Manilkara zapota "chicozapote" as a fruit source of health-beneficial bioactive compounds and its effects on chronic degenerative and infectious diseases, a review.

Manilkara zapota "chicozapote" is an autochthonous evergreen tree from the Southern regions of Mexico, Belize, and Guatemala. Currently, it is widely distributed and extensively grown in Mexico and Southeast Asia. Traditionally, different structures of the plant have been used for medical purposes; seeds have diuretic and purgative properties, aiding in digestive complications and eliminating bladder and kidney stones. Tree bark has antidiarrheal, antipyretic, antibiotic, and astringent properties. Fruits and leaves have been used to treat cold, cough, diarrhea, indigestion, fever, hemorrhages, wounds, and ulcers. Chicozapote fruit is yellow and brown, with an oval shape and rough peel, it is an excellent source of nutrients, such as sugars, proteins, amino acids, and minerals, and is rich in phytochemical components, such as flavonoids, phenolic acids, and tannins. These bioactive compounds exert several biological activities, i.e., as an antioxidant, antidiabetic, antimicrobial, anti-inflammatory, cytotoxic, and anti-arthritic agents, to name a few. These beneficial properties assist in preventing chronic and degenerative diseases, such as cancer, diabetes, neurological, infectious, and cardiovascular diseases. The use of chicozapote is still limited to its fresh form, and its non-edible structures produce a lot of waste. Therefore, an alternative valorizing and preserving strategy is to use the fruit as a raw source to design functional foods and pharmacological products. Here, the nutritional and phytochemical profiles and the current view regarding methodologies and conditions, for the extraction and characterization of its bioactive compounds, are described, and focus is placed on their multiple biological effects and specific functional mechanisms.

Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer.

Chromosomal instability (CIN), the persistent reshuffling of chromosomes during mitosis, is a hallmark of human cancers that contributes to tumor heterogeneity and has been implicated in driving metastasis and altering responses to therapy. Though multiple mechanisms can produce CIN, lagging chromosomes generated from abnormal merotelic attachments are the major cause of CIN in a variety of cell lines, and are expected to predominate in cancer. Here, we quantify CIN in breast cancer using a tumor microarray, matched primary and metastatic samples, and patient-derived organoids from primary breast cancer. Surprisingly, misaligned chromosomes are more common than lagging chromosomes and represent a major source of CIN in primary and metastatic tumors. This feature of breast cancers is conserved in a majority of breast cancer cell lines. Importantly, though a portion of misaligned chromosomes align before anaphase onset, the fraction that remain represents the largest source of CIN in these cells. Metastatic breast cancers exhibit higher rates of CIN than matched primary cancers, primarily due to increases in misaligned chromosomes. Whether CIN causes immune activation or evasion is controversial. We find that misaligned chromosomes result in immune-activating micronuclei substantially less frequently than lagging and bridge chromosomes and that breast cancers with greater frequencies of lagging chromosomes and chromosome bridges recruit more stromal tumor-infiltrating lymphocytes. These data indicate misaligned chromosomes represent a major mechanism of CIN in breast cancer and provide support for differential immunostimulatory effects of specific types of CIN. Significance: We surveyed the single-cell landscape of mitotic defects that generate CIN in primary and metastatic breast cancer and relevant models. Misaligned chromosomes predominate, and are less immunostimulatory than other chromosome segregation errors.

Mesenchymal Stem Cells: Case Report of an Adjuvant Ambulatory Therapy for a COVID-19 High-Risk and Steroid-hypersensitive Patients.

INTRODUCTION: Due to the rapid progression of COVID-19 to severe and critical stages, thousands of patients have required the use of intensive care unit (ICU) treatment, placing an excessive strain on health systems. Immunomodulatory effects of Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) have shown promising results in the treatment of patients with COVID-19. However, the effect of promptly applied cell therapy on ambulatory patient prognosis has not been described. This case report presents the clinical outcome of a multimorbid, steroid-hypersensitive, COVID-19 patient treated with WJ-MSCs transplantation. CASE PRESENTATION: A 67-year-old woman with Type 2 diabetes, overweight (82 kg, 168 cm, BMI = 29.053), hypertension (190/60 mmHg) and steroid-hypersensitivity, tested positive for COVID-19 after presenting typical symptoms such as fatigue, chest pain, myalgia, nasal congestion, dysgeusia, anosmia and oxygen saturation (SpO2) 94% - 96%, with normal body temperature (36°C). The patient received pharmacologic treatment but, when symptoms worsened, WJ-MSCs were transplanted to modulate the suspected onset of the cytokine release syndrome. Significant improvement of symptoms and clinical parameters (inflammatory markers and CT score) was observed, and the patient fully recovered within a short period of time. CONCLUSION: The present case report exhibits the favorable outcome of using Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) as an ambulatory and adjuvant therapy for COVID-19. Prompt WJ-MSCs infusion can be a safe ambulatory adjuvant therapy in COVID-19 infection care, preventing disease progression to critical stages and avoiding hospital overcrowding.

