N-phenyl pyrazoline derivative inhibits cell aggressiveness and enhances paclitaxel sensitivity of triple negative breast cancer cells.

Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase inhibitors have been tested in clinical trials to treat TNBC patients. In the previous study, we found that N-phenylpyrazoline small molecule acts as a protein kinase inhibitor in cervical cancer cells. However, there remains unknown about N-phenyl pyrazoline potency as a kinase inhibitor and its anti-cancer activity in TNBC cells. In this study, we investigated the activity of N-phenyl pyrazoline against TNBC cells via tyrosine kinase inhibition. Based on the MTT assay, the IC50 values for the N-phenyl pyrazoline 2, 5, A, B, C, and D against Hs578T were 12.63 µM, 3.95 µM, not available, 18.62 µM, 30.13 µM, and 26.79 µM, respectively. While only P5 exhibited the IC50 against MDA MB 231 (21.55 µM). Further, N-phenyl pyrazoline 5 treatment significantly inhibited the cell proliferation rate of Hs578T and MDA MB 231 cells. The migration assay showed that treatment with the compound N-phenyl pyrazoline 5 with 4 µM concentration significantly reduced cell migration of Hs578T cells. N-phenyl pyrazoline 5 treatment at 1 µM and 2 µM was able to reduce the tumorsphere size of Hs578t cells. A combination treatment of P5 and paclitaxel showed a synergistic effect with a combination index score > 1 in both TNBC cells. Further, the P5 predictively targeted the protein kinases that significantly correlated to breast cancer prognosis. The GSEA analysis result shows that receptor tyrosine kinase, Notch3, Notch4, and Ephrin signaling pathways were targeted by P5. The P5 treatment reduced the EGFR expression level and activation in TNBC cells.

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study.

Background: Multidrug resistance in various cancer types is a major obstacle in cancer treatment. The concept of a single drug molecular target often causes treatment failure due to the complexity of the cellular processes. Therefore, combination chemotherapy, in which two or more anticancer drugs are co-administered, can overcome this problem because it potentially have synergistic efficacy besides reducing resistance, and drug doses. Previously, we reported that pyrazoline B had promising anticancer activity in both in silico and in vitro studies. To increase the efficacy of this drug, co-administration with established anticancer drugs such as doxorubicin and paclitaxel is necessary. Materials and Methods: In this study, we used an in silico approach to predict the synergistic effect of pyrazoline B with paclitaxel or doxorubicin using various computational frameworks and compared the results with those of an established study on the combination of doxorubicin-cyclophosphamide and paclitaxel-ascorbic acid. Results and Discussion: Drug interaction analysis showed the combination was safe with no contraindications or side effects. Furthermore, molecular docking studies revealed that doxorubicin-pyrazoline B and doxorubicin-cyclophosphamide may synergistically inhibit cancer cell proliferation by inhibiting the binding of topoisomerase I to the DNA chain. Moreover, the combination of pyrazoline B-paclitaxel may has synergistic activity to cause apoptosis by inhibiting Bcl2 binding to the Bax fragment or inhibiting cell division by inhibiting α-ß tubulin disintegration. Paclitaxel-ascorbic acid had a synergistic effect on the inhibition of α-ß tubulin disintegration. Conclusion: The results show that this combination is promising for further in vitro and in vivo studies.

The Potentials of Ageratum conyzoides and Other Plants from Asteraceae as an Antiplasmodial and Insecticidal for Malaria Vector: An Article Review.

Background: Malaria is a life-threatening disease prevalent in tropical and subtropical regions. Artemisinin combination therapy (ACT) used as an antimalarial treatment has reduced efficacy due to resistance, not only to the parasite but also to the vector. Therefore, it is important to find alternatives to overcome malaria cases through medicinal plants such as Ageratum conyzoides and other related plants within Asteraceae family. Purpose: This review summarizes the antimalarial and insecticidal activities of A. conyzoides and other plants belonging to Asteraceae family. Data Source: Google Scholar, PubMed, Science Direct, and Springer link. Study Selection: Online databases were used to retrieve journals using specific keywords combined with Boolean operators. The inclusion criteria were articles with experimental studies either in vivo or in vitro, in English or Indonesian, published after 1st January 2000, and full text available for inclusion in this review. Data Extraction: The antimalarial activity, insecticidal activity, and structure of the isolated compounds were retrieved from the selected studies. Data Synthesis: Antimalarial in vitro study showed that the dichloromethane extract was the most widely studied with an IC50 value <10 µg/mL. Among 84 isolated active compounds, 2-hydroxymethyl-non-3-ynoic acid 2-[2,2']-bithiophenyl-5- ethyl ester, a bithienyl compound from the Tagetes erecta plant show the smallest IC50 with value 0.01 and 0.02 µg/mL in Plasmodium falciparum MRC-pf-2 and MRC-pf-56, respectively. In vivo studies showed that the aqueous extract of A. conyzoides showed the best activity, with a 98.8% inhibition percentage using a 100 mg/kg dose of Plasmodium berghei (NK65 Strain). (Z)- γ-Bisabolene from Galinsoga parviflora showed very good insecticidal activity against Anopheles stephensi and Anopheles subpictus with LC50 values of 2.04 µg/mL and 4.05 µg/mL. Conclusion: A. conyzoides and other plants of Asteraceae family are promising reservoirs of natural compounds that exert antimalarial or insecticidal activity.

