OS or PFS) upon univariate analysis were subsequently included in a Cox proportional hazard model. RESULTS: This study used data from 668 AML patients. After induction therapy, the CR rate in the IA group was 70.63% and ORR was 79.87%, which were significantly higher than those in the DA group (with a CR rate of 56.99% and an ORR of 70.14%) (P = 0.0002 and P = 0.0035, respectively). There were no significant differences in drug safety between the two chemotherapy regimens used in IA and DA (P > 0.05). The recurrence rate was lower in patients with an MRD < 0.001 than in patients with an MRD ≥ 0.001. A continuous negative MRD during the period is significant because it is associated with prolonged OS and PFS of AML patients. Data from 100 patients in the two groups who underwent allo-HSCT were analyzed using univariate analysis and the Cox proportional hazards model. From the multivariate analysis, MRD was found to be the only independent predictor of OS (P = 0.042; HR 1; 95%CI 0.00-0.76). CONCLUSION: In the treatment of adult AML patients, IA regimen is associated with a high CR rate and ORR rate and does not increase treatment-related toxicity. IA regimen prolongs OS and PFS in AML patients and reduces the likelihood of leukemia cells' subsequent infiltration into the central nervous system. There is a high correlation between the level of MRD after treatment and the patient's bone marrow recurrence. To obtain superior treatment effects for patients undergoing allo-HSCT, the MRD should be reduced to less than 0.001 before pretreatment. A negative MRD before allo-HSCT can prolong OS in patients with AML. We examined the clinical characteristics and outcomes of AML patients in China, finding novel information on prognostic factors and primary treatment of AML that may be applicable in routine clinical practice.

N6-Methyladenosine RNA Methylation in Cardiovascular Diseases.

N6-methyladenosine (m6A) modification is the most universal and abundant post-transcriptional modification of eukaryotic RNA and occurs mainly at the consensus motif RR (m6A) CH (R = A or G, H = A, C, or U) in long internal exons, near stop codons, or in the 3' untranslated region (UTR). "Writers," "erasers," and "readers" are responsible for the occurrence, removal, and recognition of m6A modification, respectively. Substantial evidence has shown that m6A RNA modification can exert important functions in physiological and pathological processes. Cardiovascular diseases (CVDs) are a wide array of disorders affecting heart or vessels, including atherosclerosis (AS), hypertension (HT), ischemia/reperfusion (I/R) injury, myocardial infarction (MI), stroke, cardiac hypertrophy, heart failure (HF), and so on. Despite the advances in lipid-lowering drugs, antihypertensives, antiplatelet agents, and anticoagulation therapy, CVDs are still the leading cause of death worldwide. Recent studies have suggested that m6A modification of RNA may contribute to the pathogenesis of CVDs, providing a novel research insight for CVDs. Herein, we provide an up-of-date summarization of the molecular mechanism of m6A and the roles of m6A in different types of CVDs. At last, we propose that m6A might be a potiential biomarker or therapeutic target for CVDs.

Autophagy in skin barrier and immune-related skin diseases.

Autophagy is a process which is highly conserved in eukaryotes to degrade or recycle cytoplasmic components through lysosomes to maintain cellular homeostasis. Recent studies have shown that autophagy also plays critical roles in cell apoptosis, inflammation, pathogen clearance, and so on under stressed conditions and thereby has been linked to a variety of human disorders. The skin is the largest organ of the body and serves as the first line of defense against environmental insult. Skin as a nutrient-poor environment requires recycling of limited resources via the autophagy machinery to maintain homeostasis. Therefore, dysregulation of autophagy has been linked to skin diseases. In this review, we describe the molecular machinery and regulation of autophagy, discuss its role in keratinocytes and skin barrier, skin immune cells, and immune-related skin diseases including autoimmune skin disorders, allergic skin diseases, infectious skin disorders, and antitumor immunity against skin tumor. Finally, we highlight the potential of autophagy as a therapeutic target for immune-related skin diseases, and delivery of autophagy-related molecules (such as inducers, inhibitors, or nucleic acid molecules) by virtue of physical materials (such as nanoparticles) or biological materials (such as peptides) to skin topically may obtain clinical benefits in immune-related skin diseases. Moreover, developing autophagy-related gene product-based biomarkers may be promising to diagnose immune-related skin diseases.

Glabridin resensitizes p-glycoprotein-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents.

