Adjuvant therapy with zinc supplementation; anti-inflammatory and anti-oxidative role in multiple myeloma patients receiving autologous hematopoietic stem cell transplantation: a randomized controlled clinical trial.

Multiple myeloma (MM) patients are often accompanied by heightened levels of oxidative stress, even following bone marrow transplantation. Trace mineral supplements have been found to regulate and inhibit the activity of oxidative radicals and inflammatory factors, which are involved in the pathogenesis of MM. The study sought to evaluate the effectiveness of the supplementation by analyzing changes in oxidative, anti-oxidative, and inflammation markers. Patients were randomly assigned to a zinc or placebo group, with the former receiving 30 mg of zinc or placebo tablets daily for 1 month. Blood samples were collected from the patients on the day of transplantation, 15 days, and 30 days post-transplantation. Real-time PCR was employed to measure the expression of oxidative/antioxidative genes. Furthermore, the protein level of oxidative markers in serum samples was assessed. Finally, serum TNF-α concentrations were measured using the ELISA technique. The expression levels of SOD1, SOD2, and NRF2 genes were significantly higher on days 15 and 30 compared to the control group (P < 0.05), with a greater increase on day 30 (P < 0.05). Conversely, the expression levels of Keap1 and NOX2 genes were lower on day 30 than those of the control group (P < 0.05), with a further decrease from day 15 to day 30 (P < 0.05). The experimental group exhibited a notable reduction in TNF-α cytokine levels on day 30 compared to the control and placebo groups (P < 0.05). All findings were coordinated according to the nutritional questionnaire. Our findings suggest a potential benefit of zinc supplementation in managing the adverse effects of chemotherapy in MM patients, warranting further investigation.

Changes in hormones, Leukocyte Telomere Length (LTL), and p16INK4a expression in SM-exposed individuals in favor of the cellular senescence.

Sulfur mustard (SM) is a chemical warfare agent with well-known severe toxic effects and may cause long-term debilitating injuries. We aimed to evaluate aging and longevity in Iranian SM-exposed survivors using some endocrine and molecular biomarkers for the first time. Dehydroepiandrosterone (DHEA), prolactin (PRL), cortisol, testosterone, and luteinizing hormone (LH) were measured in 289 male SM-veterans and 66 age-matched males using the ELISA method. Leukocyte Telomere Length (LTL) measurement and p16INK4a expression were measured in the peripheral blood leukocytes of 55 males who were exposed to SM. We found a significantly lower serum DHEAS level and higher serum PRL level in SM-exposed groups (without any related to the severity of lung injuries) compared to healthy controls, but no significant difference in serum levels of cortisol, testosterone, and LH. The molar ratio of DHEAS/cortisol was significantly higher in controls compared to the SM-exposed individuals especially those with severe lung damage. Some biological parameters of allostatic load score such as DHEAS and DHEAS/cortisol ratio significantly decreased long-term after the SM exposure. Additionally, we found that LTL was shorter in SM-exposed veterans rather than unexposed controls while p16INK4a gene expression significantly increased in these groups. It seems that DHEAS, DHEAS/cortisol ratio, LTL, and p16INK4a gene expression have changed significantly in favor of cellular senescence in SM-exposed patients. Therefore, it seems that SM exposure increases biological age compared to chronological age in SM-exposed survivors.

PEGylated Pemetrexed and PolyNIPAM Decorated Gold Nanoparticles: A Biocompatible and Highly Stable CT Contrast Agent for Cancer Imaging.

This study describes a multifunctional nanoparticle platform for targeted CT imaging and therapy of cancers. Pemetrexed (conjugated with polyethylene glycol, MW 2000 Da) and polyNIPAM (PEGylated) were designed for targeted delivery to folate receptors and thermally ablated tumors, respectively. These moieties were coated on gold nanoparticles (7 and 30 nm), and the prepared compounds were characterized using 1H NMR, FT-IR, CHNS, DLS, TEM, TGA, and UV-vis. The resulting agents exhibited 2-4 times higher X-ray attenuation compared to Visipaque and demonstrated specific accumulation in tumor tissue (4T1 xenograft model) 90 min after injection in mice. The nanoparticles displayed anticancer activity against 4T1 and MDA-MB-231 breast cancer cells (IC50: 182.87 and 206.18 µg/mL) and good biocompatibility. Importantly, the platform showed excellent stability over a year and at pH 2-12 and temperature range of -78 to 40 °C, and a water-dichloromethane extraction method was optimized for efficient purification, facilitating large-scale production.

New insight into the role of the ADAM protease family in breast carcinoma progression.

