Maslinic acid exerts anticancer effects by targeting cancer hallmarks.

BACKGROUND: Natural products have long been regarded as a source of anticancer compounds with low toxicity. Evidence revealed that maslinic acid (MA), a widely distributed pentacyclic triterpene in common foodstuffs, exhibited pronounced inhibitory effects against various cancer cell lines. Most cancer cells thrive by acquiring cancer hallmarks, as coined by Hanahan and Weinberg in 2000 and 2011. PURPOSE: This represents the first systematic review concerning the anticancer properties of MA as these cancer hallmarks are targeted. It aims to summarize the antineoplastic activities of MA, discuss the diverse mechanisms of action based on the effects of MA exerted on each hallmark. METHODS: A comprehensive literature search was conducted using the search terms "maslinic," "cancer," "tumor," and "neoplasm," to retrieve articles from the databases MEDLINE, EMBASE, Web of Science, and Scopus published up to September 2022. Study selection was conducted by three reviewers independently from title and abstract screening until full-text evaluation. Data extraction was done by one reviewer and counterchecked by the second reviewer. RESULTS: Of the 330 articles assessed, 40 papers met the inclusion criteria and revealed that MA inhibited 16 different cancer cell types. MA impacted every cancer hallmark by targeting multiple pathways. CONCLUSION: This review provides insights regarding the inhibitory effects of MA against various cancers and its remarkable biological properties as a pleiotropic bioactive compound, which encourage further investigations.

Traditional Chinese Medicine Body Constitutions as Predictors for Depression: A Systematic Review and Meta-Analysis.

Traditional Chinese medicine body constitution (TCMBC) reflects a person's vulnerability to diseases. Thus, identifying body constitutions prone to depression can help prevent and treat depression. The review aimed to assess and summarize the existing evidence that explores the relationship between TCMBC and depression. Psychology and Behavioral Sciences Collection, MEDLINE, PubMed, CNKI, Wanfang, SinoMed, Embase, VIP, CINAHL, and CMJ were searched from inception to April 2021. Observational studies assessing the association between TCMBC and depression were selected. The quality of the included studies were assessed using the Newcastle-Ottawa Scale (NOS). Eighteen studies were included in the systematic review and thirteen in the meta-analysis. The pooled odd ratios of developing depression for Qi-stagnation, Qi-deficiency, Yang-deficiency, Yin-deficiency, and Balanced constitutions were 3.12 (95% CI, 1.80-5.40; I2 = 94%), 2.15 (95% CI, 1.54-3.01; I2 = 89%), 1.89 (95% CI, 0.71-5.03; I2 = 81%), 1.41 (95% CI, 0.91-2.20; I2 = 57%), and 0.60 (95% CI, 0.40-0.90; I2 = 94%), respectively. The findings suggest that the evaluation of a person's TCMBC could be useful the in prevention and treatment of depression. However, more case-control and cohort studies are required to further confirm the association between TCMBC and depression.

Isolation of exosome from the culture medium of Nasopharyngeal cancer (NPC) C666-1 cells using inertial based Microfluidic channel.

Isolation of exosome from culture medium in an effective way is desired for a less time consuming, cost saving technology in running the diagnostic test on cancer. In this study, we aim to develop an inertial microfluidic channel to separate the nano-size exosome from C666-1 cell culture medium as a selective sample. Simulation was carried out to obtain the optimum flow rate for determining the dimension of the channels for the exosome separation from the medium. The optimal dimension was then brought forward for the actual microfluidic channel fabrication, which consisted of the stages of mask printing, SU8 mould fabrication and ended with PDMS microchannel curing process. The prototype was then used to verify the optimum flow rate with polystyrene particles for its capabilities in actual task on particle separation as a control outcome. Next, the microchip was employed to separate the selected samples, exosome from the culture medium and compared the outcome from the conventional exosome extraction kit to study the level of effectiveness of the prototype. The exosome outcome from both the prototype and extraction kits were characterized through zetasizer, western blot and Transmission electron microscopy (TEM). The microfluidic chip designed in this study obtained a successful separation of exosome from the culture medium. Besides, the extra benefit from this microfluidic channels in particle separation brought an evenly distributed exosome upon collection while the exosomes separated through extraction kit was found clustered together. Therefore, this work has shown the microfluidic channel is suitable for continuous separation of exosome from the culture medium for a clinical study in the future.

