Cytotoxicity of Callerya speciosa Fractions against Myeloma and Lymphoma Cell Lines.

Callerya speciosa is widely distributed in tropical and subtropical countries and is traditionally used for preventing numerous disorders. In this study, a bioguided fractionation of ethyl acetate extract (SE) from C. speciosa root was carried out to target antioxidant and cytotoxic activities. Of the four fractions (SE1-SE4) obtained by column chromatography, SE4 had the strongest anti-radical ability in the DPPH and ABTS assays (IC50 = 0.05 and 0.17 mg/mL, respectively), with results close to butylated hydroxytoluene (BHT), a common antioxidant agent. The cytotoxic activities against the selected cells were analyzed in this study by MTT assay. Accordingly, SE2, SE3, and SE4 significantly inhibited the viability of multiple myeloma cell lines, comprising U266 (IC50 = 0.38, 0.09, and 0.11 mg/mL, respectively) and KMS11 (IC50 = 0.09, 0.17, and 0.15 mg/mL, respectively), mantle cell lymphoma Mino (IC50 = 0.08, 0.16, and 0.15 mg/mL, respectively), and the noncancerous cell line LCL (IC50 = 0.40, 0.32, and 0.21 mg/mL, respectively). At a concentration of 125 µg/mL, SE2, SE3, and SE4 induced the cell apoptosis of U266 (32.2%, 53.2%, and 55.6%, respectively), KMS11 (36.9%, 40.8%, and 47.9%, respectively), Mino (36.6%, 39.8%, and 22.0%, respectively), and LCL (12.4%, 17.5%, and 23.5%, respectively) via annexin V assay. The dominant compounds detected in fractions by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), were identified as isoflavones. This is the first report describing C. speciosa as a promising natural source of antileukemia and antimyeloma agents, which may be useful for the development of blood cancer treatments.

Anti-Diabetes, Anti-Gout, and Anti-Leukemia Properties of Essential Oils from Natural Spices Clausena indica, Zanthoxylum rhetsa, and Michelia tonkinensis.

Essential oils (EOs) of Clausena indica fruits, Zanthoxylum rhetsa fruits, and Michelia tonkinensis seeds were analyzed for their phytochemical profiles and biological activities, including anti-diabetes, anti-gout, and anti-leukemia properties. Sixty-six volatile compounds were identified by gas chromatography-mass spectrometry (GC-MS), in which, myristicin (68.3%), limonene (44.2%), and linalool (49.3%) were the most prominent components of EOs extracted from C. indica, Z. rhetsa, and M. tonkinensis, respectively. In addition, only EOs from C. indica inhibited the activities of all tested enzymes comprising α-amylase (IC50 = 7.73 mg/mL), α-glucosidase (IC50 = 0.84 mg/mL), and xanthine oxidase (IC50 = 0.88 mg/mL), which are related to type 2 diabetes and gout. Remarkably, all EOs from C. indica, Z. rhetsa (IC50 = 0.73 mg/mL), and M. tonkinensis (IC50 = 1.46 mg/mL) showed a stronger anti-α-glucosidase ability than acarbose (IC50 = 2.69 mg/mL), a known anti-diabetic agent. Moreover, the growth of leukemia cell Meg-01 was significantly suppressed by all EOs, of which, the IC50 values were recorded as 0.32, 0.64, and 0.31 mg/mL for EOs from C. indica, Z. rhetsa, and M. tonkinensis, respectively. As it stands, this is the first report about the inhibitory effects of EOs from C. indica and Z. rhetsa fruits, and M. tonkinensis seeds on the human leukemia cell line Meg-01 and key enzymes linked to diabetes and gout. In conclusion, the present study suggests that EOs from these natural spices may be promising candidates for pharmaceutical industries to develop nature-based drugs to treat diabetes mellitus or gout, as well as malignant hematological diseases such as leukemia.

Immunological and Preventive Effects of Hochuekkito and Kakkonto Against Coronavirus Disease in Healthcare Workers: A Retrospective Observational Study.