Protease and adhesion molecules play a very emphasized role in the occurrence or progression of metastasis in many types of cancers. In this context, a molecule that contains both protease and adhesion functions play a crucial role in metastasis. ADAMs (a disintegrin and metalloprotease) are molecules with this special characteristic. Recently, a lot of attention has been attracted to various ADAM molecules and researchers have tried to elucidate the role of ADAMs in breast cancer occurrence and progression. Disrupting ADAMs protease and adhesion capabilities can lead to the discovery of worthy therapeutic targets in breast cancer treatment. In this review, we intend to discuss the mechanism of action of various ADAM molecules, their relation to pathogenic processes of breast cancer, and their potential as possible targets for breast cancer treatment.

Antimicrobial Potential of the Green Microalgae Isolated from the Persian Gulf.

Background: We aimed to investigate the antibacterial activity of Persian Gulf microalgae extracts on some Gram-positive and negative bacterial species in order to find new compounds with antibacterial activity. Methods: After sampling microalgae from December 2020 to April 2021 from the northernmost part of Qeshm Island in Persian Gulf, the antibacterial activity of methanolic and ethyl acetate extract of microalgae were tested in three concentrations of 125, 250, and 500 mg/ml on Gram-positive bacteria including Staphylococcus aureus, Bacillus cereus, and Gram-negative bacteria including Pseudomonas aeruginosa and Escherichia coli by disk-diffusion assay and the results were compared with two standard antibiotics including ciprofloxacin and streptomycin. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were assessed spectrophotometrically using microplate and enzyme-linked immunosorbent assay (ELISA) reader. Results: Methanolic and ethyl acetate extracts had antibacterial effects against Gram-positive and negative bacteria. Compared to ethyl acetate extract, the methanolic extract showed stronger effects on both Gram-positive and negative bacteria. The most antibacterial effect was related to methanolic extract with a concentration of 500 mg/ml on S. aureus by 14.6 mm inhibition zone. Evidence from MIC also confirmed that the lowest MIC was belonged to methanolic extract by 0.75 mg/ml against S. aureus. Interestingly, both of these extracts showed more antibacterial activity on Gram-positive bacteria than Gram-negative bacteria. Conclusion: The investigation proved the efficacy of microalgae extracts isolated from Persian Gulf as natural antimicrobials and suggested the possibility of employing them in medicines as antimicrobial agents.

Apple pectin-based Zataria multiflora essential oil (ZEO) nanoemulsion: An approach to enhance ZEO DNA damage induction in breast cancer cells as in vitro and in silico studies reveal.

Zataria multiflora essential oil (ZEO) is a natural complex of compounds with a high apoptotic potential against breast cancer cells and minor toxicity toward normal cells; however, similar to many essential oils, ZEO utilization in pharmaceutical industries has limitations due to its labile and sensitive ingredients. Nanoemulsification based on natural polymers is one approach to overcome this issue. In this study, an apple pectin-ZEO nanoemulsion (AP-ZEONE) was prepared and its morphology, FTIR spectra, and physical properties were characterized. Furthermore, it was shown that AP-ZEONE substantially suppresses the viability of MDA-MB-231, T47D, and MCF-7 breast cancer cells. AP-ZEONE significantly induced apoptotic morphological alterations and DNA fragmentation as confirmed by fluorescent staining and TUNEL assay. Moreover, AP-ZEONE induced apoptosis in MDA-MB-231 cells by loss of mitochondrial membrane potential (ΔΨm) associated with the accumulation of reactive oxygen species (ROS), G2/M cell cycle arrest, and DNA strand breakage as flow cytometry, DNA oxidation, and comet assay analysis revealed, respectively. Spectroscopic and computational studies also confirmed that AP-ZEONE interacts with genomic DNA in a minor groove/partial intercalation binding mode. This study demonstrated the successful inhibitory effect of AP-ZEONE on metastatic breast cancer cells, which may be beneficial in the therapy process.

New insights into the inhibitory roles and mechanisms of D-amino acids in bacterial biofilms in medicine, industry, and agriculture.