Antioxidant, Anti-Inflammatory and Cytotoxic Activity of Phenolic Compound Family Extracted from Raspberries (Rubus idaeus): A General Review.

Raspberries (Rubus idaeus) possess a wide phenolic family profile; this serves the role of self-protection for the plant. Interest in these compounds have significantly increased, since they have been classified as nutraceuticals due to the positive health effects provided to consumers. Extensive chemical, in vitro and in vivo studies have been performed to prove and validate these benefits and their possible applications as an aid when treating several chronic degenerative diseases, characterized by oxidative stress and an inflammatory response. While many diseases could be co-adjuvanted by the intake of these phenolic compounds, this review will mainly discuss their effects on cancer. Anthocyanins and ellagitannins are known to provide a major antioxidant capacity in raspberries. The aim of this review is to summarize the current knowledge concerning the phenolic compound family of raspberries, and topics discussed include their characterization, biosynthesis, bioavailability, cytotoxicity, antioxidant and anti-inflammatory activities.

Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs.

Potassium channels are important regulators of cellular homeostasis and targeting these proteins pharmacologically is unveiling important mechanisms in cancer cell biology. Here we demonstrate that pharmacological stimulation of the Kv11.1 potassium channel activity results in mitochondrial reactive oxygen species (ROS) production and fragmentation in breast cancer cell lines and patient-derived organoids independent of breast cancer subtype. mRNA expression profiling revealed that Kv11.1 activity significantly altered expression of genes controlling the production of ROS and endoplasmic-reticulum (ER) stress. Characterization of the transcriptional signature of breast cancer cells treated with Kv11.1 potassium channel activators strikingly revealed an adaptive response to the potentially lethal augmentation of ROS by increasing Nrf2-dependent transcription of antioxidant genes. Nrf2 in this context was shown to promote survival in breast cancer, whereas knockdown of Nrf2 lead to Kv11.1-induced cell death. In conclusion, we found that the Kv11.1 channel activity promotes oxidative stress in breast cancer cells and that suppression of the Nrf2-mediated anti-oxidant survival mechanism strongly sensitized breast cancer cells to a lethal effect of pharmacological activation of Kv11.1.

Effect of Curcumin Nanoemulsions Stabilized with MAG and DAG-MCFAs in a Fructose-Induced Hepatic Steatosis Rat Model.

Current changes in diet, characterized by an increase in the intake of sweetened beverages, are heavily related to metabolic disorders such as non-alcoholic fatty liver. This condition can produce simple steatosis and, in worse cases, potentially result in steatohepatitis, fibrosis, and cirrhosis, comparable to the damage caused by the consumption of more or less 20-30 g of alcohol per day. The main objective of this research was to evaluate the effect of curcumin (Curcuma longa) nanoemulsions, using mono- and diacylglycerides medium chain fatty acids as stabilizers in an in vivo hepatic steatosis rat model. Pathology was induced by providing 30% fructose intake in the drinking water. Globule sizes under 200 nm that were stable for 4 weeks were obtained; curcumin encapsulated in the nanoemulsion was >70%. The results revealed an improvement regarding body and liver weight in the animals treated with curcumin nanoemulsions. A decrease in total cholesterol, LDL, AST/ALT, and HDL in serum was observed; however, no apparent improvement regarding serum glucose or triacylglycerides values was noted. Histological analysis showed a significant decrease in the extent of steatosis, inflammation, and brown adipose tissue in the treated animals.

Effective antimicrobial activity of ZnO and Yb-doped ZnO nanoparticles against Staphylococcus aureus and Escherichia coli.