Amid the global outbreak of coronavirus disease 2019 (COVID-19), it may be expected that low-toxicity natural compounds, such as Kampo formulas, will have a preventive effect on COVID-19. Although the biological properties and safety of the representative Kampo compounds, hochuekkito (HET) and kakkonto (KKT), have been confirmed in various animal model experiments, clinical studies, and a few human studies to induce biological effects on various infectious diseases without significant toxicity, it is unclear whether HET and KKT are safe and effective for COVID-19 prevention. The study population included healthcare workers (HCWs), as they are at a higher risk of infection than the other populations. We retrospectively investigated the immunological and preventive effects of HET and KTT against COVID-19. We included 27 HCWs (aged 21-72 years, F:M = 18:9) from hospitals and clinics of the Hokuriku-Tokai region. The HCWs received HET and KKT for general fatigue and myalgia during this period for 28 days. We obtained patient clinical data from electronic medical records. We analyzed the changes in immunomodulation before and after the administration of the formulas from residual specimens based on the expression of relevant surface markers. The specimens were also tested for the presence of antibodies against severe acute respiratory syndrome coronavirus 2. The following side effects were reported: abdominal discomfort in five patients, diarrhea in two, and loose or soft stool in three. All 27 HCWs tested negative for COVID-19 antibodies. HET and KKT administration significantly increased the absolute number of circulating lymphocytes expressing the activating receptors NKp46, NKp30, and suppressing receptor NKG2A. There was also a significant increase in the absolute number of circulating lymphocytes expressing the receptors TLR4, OX40, 4-1BB, GITR, PD-1, and ICOS. These data indicate that HET and KKT can enhance and modulate NK activity in circulating human immune cells. The immunomodulatory effects, such as activation and regulation of T cells, are consistent with a putative improvement in infectious immunosurveillance. An increase in the number of T cells and CD4/CD8-positive cells indicates an enhanced ability to protect against infection. HET and KKT may prevent the onset or worsening of COVID-19 through their immunomodulatory effects.

Cytopenia associated with copper deficiency.

Introduction: Due to an increased incidence of copper deficiency, we investigated adult patients who had low serum levels of copper with cytopenia at our hospital from March 2014 to March 2021. Methods: We retrospectively reviewed the clinical data of patients who had been diagnosed with cytopenia due to copper deficiency at the Aichi Medical University Hospital from March 2014 to March 2021. Results: In the 15 patients with cytopenia secondary to low serum copper level, 11 had cytopenia of two to three lineages; three (27%) had pancytopenia, and eight (73%) had bicytopenia. Of the 15 patients, nine (60%) underwent bone marrow examinations; three (30%) showed typical morphologic features associated with copper deficiency, such as multiple clear cytoplasmic vacuoles in erythroblasts and myeloid cells, and three (30%) showed dysplastic features as observed in myelodysplastic syndrome. Among the 14 (93%) patients who were treated with copper supplements, had cessation of zinc supplements, or both, 11 (73%) and eight (53%) showed normal copper levels and hematological improvement, respectively. Conclusion: Copper deficiency is more common than expected and should be considered in patients with unexplained cytopenia.

Immunomodulatory and Metabolic Changes after Gnetin-C Supplementation in Humans.

Gnetin-C is a naturally occurring stilbene derived from the seeds of Gnetum gnemon L., an edible plant native to Southeast Asia that is called melinjo. Although the biological properties and safety of G. gnemon extract, which contains nearly 3% Gnetin-C, have been confirmed in various human studies, whether or not pure Gnetin-C is safe for humans is unclear at present. We conducted a randomized, double-blind, placebo-controlled trial. Healthy subjects were randomly divided into two groups. The interventional group (n = 6) was given Gnetin-C, and the control group (n = 6) was provided a placebo, for 14 days. Lipid profiles, biomarkers of oxidative stress and circulating blood cells were assessed before and after the intervention. All subjects completed the study, with no side effects reported across the study duration. Gnetin-C supplementation demonstrated a statistically significant increase in the absolute number of circulating natural killer (NK) cells expressing the activating receptors NKG2D and NKp46. NK cells derived from subjects who received Gnetin-C for two weeks showed higher cytotoxicity against K562 target cells than those before receiving Gnetin-C. In addition, Gnetin-C also resulted in a significant decrease in the absolute neutrophil count in the blood compared with the placebo. Furthermore, Gnetin-C significantly reduced the levels of uric acid, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total adiponectin, and high-molecular-weight adiponectin. These data indicate that Gnetin-C has biological effects of enhancing the NK activity on circulating human immune cells. The immunomodulatory effects are consistent with a putative improvement in cancer immunosurveillance via the upregulation of the NKG2D receptor. The study was registered with UMIN-CTR, number 000030364, on 12 December 2017.