Biofilms are complex aggregates of microbes that are tightly protected by an extracellular matrix (ECM) and may attach to a surface or adhere together. A higher persistence of bacteria on biofilms makes them resistant not only to harsh conditions but also to various antibiotics which led to the emergence of problems in different applications. Recently, it has been discovered that many bacteria produce and release various D-amino acids (D-AAs) to inhibit biofilm formation, which made a great deal of interest in research into the control of bacterial biofilms in diverse fields, such as human health, industrial settings, and medical devices. D-AAs have various mechanisms to inhibit bacterial biofilms such as: (i) interfering with protein synthesis (ii) Inhibition of extracellular polymeric materials (EPS) productions (protein, eDNA, and polysaccharide) (iii) Inhibition of quorum sensing (autoinducers), and (iv) interfere with peptidoglycan synthesis, these various modes of action, enables these small molecules to inhibit both Gram-negative and Gram-positive bacterial biofilms. Since most biofilms are multi-species, D-AAs in combination with other antimicrobial agents are good choices to combat a variety of bacterial biofilms without displaying toxicity on human cells. This review article addressed the role of D-AAs in controlling several bacterial biofilms and described the possible or definite mechanisms involved in this process.

Immunomodulatory roles of microbiota-derived short-chain fatty acids in bacterial infections.

In recent years, an overwhelming amount of evidence has positively recommended a significant role of microbiota in human health and disease. Microbiota also plays a crucial role in the initiation, preparation, and function of the host immune response. Recently, it has been shown that short-chain fatty acids (SCFAs) are the primary metabolites of the intestinal microbiota produced by anaerobic fermentation, which contributes to the host-pathogen interaction. SCFAs, such as propionate, acetate, and butyrate, are bacterial metabolites with immunomodulatory activity, and they are indispensable for the maintenance of homeostasis. Some evidence indicates that they are involved in the development of infections. In the present study, we provide the latest findings on the role of SCFAs in response to bacterial infections.

Incorporation of Zataria multiflora essential oil into chitosan biopolymer nanoparticles: A nanoemulsion based delivery system to improve the in-vitro efficacy, stability and anticancer activity of ZEO against breast cancer cells.

In the search of new alternative anticancer agents, essential oils (Eos) play a critical role, exerting selective anti-cancer properties and limiting the toxicity of conventional therapies. However, these compounds still face some challenges. Nanoemulsification (NE) protects labile and sensitive EO ingredients until they are released in the system. Herein, Zataria Multiflora Essential Oil (ZEO) loaded into chitosan (CS) nanoparticles was prepared in aqueous solution by mild emulsification into nanometric particles. FTIR spectroscopy exhibited no covalent interaction between active groups of ZEO and functional groups of CS. The outcomes revealed that CS/ZEONE increasingly improves the proliferation inhibition rate of Breast cancer cells as confirmed by MTT, morphological changes, DNA fragmentation and FACS analyses. Our findings suggested that CS/ZEONE exposure induces apoptosis, generates ROS, and triggers mitochondrial membrane permeabilization as well as DNA damage without harming normal cells. To find out the mechanism more precisely, the interaction of CS/ZEONE with gDNA was elucidated and Intercalative binding with strong stabilization of the DNA helix has been proposed. In conclusion, our data suggested that CS/ZEONE can be further explored as a promising antiproliferative and therapeutic candidate against breast cancer.

Oxidative DNA damage induced by ROS-modulating agents with the ability to target DNA: A comparison of the biological characteristics of citrus pectin and apple pectin.

DNA targeting anticancer agents have been very successful in clinic, especially, when used in combinatorial therapy. But unfortunately, they often exhibit high levels of toxicity towards normal cells. Hence, much effort has been put into finding agents with more selectivity, and less toxicity. Pectins are natural polysaccharides, and beneficial nutritional fibers that have attracted attentions due to their antitumor properties. However, their molecular targets, and mechanism of action are widely unknown. Here, we have reported that citrus pectin (CP) and apple pectin (AP) selectively suppress viability in MDA-MB-231, MCF-7 and T47D human Breast cancer cells, while non-toxic to L929 normal cells. Upon CP, and AP treatments, cancer cells' ROS content increased rapidly, and led to the collapse of the mitochondrial transmembrane potential which functions upstream of the caspase-dependent apoptosis. CP and AP treated cancer cells were also arrested at the S and G1 or G2/M phases of the cell cycle, respectively. Furthermore, mRNA expression of Galectin-3 (a multi-functional lectin involved in cell adhesion, cell cycle, and apoptosis) reduced in both CP and AP treated cells. Growth inhibition of MDA-MB-231 cells by CP, and AP was concomitant with DNA damage (oxidation, and strand breaks). In this context, in an effort to clarify the mechanism of action, we showed that CP, and AP are able to interact with DNA. The strength and mode of DNA binding were established by spectroscopy techniques. We demonstrated that CP, and AP bind to dsDNA by intercalation, and groove binding/partial intercalation, respectively. In conclusion, our findings suggest that CP, and AP induce apoptosis in MDA-MB-231 cells by increasing the release of ROS, which may be related to the mitochondrial apoptosis pathway, and direct interactions with DNA. Our data indicate that these compounds may be potentially useful in cancer treatment.