Multidrug resistance (MDR) remains an obstacle to chemotherapy related with the overexpression of several efflux membrane proteins, and p-glycoprotein (P-gp) is the most studied among them. Thus, continuous investigational efforts are necessary to find valuable MDR reversal agents, and the flavonoid compound glabridin (GBD) seems to be a promising candidate. This study aimed to investigate the potential of GBD against MDR and explore the possible mechanisms. First, we found that GBD could decrease the half maximal inhibitory concentration of paclitaxel and doxorubicin (DOX) in breast cancer cells like MDA-MB-231/MDR1 cells and MCF-7/ADR cells. It was further explained that GBD enhanced the apoptosis of MDA-MB-231/MDR1 cells induced by DOX, due to the increased accumulation of DOX. Then, tests were performed to explore the possible MDR reversal mechanisms. On one hand, GBD can suppress the expression of P-gp. On the other hand, GBD can downregulate the activity of P-gp ATPase when cotreated with DOX or verapamil, revealing that GBD was a substrate of P-gp. Moreover, the obtained kinetic inhibition parameters proved that GBD was a competitive inhibitor of P-gp, and in molecular docking simulation modeling, GBD exhibited stronger binding affinity with P-gp than DOX. In conclusion, GBD can increase the accumulation of DOX in MDA-MB-231/MDR1 cells by suppressing the expression of P-gp and competitively inhibiting the P-gp efflux pump and enhance the apoptosis of MDA-MB-231/MDR1 cells induced by DOX, and thus realize reversal effects on MDR. Therefore, the combination therapy of anticancer drugs and flavonoid-like GBD is a promising strategy to overcome P-gp-mediated MDR.

Inhibition of P-Glycoprotein Mediated Efflux in Caco-2 Cells by Phytic Acid.

Phytic acid (IP6) is a natural phosphorylated inositol, which is abundantly present in most cereal grains and seeds. This study investigated the effects of IP6 regulation on P-glycoprotein (P-gp) and its potential mechanisms using in situ and in vitro models. The effective permeability of the typical P-gp substrate rhodamine 123 (R123) in colon was significantly increased from (1.69 ± 0.22) × 10-5 cm/s in the control group to (3.39 ± 0.417) × 10-5 cm/s (p < 0.01) in the 3.5 mM IP6 group. Additionally, IP6 can concentration-dependently decrease the R123 efflux ratio in both Caco-2 and MDCK II-MDR1 cell monolayers and increase intracellular R123 accumulation in Caco-2 cells. Furthermore, IP6 noncompetitively inhibited P-gp by impacting R123 efflux kinetics. The noncompetitive inhibition of P-gp by IP6 was likely due to decreases in P-gp ATPase activity and P-gp molecular conformational changes induced by IP6. In summary, IP6 is a promising P-gp inhibitor candidate.

Preparation and evaluation of chitosan-based nanogels/gels for oral delivery of myricetin.

A novel nanogel/gel based on chitosan (CS) for the oral delivery of myricetin (Myr) was developed and evaluated comprehensively. The particle size of the obtained Myr-loaded CS/ß-glycerol phosphate (ß-GP) nanogels was in the range of 100-300nm. The rheological tests showed that the sol-gel transition happened when the nanogels were exposed to physiological temperatures, and 3D network structures of the gelatinized nanogels (gels) were confirmed by Scanning Electron Microscopy. Myr was released from CS/ß-GP nanogel/gel in acidic buffers via a Fickian mechanism, and this release was simultaneously accompanied by swelling and erosion. Moreover, the nanogel/gel exhibited no cytotoxicity by MTT assay, and the oral bioavailability of Myr in rats was improved with an accelerated absorption rate after Myr was loaded into CS/ß-GP nanogel/gel. In summary, all of the above showed that CS/ß-GP nanogel/gel was an excellent system for orally delivering Myr.

Preformulation studies of myricetin: a natural antioxidant flavonoid.

Myricetin is a natural flavonoid which has attracted great interest due to its antioxidant and free-radical scavenging activities. Unfortunately, physicochemical properties of myricetin are largely unknown so far and this would impair the design and development of myricetin formulations. In this paper, a series of studies were performed to investigate physicochemical properties of myricetin, such as its solubility in aqueous/organic solvents, aqueous solubility with different solubilizers, buffers and pHs, dissociation constant (pKa), partition coefficients of log P and log D at various pHs, intrinsic dissolution rate (IDR), and its stability at different temperatures and pHs. The results demonstrated that myricetin is a lipophilic compound with low water solubility but higher solubility in organic solvents or use of solubilizers. Myricetin is also a weak acidic compound with a pKa of 6.63 +/- 0.09, low IDR of 11.66 +/- 0.82 microg/min/cm2 at 37 degrees C. It is most stable at a pH of 2.0 and the degradation of myricetin is both temperature and pH dependent. Therefore, enhancement of the aqueous solubility and dissolution rate of myricetin and prevention from its rapid degradation at high pH and temperature should be considered for further formulation development of myricetin. In summary, these data will be used as rational support to create an efficacious formulation for the delivery of myricetin.