Rationale for assessing the therapeutic potential of resveratrol in hematological malignancies.

Promising results from pre-clinical studies on the naturally-occurring polyphenol resveratrol have generated considerable interest and somewhat excessive expectations regarding the therapeutic potential of this compound for treating or preventing various diseases, including cardiovascular and neurodegenerative disorders and cancer. Resveratrol has potent inhibitory activity in vitro against various tumor types, including cell lines derived from virtually all blood malignancies. Pharmacological studies have shown that resveratrol is safe for humans but has poor bioavailability, due to its extensive hepatic metabolism. Curiously, a substantial proportion of the orally administered resveratrol can reach the bone marrow compartment. Notably, various pathways dysregulated in blood cancers are known to be molecular targets of resveratrol, thus substantiating the potential utility of this agent in blood malignancies. In this review, we primarily focus on the scientific evidence that supports the potential utility of resveratrol for the management of select hematological malignancies. In addition, potential clinical trials with resveratrol are suggested.

Comparison of Autologous and Unrelated Transplants for Cytogenetically Normal Acute Myelogenous Leukemia.

Allogeneic stem cell transplantation (SCT) from an HLA-matched sibling donor (MSD) is a postremission treatment that offers a potential cure for adults with cytogenetically normal (CN) acute myelogenous leukemia (AML) in first complete remission (CR1). The best alternative in the absence of an MSD remains unclear, however. The aim of this study was to retrospectively compare the outcomes of autologous peripheral blood stem cell transplantation (auto-PBSCT; n = 177) and allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor (MUD; n = 173) in adult patients with CN-AML/CR1. Both the multivariate analysis (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.71 to 1.97; P = .53) and propensity score models (HR, 1.40; 95% CI, 0.80 to 2.43; P = .24) indicated that the leukemia-free survival (LFS) rate of auto-PBSCT was not significantly different from that of MUD-BMT. These results suggest that in the absence of an available MSD, auto-PBSCT remains a viable alternative as postremission therapy in patients with CN-AML/CR1.

Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission.

BACKGROUND: While unrelated bone marrow transplantation (UBMT) has been widely used as alternative donor transplantation, the use of umbilical cord blood transplantation (UCBT) is increasing recently. METHODS: We conducted a decision analysis to address which transplantation procedure should be prioritized for younger patients with acute myeloid leukemia (AML) harboring high- or intermediate-risk cytogenetics in first complete remission (CR1), when they lack a matched related donor but have immediate access to a suitable umbilical cord blood unit. Main sources for our analysis comprised the data from three phase III trials for a chemotherapy cohort (n = 907) and the registry data for a transplantation cohort (n = 752). RESULTS: The baseline analysis showed that when the 8/8 match was considered for UBMT, the expected 5-year survival rate was higher for UBMT than for UCBT (58.1% vs. 51.8%). This ranking did not change even when the 7/8 match was considered for UBMT. Sensitivity analysis showed consistent superiority of UBMT over UCBT when the time elapsed between CR1 and UBMT was varied within a plausible range of 3-9 months. CONCLUSIONS: These results suggest that 8/8 or 7/8 UBMT is a better transplantation option than UCBT even after allowing time required for donor coordination.

[Usefulness of reticulocyte hemoglobin equivalent for the safety of pre-operative autologous blood donation].

Pre-operative autologous blood donation (PABD) provides safe blood for patients at the expense of the risk of iron deficiency anemia that may compromise the patients. The reticulocyte hemoglobin equivalent (RET-He) is an indirect measure of the functional iron available for the erythropoiesis over the previous 2-3 days. The aim of this study was to evaluate the clinical usefulness of RET-He quickly measured by the automated hematology analyzer Sysmex XE-2100 in patients undergoing PABD at our hospital. Receiver-operating characteristic curve analysis revealed that RET-He was reliable in the diagnosis of iron deficiency anemia. Two of 14 patients in the absence of post-PABD iron replacement developed marked anemia with low RET-He levels after PABD, suggesting that this anemia was due to iron deficiency. Of 26 patients receiving post-PABD iron replacement, 8 who had already showed low RET-He levels at PABD developed statistically significant reduction in hemoglobin levels after PABD despite adequate iron replacement, indicating that the 8 patients had iron deficiency prior to PABD. These findings suggest that automated measurement of RET-He may contribute to improve the safety of PABD.