DNA damage and telomere length shortening in the peripheral blood leukocytes of 20 years SM-exposed veterans.

Sulfur mustard (SM) is a vesicant chemical warfare agent, and a very potent alkylating agent. SM exerts its cytotoxicity via direct alkylation of biomacromolecules, and overproduction of reactive oxygen species (ROS). Previous studies have shown that SM-induced oxidative stress has adverse effects on antioxidant defense system, and damages lipids and proteins. The aim of this study was to investigate the effect of SM-induced oxidative stress on DNA damage, and cellular senescence in SM-exposed victims. For this purpose, MDA levels as a measure of oxidative stress in the serum, 8-oxo-dG content of the genomic DNA, and OGG1 expression as two biomarkers of oxidative DNA damage, as well as, telomere length, and p16INK4a expression as two biomarkers of cellular senescence were measured in the peripheral blood leukocytes of 215 males who were exposed to SM 20 to 25 years ago, and 53 unexposed healthy males as the control group. Our results indicated that the levels of 8-oxo-dG, and OGG1 mRNA expression were significantly higher in SM-exposed individuals. Furthermore, a significant increase in the expression of p16INK4a was observed in SM-exposed patients, and leukocyte telomere length (LTL) was also significantly shorter in severe/very severe cases of SM-exposed patients when compared with unexposed controls. In conclusion, our data indicate that oxidative DNA damage is higher in SM-exposed patients, and their immune system has subjected to cellular senescence.

Monitoring ZEO apoptotic potential in 2D and 3D cell cultures and associated spectroscopic evidence on mode of interaction with DNA.

Recognizing new anticancer compounds to improve Breast cancer treatment seems crucial. Essential oil of Zataria Multiflora (ZEO) is a secondary metabolite with some biological properties, yet underlying cellular and molecular anticancer properties of ZEO is unclear. GC/MS analysis revealed that carvacrol is the major ingredient of the essential oil. ZEO increasingly suppressed viability in MDA-MB-231, MCF-7 and T47D Breast cancer cells while nontoxic to L929 normal cells in monolayer cell cultures (2D), whereas MDA-MB-231 multicellular spheroids (3D) were more resistant to inhibition. ZEO significantly induced cell apoptosis confirmed by fluorescent staining, flow cytometry analysis and DNA fragmentation in MDA-MB-231 2D and 3D cell cultures. ZEO increased ROS generation and subsequent loss of ΔΨm, caspase 3 activation and DNA damage which consequently caused G1 and G2/M cell cycle arrest in a dose- and time-dependent manner in 2D. S phase arrest occurred in cell spheroids therefore ZEO possible DNA interaction with gDNA was investigated and revealed ZEO binds DNA via intercalation. Altogether, these data corroborate anticancer properties of ZEO and suggest that cell culture format (2D monolayer vs. 3D spheroid) plays a critical role in drug response and provides new insights into the mechanisms underlying ZEO cytotoxicity effect on Breast cancer cells.

Association of glutathione S-transferase polymorphisms with the severity of mustard lung.

Introduction: Glutathione S-transferase (GST) is one of the major detoxifiers in alveoli. Polymorphism in GST genes can influence the ability of individuals to suppress oxidative stress and inflammation. The present study was aimed to explore the hypothesis that the genetic polymorphisms of GST T1, M1 and P1 are associated with the severity of the mustard lung in the sulfur mustard-exposed individuals. Methods: Blood samples were taken from 185 sulfur mustard-exposed and 57 unexposed subjects. According to the stage of the mustard lung, sulfur mustard-exposed patients were categorized in the mild/moderate and severe/very severe groups. A multiplex PCR method was conducted to identify GSTM1 and GSTT1 null genotypes. To determine the polymorphisms of GSTP1 in exon 5 (Ile105Val) and exon 6 (Ala114Val), RFLP-PCR method was performed. Results: The frequency of GSTM1 homozygous deletion was significantly higher in the severe/very severe patients compared with the mild/moderate subjects (66.3% vs. 48%, P = 0.013). The GSTM1 null genotype was associated with the severity of mustard lung (adjusted odds ratio [OR], 2.257; 95% CI, 1.219-4.180). There was no significant association between GSTT1 and GSTP1 polymorphisms with the severity of the mustard lung. Conclusion: The different distribution of GSTM1 null genotype in severe/very severe and mild/moderate groups indicated that the severity of the mustard lung might be associated with the genetic polymorphism(s).