Identification of KRAS mutation and HER2 expression in Indonesian colorectal cancer population: a cross-sectional study.

In Indonesia, colorectal cancer is the third most common type. In 2008, Indonesia ranked fourth in the Association of Southeast Asian Nations (ASEAN) countries, with an incidence rate of 17.2 per 100 000 population. This figure is predicted to continue to increase from year to year. In 30% of colorectal cancer patients diagnosed after metastases, some patients will develop metastases after undergoing surgical resection of the primary tumor. The survival of metastatic colorectal cancer patients has improved significantly in the last 20 years with the introduction of target-oriented drugs, anti-epidermal growth factor receptor (EGFR), and anti-human epidermal growth factor receptor-2 (HER2). This study aims to assess the relationship between Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation and HER2 expression for targeted therapy implementation. Patients and methods: This research is a cross-sectional study. The research subjects in this study were colorectal cancer patients in the digestive surgery division. There were 58 study subjects. Examination of KRAS mutations was carried out by PCR on fresh tumor tissue obtained from surgery or colonoscopy. Meanwhile, the HER2 examination used the immunohistochemistry method of paraffin blocks for anatomical pathology examination. Results: Examination of KRAS mutations showed 28/58 (43.8%) patients with colorectal cancer, while HER2 overexpression was found in 6/58 (10.3%) patients with colorectal cancer. Univariate analysis of KRAS mutations and HER2 expression showed that four subjects with KRAS mutations had excess HER2 expression (P=0.341). Conclusion: There is no association between KRAS mutations and HER2 overexpression in colorectal cancer patients.

Breynia cernua: Chemical Profiling of Volatile Compounds in the Stem Extract and Its Antioxidant, Antibacterial, Antiplasmodial and Anticancer Activity In Vitro and In Silico.

Breynia cernua has been used as an alternative medicine for wounds, smallpox, cervical cancer, and breast cancer. This plant is a potential source of new plant-derived drugs to cure numerous diseases for its multiple therapeutic functions. An in vitro study revealed that the methanol extract of B. cernua (stem) exhibits antioxidant activity according to DPPH and SOD methods, with IC50 values of 33 and 8.13 ppm, respectively. The extract also exerts antibacterial activity against Staphylococcus aureus with minimum bactericidal concentration of 1875 ppm. Further analysis revealed that the extract with a concentration of 1-2 ppm protects erythrocytes from the ring formation stage of Plasmodium falciparum, while the extract with a concentration of 1600 ppm induced apoptosis in the MCF-7 breast cancer cell line. GC-MS analysis showed 45 bioactive compounds consisting of cyclic, alkyl halide, organosulfur, and organoarsenic compounds. Virtual screening via a blind docking approach was conducted to analyze the binding affinity of each metabolite against various target proteins. The results unveiled that two compounds, namely, N-[ß-hydroxy-ß-[4-[1-adamantyl-6,8-dichloro]quinolyl]ethyl]piperidine and 1,3-phenylene, bis(3-phenylpropenoate), demonstrated the best binding score toward four tested proteins with a binding affinity varying from -8.3 to -10.8 kcal/mol. Site-specific docking analysis showed that the two compounds showed similar binding energy with native ligands. This finding indicated that the two phenolic compounds could be novel antioxidant, antibacterial, antiplasmodial, and anticancer drugs. A thorough analysis by monitoring drug likeness and pharmacokinetics revealed that almost all the identified compounds can be considered as drugs, and they have good solubility, oral bioavailability, and synthetic accessibility. Altogether, the in vitro and in silico analysis suggested that the extract of B. cernua (stem) contains various compounds that might be correlated with its bioactivities.

The Use of Biomaterials in Three-Dimensional Culturing of Cancer Cells.