2-Methoxy-1,4-naphthoquinone (MNQ) regulates cancer key genes of MAPK, PI3K, and NF-κB pathways in Raji cells

2-Methoxy-1,4-naphthoquinone (MNQ) has been shown to cause cytotoxic towards various cancer cell lines. This study is designed to investigate the regulatory effect of MNQ on the key cancer genes in mitogen-activated protein kinase, phosphoinositide 3-kinase, and nuclear factor кB signaling pathways. The expression levels of the genes were compared at different time point using polymerase chain reaction arrays and Ingenuity Pathway Analysis was performed to identify gene networks that are most significant to key cancer genes. A total of 43 differentially expressed genes were identified with 21 up-regulated and 22 down-regulated genes. Up-regulated genes were involved in apoptosis, cell cycle and act as tumor suppressor while down-regulated genes were involved in anti-apoptosis, angiogenesis, cell cycle and act as transcription factor as well as proto-oncogenes. MNQ exhibited multiple regulatory effects on the cancer key genes that targeting at cell proliferation, cell differentiation, cell transformation, apoptosis, reduce inflammatory responses, inhibits angiogenesis and metastasis.

Temporal gene expression profiling of maslinic acid-treated Raji cells.

Maslinic acid is a novel phytochemical reported to target multiple signaling pathways. A complete gene expression profile was therefore constructed to illustrate the anti-tumourigenesis effects of maslinic acid in Raji cells across five time-points. Microarray analysis was used to identify genes that were differentially expressed in maslinic acid treated Raji cells at 0, 4, 8, 12, 24 and 48 h. Extracted RNA was hybridized using the AffymetrixGeneChip to obtain expression profiles. A total of 109 genes were found to be significantly expressed over a period of 48 hours. By 12 hours, maslinic acid regulates the majority of genes involved in the cell cycle, p53 and NF-κB signaling pathways. At the same time, XAF1, APAF1, SESN3, and TP53BP2 were evidently up-regulated, while oncogenes, FAIM, CD27, and RRM2B, were down-regulated by at least 2-fold. In conclusion, maslinic acid shows an hourly progression of gene expression in Raji cells.

Apoptotic and cytostatic actions of maslinic acid in colorectal cancer cells through possible IKK-β inhibition

Objective: To explore the anti-cancer activity of maslinic acid against colorectal cancer (CRC) cell lines and its possible mechanism. Methods: The inhibitory effect of maslinic acid was screened against five CRC cell lines (HT-29, HCT 116, SW480, SW48, and LS 174T) via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis and cell cycle analyses were carried out using annexin Ⅴ-FITC/propidium iodide staining and propidium iodide staining, respectively and subjected to fluorescence-activated cell sorting analysis. Protein expression studies of inhibitor of κB kinase-β (IKK-β), checkpoint kinase 1 (Chk1) and cyclin D1 were conducted using the JESS system. Results: Maslinic acid exhibited growth inhibitory effect in a dose- and time-dependent manner in HT-29 and HCT 116 cell lines. A more prominent apoptosis induced by maslinic acid was observed in HCT 116 cell line. However, in HT-29 cell line, maslinic acid induced cell cycle arrest by inhibiting the G1-S transition, which was accompanied by the downregulation of cyclin D1. The expression of unphosphorylated IKK-β protein was increased in both (HT-29 and HCT 116) cell lines after maslinic acid treatment. Conclusions: Maslinic acid inhibits the growth of HT-29 and HCT 116 cells in a different manner, induces cell cycle arrest in HT-29 cells and causes apoptosis in HCT 116 cells partially via NF-κB pathway inhibition.

Anti-Cancer Effects of Synergistic Drug-Bacterium Combinations on Induced Breast Cancer in BALB/c Mice.

