Isorhamnetin: what is the in vitro evidence for its antitumor potential and beyond?

Isorhamnetin (ISO) is a phenolic compound belonging to flavonoid family, showcasing important in vitro pharmacological activities such as antitumor, anti-inflammation, and organ protection. ISO is predominantly extracted from Hippophae rhamnoides L. This plant is well-known in China and abroad because of its "medicinal and food homologous" characteristics. As a noteworthy natural drug candidate, ISO has received considerable attention in recent years owing to its low cost, wide availability, high efficacy, low toxicity, and minimal side effects. To comprehensively elucidate the multiple biological functions of ISO, particularly its antitumor activities and other pharmacological potentials, a literature search was conducted using electronic databases including Web of Science, PubMed, Google Scholar, and Scopus. This review primarily focuses on ISO's ethnopharmacology. By synthesizing the advancements made in existing research, it is found that the general effects of ISO involve a series of in vitro potentials, such as antitumor, protection of cardiovascular and cerebrovascular, anti-inflammation, antioxidant, and more. This review illustrates ISO's antitumor and other pharmacological potentials, providing a theoretical basis for further research and new drug development of ISO.

Curcumin in combination with homoharringtonine suppresses lymphoma cell growth by inhibiting the TGF-ß/Smad3 signaling pathway.

Both homoharringtonine (HHT) and curcumin exhibit anti-proliferative effects on lymphoma cells, but the effects of combined HHT and curcumin treatment remain unclear. Here, we investigated the effects of HHT/curcumin combination on the proliferation, apoptosis, and invasion in lymphoma cells. CCK-8, flow cytometry, and transwell assays were used to assess proliferation, apoptosis, and invasion of U937 and Raji cells. p-Smad3, E-cadherin, and N-cadherin expression were also measured in Raji cells using Western blot assays. Combination of HHT and curcumin synergistically inhibited U937 and Raji cell proliferation and invasion. In addition, the combination treatment markedly increased apoptosis of Raji cells as evidenced by increased Bax, cleaved caspase 3, and cleaved caspase 9 expression. Meanwhile, the combination treatment promoted anti-tumor mechanisms in Raji cells as indicated by decreases in p-Smad3 and N-cadherin and increases in E-cadherin. In vivo experiments showed that the combination treatment suppressed tumor growth in a mouse Raji xenograft model. Our findings indicate that combination of HHT and curcumin inhibited lymphoma cell growth by downregulating the TGF-ß/Smad3 pathway. These results suggest that HHT combined with curcumin might be a promising therapeutic approach for the treatment of lymphoma.

The Combination of Jiedu Xiaoluo Decoction with Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) Accelerates Disease Remission of Non-Hodgkin Lymphoma.

OBJECTIVE: This study aimed to explore the therapeutic effects of autologous peripheral blood stem cell transplantation (APBSCT) with Jiedu Xiaoluo decoction (JDX) on non-Hodgkin lymphoma (NHL). METHOD: B lymphoma cells A20 were used to establish nude mice-transplanted tumor model. The peripheral blood of mice was analyzed by automatic blood cell counter. Inflammatory cytokines in tumor tissues were measured by ELISA, real-time qRT-PCR, and western blotting assays. Immunohistochemical staining was employed to evaluate tumor cell growth and apoptosis. CCK8 and Transwell assays were used to detect cell viability, migration, and invasion. Cell apoptosis in vitro was evaluated with flow cytometry. RESULT: In the in vitro co-culture system of A20 cells and hemopoietic stem cells (HSC), JDX notably inhibited the proliferation, migration, and invasion and promoted apoptosis of A20 cells compared to HSC treatment alone. In animal tumor xenografts of NHL, the combination of APBSCT with JDX significantly promoted hematopoietic reconstitution, inhibited tumorigenesis of A20 cell, promoted the inflammatory microenvironment remission, inhibited cell proliferation, and promoted apoptosis compared to APBSCT alone. CONCLUSION: The combination of APBSCT with JDX might be an effective strategy to treat NHL through inhibiting tumorigenesis and reconstructing hematopoietic and immune microenvironment. Our finding provided a novel insight into the clinical application of Traditional Chinese Medicine (TCM) against NHL.

PGC-1α activator-induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer.