Cell culture is an important tool in biological research. Most studies use 2D cell culture, but cells grown in 2D cell culture have drawbacks, including limited cell and cell-extracellular matrix interactions, which make it inaccurate to model conditions in vivo. Anticancer drug screening is an important research and development process for developing new drugs. As an experiment to mimic the cancer environment in vivo, several studies have been carried out on 3-dimensional (3D) cell cultures with added biomaterials. The use of hydrogel in 3D culture cells is currently developing. The type of hydrogel used might influence cell morphology, viability, and drug screening outcome. Therefore, this review discusses 3D cell culture research regarding the addition of biomaterials.

CeO2@NH2 functionalized electrodes for the rapid detection of SARS-CoV-2 spike receptor binding domain.

A detection method based on an electrochemical aptasensor has been developed as an alternative fast, portable, simple, inexpensive, and high-accuracy detection method for detecting the SARS-CoV-2 Spike Receptor Binding Domain (spike RBD). The CeO2@NH2 functionalized Screen Printed Carbon Electrode (SPCE) was used to immobilize an aminated aptamer of spike RBD protein via glutaraldehyde as a linker. The aptamer's interaction with the SARS-CoV-2 Spike RBD was measured via the [Fe(CN)6]4-/3- redox system signal. Experimental conditions were optimized using a Box-Behnken experimental design and showed that the optimal conditions of the SARS-CoV-2 aptasensor were 1.5 ng mL-1 of aptamer, immobilization of aptamer for 60 minutes, and Spike RBD incubation for 10 minutes. The developed aptasensor was able to detect the standard SARS-CoV-2 Spike RBD with a detection limit of 0.017 ng mL-1 in the range of 0.001-100 ng mL-1. This aptasensor was used to detect salivary and oropharyngeal swab samples of normal individuals with the addition of Spike RBD, and the recoveries were 92.96% and 96.52%, respectively. The testing on nasopharyngeal swab samples of COVID-19 patients showed that the aptasensor results were comparable with the qRT-PCR results. Thus, the developed aptasensor has the potential to be applied as a SARS-CoV-2 rapid test method for clinical samples.

Optimization of nucleic acid extraction methods for rapid detection in pandemic situations or diseases with high prevalence.

Image 1.

Oral Administration of Piperine as Curative and Prophylaxis Reduces Parasitaemia in Plasmodium berghei ANKA-Infected Mice.

Malaria remains a public health problem and a leading cause of death worldwide. Consequently, the discovery of novel agents, including substances from medicinal plants, is urgently needed. Piper nigrum has long been used by the community in the treatment of the symptoms of malaria. In a previous study, Piper nigrum was demonstrated to exhibit promising antiplasmodial activity against Plasmodium falciparum 3D7 and INDO strains. The aim of this study was to further investigate the antimalarial activity (curative and prophylactic) of piperine (a major isolated constituent of Piper nigrum) in Plasmodium berghei ANKA-infected mice. Piperine 10, 20, and 40 mg/kg body weight (bw), artesunate 5 mg/kg bw, and DMSO were administered orally for four days to different groups of Swiss Webster mice. Then, mice were monitored for parasitaemia, body weight, rectal temperature, survival rate, and clinical parameters. Piperine 40 mg/kg bw in curative and prophylactic tests had the maximum parasitaemia chemosuppression of 79.21% and 58.8% (p < 0.05), respectively, with a significant effect on the survival rate compared with control animals. In the curative test, piperine 40 mg/kg bw reduced the mean clinical score compared with the control group. Additionally, piperine showed an ability to protect organs (lungs, liver, spleen, and kidneys) from some damage in a dose-dependent manner. This study can be used as a basis for further discovery of novel chemotherapeutic or chemoprophylactic compounds.

The Potential use of a Curcumin-Piperine Combination as an Antimalarial Agent: A Systematic Review.

Malaria remains a significant global health problem, but the development of effective antimalarial drugs is challenging due to the parasite's complex life cycle and lack of knowledge about the critical specific stages. Medicinal plants have been investigated as adjuvant therapy for malaria, so this systematic review summarizes 46 primary articles published until December 2020 that discuss curcumin and piperine as antimalarial agents. The selected articles discussed their antioxidant, anti-inflammatory, and antiapoptosis properties, as well as their mechanism of action against Plasmodium species. Curcumin is a potent antioxidant, damages parasite DNA, and may promote an immune response against Plasmodium by increasing reactive oxygen species (ROS), while piperine is also a potent antioxidant that potentiates the effects of curcumin. Hence, combining these compounds is likely to have the same effect as chloroquine, that is, attenuate and restrict parasite development, thereby reducing parasitemia and increasing host survival. This systematic review presents new information regarding the development of a curcumin-piperine combination for future malaria therapy.

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.