Cancer development and progression are extremely complex due to the alteration of various genes and pathways. In most cases, multiple agents are required to control cancer progression. The purpose of this study is to investigate, using a mouse model, the synergistic interactions of anti-cancer agents, 1'-S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP), and cisplatin (CDDP) in double and triple combinations to treat chemo-sensitize and immune-sensitize breast cancer. Changes in tumor volume and body weight were monitored. Organs were harvested and stained using hematoxylin-eosin for histopathological assessment. Milliplex enzyme-linked immunosorbent assay (ELISA) was performed to determine cytokine levels, while immunohistochemistry (IHC) was conducted on tumor biopsies to verify systemic drug effects. In vivo mouse models showed tumor regression with maintenance of regular body weight for all the different treatment regimens. IHC results provided conclusive evidence indicating that combination regimens were able to down-regulate nuclear factor kappa-B activation and reduce the expression of its regulated pro-inflammatory proteins. Reduction of pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IFN-É£) levels were observed when using the triple combination, which indicated that the synergistic drug combination was able to significantly control cancer progression. In conclusion, ACA, MIP, and CDDP together serve as promising candidates for further development and for subsequent clinical trials against estrogen-sensitive breast cancer.

Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells.

BACKGROUND: Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects. MATERIALS AND METHODS: In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression. RESULTS: All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation. CONCLUSION: Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.

Cytotoxic and apoptotic effects of heat killed Mycobacterium indicus pranii (MIP) on various human cancer cell lines.

Mycobacterium indicus pranii (MIP) is a non-pathogenic mycobacterium, which has been tested on several cancer types like lung and bladder where tumour regression and complete recovery was observed. In discovering the potential cytotoxic elements, a preliminary test was carried out using four different fractions consisting of live bacteria, culture supernatant, heat killed bacteria and heat killed culture supernatant of MIP against two human cancer cells A549 and CaSki by 3-(4,5-dimethyl thiazol)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis was investigated in MCF-7 and ORL-115 cancer cells by poly-(ADP-ribose) polymerase (PARP) and DNA fragmentation assays. Among four MIP fractions, only heat killed MIP fraction (HKB) showed significant cytotoxicity in various cancer cells with inhibitory concentration, IC50 in the range 5.6-35.0 µl/(1.0 × 10(6) MIP cells/ml), while cytotoxicity effects were not observed in the remaining fractions. HKB did not show cytotoxic effects on non-cancerous cells contrary to cancerous cells, suggesting its safe usage and ability to differentially recognize between these cells. Evaluation on PARP assay further suggested that cytotoxicity in cancer cells were potentially induced via caspase-mediated apoptosis. The cytotoxic and apoptotic effects of MIP HKB have indicated that this fraction can be a good candidate to further identify effective anti-cancer agents.

Effect of signal peptides on the secretion of ß-cyclodextrin glucanotransferase in Lactococcus lactis NZ9000.

Cyclodextrin glucanotransferase (CGTase) is an extracellular enzyme which catalyzes the formation of cyclodextrin from starch. The production of CGTase using lactic acid bacterium is an attractive alternative and safer strategy to produce CGTase. In this study, we report the construction of genetically modified Lactococcus lactis strains harboring plasmids that secrete the Bacillus sp. G1 ß-CGTase, with the aid of the signal peptides (SPs) SPK1, USP45 and native SP (NSP). Three constructed vectors, pNZ:NSP:CGT, pNZ:USP:CGT and pNZ:SPK1:CGT, were developed in this study. Each vector harbored a different SP fused to the CGTase. The formation of halo zones on starch plates indicated the production and secretion of ß-CGTase by the recombinants. The expression of this enzyme is shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and zymogram analysis. A band size of ∼75 kDa corresponding to ß-CGTase is identified in the intracellular and the extracellular environments of the host after medium modification. The replacement of glucose by starch in the medium was shown to induce ß-CGTase production in L. lactis. Although ß-CGTase production is comparatively low in NZ:SPK1:CGT, the SP SPK1 was shown to have higher secretion efficiency compared to the other SPs used in this study.