[Effects of salviandic acid B (SA-B) on activity of basement membrane-type collagenase and impact of regulatory factors in rats with cardiac hypertrophy].

OBJECTIVE: To observe the effect of salviandic acid B (SA-B) on MMP-2/9 and TIMP-2 of fibrotic cardiac tissues in rats and explore the action mechanism of SA-B anti-fibrosis of heart. METHOD: Ventricular remodeling model was induced by abdominal aortic banding (AAB) in rats. Rats were randomly divided into 6 groups: normal, model, SA-B high, SA-B middle, SA-B low and captopril control group. Histological changes of heart were observed with hemotoxylin and eosin (H&E) staining and Sirius red staining. Hydroxyproline (Hyp) content in heart tissue was measured by hydrolysis method. Expression of heart tissue collagen NIV, MMP-2/9 and TIMP-2 were analyzed with Western blot The activities of heart tissue MMP-2 were determined with gelatin zymography substrate degradation method. RESULT: SA-B treated groups had lower heart inflammation and lower heart Hyp content; decreased Collagen deposit and alleviated cardiac fibrosis. SA-B treated groups obviously decreased the expression of Collagen IV, MMP-2/9 and TIMP-2. The activity of MMP-2 was decreased in treated SA-B treated groups. CONCLUSION: The mechanism of SA-B action against cardiac fibrosis may be related to down-regulating the expression of TIMP -2 and the activity of MMP-2/9, thus protect the normal basal membrane.

[Protective effect of total isoflavones from Pueraria lobata on secondary osteoporosis induced by dexamethasone in rats].

OBJECTIVE: To study the protective effect of the total isoflavones from Pueraria lobata (TIP) on secondary osteoporosis induced by dexamethasome (DXM). METHODS: Female SD rats, 4 month aged, were given intramuscularly with 1.5 mg/kg DXM twice once week. The treated groups were orally given TIP 100, 50 or 25 mg.kg-1.d-1 for 6 months. The whole body BMD and BMC were detected at 3 and 6 months. The biodynamics potency, density, ash weight and calcium content of femur were determined at 6 months. RESULTS: (1) At 3 and 6 months, BMDs in TIP 100 mg/kg group were increased by 3.4% and 8.4% than that in model group, BMC were increased by 7.0% and 9.1%, while in TIP 50 mg/kg group by 3.2%, 5.3% and 6.2%, 6.0%. (2) The Fmax and hardness in TIP 100 mg/kg group were enhanced by 10.3% and 10.5%, when in TIP 50 mg/kg group were enhanced by 3.5% and 7.1%. (3) TIP can increase wet and dry weight in slightly extent, but significantly increase wet density and dry density. (4) The ash weight and calcium content in femur were increased by 3.1% and 4.2% in TIP 100 mg/kg group, 4.3% and 6.4% in TIP 50 mg/kg group, while no change in TIP 25 mg/kg group. CONCLUSIONS: TIP can prevent secondary osteoporosis induced by DXM in rats.

[Estrogen-like effects of puerarin and total isoflavones from Pueraria lobata].

OBJECTIVE: To study the estrogen-like effects of puerarin and total isoflavones from Pueraria lobata (TIP) in vivo. METHODS: Puerarin and TIP were orally administrated to ovariectomized rats, infancy or adult mice and estrogen-treated mice at the doses of 150, 300 and 600 mg/kg for 5-9 days. The estrogen-like effects were measured by viginacytology and uterus or ovary weights. RESULTS: Puerarin and TIP significantly promoted uterus growth in ovariectomized rats and infancy mice, increased the ratios of keratocytes in vaginal smear in ovariectomized rats. The sexual cycle was partially recovered in dose-dependent manner. In E2-treated mice, puerarin and TIP obviously inhibited the growth of vigina induced by E2. No obvious effect was observed in normal adult mice. CONCLUSION: The results showed that puerarin and TIP acted as weak estrogen-like effect on estrogen-deficiency animals, while no effect on normal-estrogen level ones, but as antiestrogen-like effect in high-estrogen-level ones. These results suggested that puerarin and TIP possessed property of partial agonist of estrogen receptor.