Nanostructured Zn1-xYbxO (0.0 ≤ x ≤ 0.1) powders were prepared by the solution method using polyvinyl alcohol (PVA) and sucrose. The effect of the ytterbium doping content on the structural, morphological, optical and antimicrobial properties was analyzed. X-ray diffraction (XRD) analysis revealed that the hexagonal wurtzite structure was retained, and no secondary phases due to doping were observed. The crystallite size was under 20 nm for all the Zn1-xYbxO (0.0 ≤ x ≤ 0.1) powders. The optical band gap was calculated, and the results revealed that this value increased with the ytterbium content, and the Eg values varied from 3.06 to 3.10 eV. The surface chemistry of the powders was analyzed using X-ray photoelectron spectroscopy (XPS), and the results confirmed the oxidation state of ytterbium as 3+ for all the samples. Zn1-xYbxO (0.0 ≤ x ≤ 0.1) nanoparticles were tested as antimicrobial agents against Staphylococcus aureus and Escherichia coli, resulting in a potential antimicrobial effect at most of the tested concentrations. These results were used in an artificial neural network (ANN). The results showed that it is possible to generate a model capable of forecasting the absorbance with good precision (error of 1-2%).

Curcumin Nanoemulsions Stabilized with Modified Phosphatidylcholine on Skin Carcinogenesis Protocol.

BACKGROUND: Cancer is one of the main causes of death by disease; several alternative treatments have been developed to counteract this condition. Curcumin (diferuloylmethane), extracted from the rhizome of Curcuma longa, has antioxidant, anti-inflammatory, and anti-cancer properties; however, it has low water solubility and poor intestinal absorption. Carrier systems, such as nanoemulsions, can increase the bioavailability of lipophilic bioactive compounds. OBJECTIVE: To evaluate the effect of curcumin nanoemulsions prepared with lecithin modified with medium-chain fatty acids as an emulsifier, on the expression of the Cdk4, Ccne2, Casp8 and Cldn4 genes involved in the carcinogenesis process in K14E6 transgenic mice. METHODS: The emulsifier was prepared by interesterification of medium-chain fatty acids, pure lecithin, and immobilized phospholipase-1 on Duolite A568. An Ultraturrax homogenizer and a Branson Ultrasonic processor were used for the preparation of nano-emulsions, and a Zetasizer evaluated the particle size. qRT-PCR analysis was performed to quantify the cancer-related genes expressed in the K14E6 mice. The development and evolution of skin carcinogenesis were assessed through histological analysis to compare cell morphology. RESULTS: Ca 59% of the MCFA were incorporated via esterification into the PC within 12 hours of the reaction. An emulsifier yield used to formulate the NE of 86% was achieved. Nanoemulsions with a particle size of 44 nm were obtained. The curcumin nano-emulsion group had a 91.81% decrease in the tumorigenesis index and a reduction in tumor area of 89.95% compared to the sick group. Histological analysis showed that the group administered with free curcumin developed a microinvasive squamous cell carcinoma, as opposed to the group with nanoemulsion which presented only a slight inflammation. In gene expression, only a significant difference in Cdk4 was observed in the nanoemulsion group.

Anti-inflammatory Activity of Curcumin in Gel Carriers on Mice with Atrial Edema.

Curcumin is a bioactive compound with proven antioxidant and anti-inflammatory activities, but has low water solubility and dermal absorption. The inflammatory process is considered as the biological response to damage induced by various stimuli. If this process fails to self-regulate, it becomes a potential risk of cancer. The objective of this work was to evaluate the anti-inflammatory activity of curcumin administered to mice with induced atrial edema using two topical vehicles: organogels and O/W-type nanogels at pH 7, Organogels and O/W-type nanogels at pH 7 were prepared, characterized and the anti-inflammatory activity was assessed. A histopathological analysis of mouse ears was performed and two gel formulations were selected. Thermograms of organogels indicated that increasing the gelling agent improved the stability of the system. Deformation sweeps confirmed a viscoelastic behavior characteristic of gels in both systems. During the anti-inflammatory activity evaluations, the nanogels demonstrated greater activity (61.8 %) than organogels; Diclofenac® (2-(2,6-dichloranilino) phenylacetic acid), used as a control medication achieved the highest inhibition (85.4%); however, the drug produced the death of 2 (40%) of the study subjects caused by secondary adverse events. Histopathological analysis confirmed the data.

Preparation, characterization and bioavailability by oral administration of O/W curcumin nanoemulsions stabilized with lysophosphatidylcholine.