PURPOSE: The present study aims to investigate the efficacy and mechanisms of peroxisome proliferator-activated receptor γ coactivator 1-α agonist, as adjuvant to programmed death-1 (PD-1) blockade in hyporesponsive lung cancer cells-derived in vivo tumor model, using bezafibrate. METHODS: Mouse Lewis lung carcinoma (LLC) xenograft models were established and treated with programmed death-ligand 1 (PD-L1) monoclonal antibodies with or without bezafibrate. Tumors or peripheral blood of mice were harvested to investigate the quality, quantity, and function as well as energetic metabolism of cytotoxic T lymphocytes (CTLs) by flow cytometry or quantitative real-time polymerase chain reaction. RESULTS: The combination of bezafibrate plus anti-PD-L1 reached synergistic tumoricidal effect in LLC xenograft mouse models, even though bezafibrate alone had no effect on tumor growth. Bezafibrate significantly facilitated CD8+ T cells infiltrating into tumor tissues by enhancing the expression of CXCL9 and CXCL10 within tumors as well as the receptor CXCR3 in infiltrating CTLs. Activated CTLs within tumors were also significantly upregulated by bezafibrate. Further data demonstrated that bezafibrate treatment could maintain the survival and functional capacity of tumor-infiltrating CTLs. Moreover, cellular reactive oxygen species in infiltrating CTLs and fatty acid oxidation (FAO)-related genes (PGC-1α, Cpt1a, and LCAD) expression within tumors were significantly increased after treatment with bezafibrate. CONCLUSIONS: Bezafibrate synergized the tumoricidal effect of PD-1 blockade in hyporesponsive lung cancer by expansion of effector CTLs within tumor microenvironment. The potential mechanism may relate to the capacity of bezafibrate in regulating FAO of tumor-infiltrating CTLs.

Evaluation of pigeon pea leaves (Cajanus cajan) replacing alfalfa meal on growth performance, carcass trait, nutrient digestibility, antioxidant capacity and biochemical parameters of rabbits.

A 30-day experiment was performed to determine the effect of pigeon pea leaves (PPL) on growth performance, carcass trait, meat quality, nutrient digestibility, antioxidant capacity and biochemical parameters of growing rabbits. In a completely randomized design, PPL replaced alfalfa meal at the level of 0%, 10%, 20% and 30%, which were named PPL0 (control), PPL10, PPL20 and PML30 respectively. Two hundred New Zealand white rabbits at 6 weeks with similar weight (870.23 ± 15.98 g) were allocated to four dietary groups with five replicates containing 10 rabbits/per replicate (male). The results showed that: (a) PPL powder contained 24.26% crude protein, 4.34% crude fat, 17.86% crude fibre, 7.05% ash, 1.35% calcium, 0.28% phosphorus, 1.09% lysine and 0.20% methionine, and the chemical compositions are on DM basis; (b) the ratio of feed to gain of rabbits fed diet PPL10 was significantly better (p < 0.05) than those fed other three diets; (c) the content of longissimus dorsi (LD) moisture in the rabbits fed diets without PPL (control group) was 12% lower than that in the PPL30 diets (60.1 vs. 72.1; p < 0.05). In PPL10, PPL20 and PPL30 diets, the leg muscle (LM) b*(yellowness) value was 33%, 30% and 22.6% higher than the control group respectively. The rabbits fed diets PPL0 had lower (p < 0.05) LM crude protein and ash and higher (p < 0.05) crude fat of LD and LM as compared with those fed other diets; (d) crude protein and energy digestibility of PPL0 and PPL10 diets were significantly higher (p < 0.05) than PPL30 diets; and (e) serum glutathione peroxidase (GSH-Px) activity of the rabbits fed PPL10 and PPL30 diets was significantly higher (p < 0.05) than that fed PPL20 diets. Liver total antioxidant capacity (T-AOC) activity of the PPL30 groups was 1.3% higher (p < 0.05) than the PPL10 group. Additionally, the control group (PPL0) had the highest (p < 0.05) blood urea nitrogen (BUN), total cholesterol (TCHO) and low-density lipoprotein cholesterol (LDLC) content compared with the groups supplemented with PPL. The PPL30 group had the highest (p < 0.05) triiodothyronine (T3 ) and tetraiodothyroxine (T4 ) value among the dietary groups.

Effect of maternal pre-pregnancy underweight and average gestational weight gain on physical growth and intellectual development of early school-aged children.