Curcumin is the main and most abundant bioactive component in Curcuma longa L. with documented properties in the prevention and treatment of chronic degenerative and infectious diseases. However, curcumin has low solubility in aqueous media, hence low bioavailability when administered orally. The use of nanoemulsions as carriers can provide a partial solution to bioavailability restrictions. In our study, O/W nanoemulsions of curcumin were prepared using lysophosphatidylcholine, a phospholipid with proven emulsification capacity; nevertheless, such qualities have not been previously reported in the preparation of nanoemulsions. Lysophosphatidylcholine was obtained by enzymatic removal of one fatty acid residue from phosphatidylcholine. The objective of our work was to formulate stable curcumin nanoemulsions and evaluate their bioavailability in BALB/c mice plasma after oral administration. Formulated nanoemulsions had a droplet size mean of 154.32 ± 3.10 nm, a polydispersity index of 0.34 ± 0.07 and zeta potential of -10.43 ± 1.10 mV; stability was monitored for 12 weeks. Lastly, in vivo pharmacokinetic parameters, using BALB/c mice, were obtained; namely, Cmax of 610 ± 65.0 µg mL-1 and Tmax of 2 h. Pharmacokinetic data revealed a higher bioavailability of emulsified as opposed to free curcumin. Research regarding other potential emulsifiers that may provide better health benefits and carry nano-encapsulated bioactive compounds more effectively, is necessary. This study provides important data on the preparation and design of nanoencapsulated Curcumin using lysophosphatidylcholine as an emulsifier.

Cancer cell specific cytotoxic effect of Rhoeo discolor extracts and solvent fractions.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional or folk medicine has led to the discovery of important bioactive substances used in several health-related areas. Phytochemicals in Rhoeo discolor (R. discolor) extracts have proven to have important cancer cell specific cytotoxic activity. In the present research, we determined the cytotoxic effect of extracts of R. discolor, a plant commonly used in Mexico for both medicinal and ornamental purposes. AIM OF THE STUDY: We evaluated the cytotoxic effects against three representative human cancer cell lines: HT-29 colon cancer, Hep-G2 liver cancer and PC-3 prostate cancer cell lines, as well as a control fibroblast cell line NIH 3T3. MATERIALS AND METHODS: Ten different crude extracts were tested along with fractions derived from the five most bioactive crude extracts. Analytical data, HPLC-MS-TOF, revealed a high content of phenolic compounds such as anthocyanins, ferulic, vanillic, chlorogenic and p-coumaric acid in the extracts. Phenolic compounds have previously been reported as health beneficial with antioxidant and potential cancer specific cytotoxic effects. RESULTS: Studies revealed that low concentrations of these crude bioactive extracts (10µg/ml) and their fractions (50µg/ml) were effective as cancer specific cytotoxic agents, since they caused a significant proliferation inhibition on cancer cell lines (up to 94.2% in HT-29, 92.9% in Hep-G2 and 61.8% in PC-3 of apoptosis induction) with little harm to the control cell line (no higher than 28.3% apoptosis induction), and, importantly, the most effective extracts were mainly water, methanol and ethanol based. CONCLUSIONS: These results suggest that a diet containing these compounds may function as a medical aid or chemoprotective.

Antimicrobial Activity of Rhoeo discolor Phenolic Rich Extracts Determined by Flow Cytometry.

Traditional medicine has led to the discovery of important active substances used in several health-related areas. Phytochemicals in Rhoeo discolor extracts have proven to have important antimicrobial activity. In the present study, our group determined the antimicrobial effects of extracts of Rhoeo discolor, a plant commonly used in Mexico for both medicinal and ornamental purposes. We evaluated the in vitro activity of phenolic rich extracts against specifically chosen microorganisms of human health importance by measuring their susceptibility via agar-disc diffusion assay and flow cytometry: Gram-positive Listeria innocua and Streptococcus mutans, Gram-negative Escherichia coli and Pseudomonas aeruginosa, and lastly a fungal pathogen Candida albicans. Ten different extracts were tested in eight different doses on all the microorganisms. Analytical data revealed a high content of phenolic compounds. Both agar-disc diffusion assay and flow cytometry results demonstrated that Pseudomonas aeruginosa was the least affected by extract exposure. However, low doses of these extracts (predominantly polar), in a range from 1 to 4 µg/mL, did produce a statistically significant bacteriostatic and bactericidal effect on the rest of the microorganisms. These results suggest the addition of certain natural extracts from Rhoeo discolor could act as antibacterial and antimycotic drugs or additives for foods and cosmetics.