The aim of this study was to assess the effect of low maternal weight at pre-pregnancy and the average gestational weight gain on undernourished children and their intellectual development. From October 2012 to September 2013, we followed 1744 offspring of women who participated in a trial conducted from 2002 to 2006. Pregnant women recruited in the original trial could receive three prenatal health checks for free, at which maternal weight and height were measured. WISC-IV was used to estimate the intellectual development of children. Weight and height of both pregnant women and children were measured by trained anthropometrists using standard procedures. Having low maternal weight at pre-pregnancy was associated with an increased risk of undernutrition amongst children (underweight: OR = 2.02, 95%CI: 1.14-3.56, thinness: OR = 2.79, 95%CI: 1.50-5.17) and a decrease in verbal comprehension index (-2.70 points, 95%CI: -4.95-0.44) of children. The effect of average gestational weight gain on occurrences of underweight children (OR = 0.08, 95%CI: 0.01-0.55) was also found. We identified the effect of maternal pre-pregnancy underweight on impairment of the separate intellectual domains (verbal comprehension index) and increasing occurrence of undernourished children. Average gestational weight gain was positively associated with a decreased prevalence of underweight children but not with the intellectual development of children in rural China.

Effect of prenatal and postnatal malnutrition on intellectual functioning in early school-aged children in rural western China.

The aim of this study was to evaluate the effect of prenatal and postnatal malnutrition on the intellectual functioning of early school-aged children. We followed the offspring of women who had participated in a trial of prenatal supplementation with different combinations of micronutrients and who remained resident in the study field. We measured their intellectual functioning using the Wechsler intelligence scale for children (WISC-IV). Height-for-age, weight-for-age, and body mass index (BMI)-for-age were used as anthropometric nutritional status indices. Four of the 5 composite scores derived from the WISC-IV, except for working memory index (WMI), were significantly lower in low birth weight children after adjusting for confounds. All 5 composite scores, including full-scale intelligence quotient (FSIQ), verbal comprehension index (VCI), WMI, perceptual reasoning index (PRI), and processing speed index (PSI) were significant lower in stunted and underweight children. The differences in the means of WISC-IV test scores were greatest between stunted and nonstunted children. The means for FSIQ, VCI, WMI, PRI, and PSI were as follows: 5.88 (95% confidence interval [CI]: 2.84-8.92), 5.08 (95% CI: 1.12-8.41), 4.71 (95% CI: 1.78-7.66), 6.13 (95% CI: 2.83-9.44), and 5.81 (95% CI: 2.61-9.00). These means were lower in stunted children after adjusting for confounds. Our results suggest the important influences of low birth weight and postnatal malnutrition (stunting, low body weight) on intellectual functioning in early school-aged children.

Sex differences in the intellectual functioning of early school-aged children in rural China.

BACKGROUND: Gender disparities in China are concentrated in poor rural areas and among poor households. The difference in intelligence between boys and girls is less clear in rural China. The purpose of this paper was to assess sex differences in the intellectual function of early school-aged children in rural China. METHODS: One thousand seven hundred forty four early school-aged offspring of women who had participated in a prenatal supplementation trial with different combinations of micronutrients and continued to reside in two rural counties in China were followed. We measured their Full-Scale IQ (FSIQ), Verbal Comprehension Index (VCI), Working Memory Index (WMI), Perceptual Reasoning Index (PRI) and Processing Speed Index (PSI) using the Wechsler Intelligence Scale for Children (WISC-IV). Multilevel analyses were used to assess sex differences in intellectual functioning in 7-10-year-old children in rural China. RESULTS: Boys' adjusted mean FSIQ score was 0.97 points higher (95% CI: -2.22 - 0.28) than that of girls. Girls obtained higher mean WMI and PSI scores, with 1.32 points (95% CI: 0.14 - 2.51) and 3.10 points (95% CI: 1.82-4.38) higher adjusted means, respectively. Boys' adjusted mean VCI and PRI scores were significantly higher than those of girls, and the mean differences were 2.44 points (95% CI: 0.95 - 3.94) and 3.68 points (95% CI: 2.36 - 5.01), respectively. CONCLUSIONS: There is no evidence to suggest sex differences in the general intelligence of early school-aged children in rural China. However, a difference in general intelligence between 10-year-old boys and girls was evident. Girls and boys in rural China tended to show different specific cognitive abilities.