Long-term effect of exposure to triethylene glycol dimethacrylate (TEGDMA) on male mouse reproduction.

Our study investigated the impact on male mouse fertility and reproduction of long-term (14 weeks) exposure to triethylene glycol dimethacrylate (TEGDMA), a co-monomer of resin-based compounds, at doses of 0.01, 0.1, 1, and 10 ppm. Test and control mice were then paired with sexually mature untreated female mice and their fertility evaluated. Females paired with males exposed to all TEGDMA doses exhibited a significant decline in pregnancy rates, and significant increases in the total embryonic resorption-to-implantation ratio, except for males exposed to 0.01 ppm TEGDMA. Males in the highest dose group (10 ppm) showed significant increases in seminal vesicle and preputial gland weights. They also had significantly higher serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) than the controls, and the 0.01 ppm dosage group for FSH levels. TEGDMA exposure resulted in notable histopathological alterations in the testis, with detachment of germ cells and shedding of germinal epithelium into the tubule lumen. These results strongly indicate that TEGDMA exposure has detrimental consequences on the reproductive abilities and functions in male mice through disruption of the standard hormonal regulation of the reproductive system, leading to changes in spermatogenesis and ultimately leading to decreased fertility.

MDSC expansion during HIV infection: regulators, ART and immune reconstitution.

Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.

Oral Rinses: Some Kill and Some Cripple Candida albicans.

OBJECTIVES: Oral healthcare professionals play a crucial role in guiding patients toward evidence-based choices among the many available oral rinses. In this study, we explored how specific oral rinse formulations affect the viability and modulate critical virulence traits of the opportunistic fungal pathogen Candida albicans. MATERIALS AND METHODS: We assessed the effects of these oral rinses on the production of germ tube, production of phospholipase and hemolysin, as well as biofilm formation. RESULTS: We found that oral rinses containing cetylpyridinium chloride (CPC) and chlorhexidine (CHX) showed the greatest fungicidal activity with the lowest MFCs (0.38% and 0.78%, respectively). Oral rinses based on zinc chloride and sodium fluoride with Miswak bark extract (MIS) or essential oils (EO) had much lower fungicidal activity (8-16 times lower) compared to CHX and CPC. However, they had a significantly greater impact on the virulence traits of C. albicans. They reduced germ tube production by 86% - 89% (versus 42% for CHX and 29% for CPC), completely inhibited phospholipase and hemolysin production, and together with the CPC-based oral rinse, exerted the greatest reductions in biofilm formation across all tested concentrations. This was in contrast to both the controls and CHX, which had a minimal effect on biofilm formation. CONCLUSION: By inhibiting the virulence factors the oral rinse can have a crippling effect on C. albicans, weakening this opportunistic pathogen and hindering its potential to cause infection.

A Novel Approach: Targeting Virulence Factors of Candida albicans with Essential Oil Components.

AIMS: Focusing on phytochemicals to target the virulence factors of Candida albicans is a promising avenue for novel antifungal compounds. Given the limited prior research on essential oil (EO) components and their specific effects on C. albicans virulence, our study aimed to explore their impact and uncover the underlying mechanisms. METHODS AND RESULTS: We examined the effects on viability, dimorphic transition, biofilm formation, and changes in the expression of critical virulence-related genes. The results showed that Dehydrocostus Lactone, displayed the most potent growth-inhibiting activity with the lowest MIC value, followed by Thymol, and Costunolide. A substantial, dose-dependent decrease in germ tube formation occurred after exposure to sub-inhibitory concentrations of the EO components, with Carvacrol, Dehydrocostus Lactone, and Thymol exerting the most potent inhibitory effects. Across sub-inhibitory concentrations, Alpha Bisabolol consistently showcased the most potent antibiofilm activity followed by lower but significant inhibitory effects with Dehydrocostus Lactone, Thymol, Alpha Pinene, Costunolide, Carvone, and Carvacrol. Alpha Bisabolol, Alpha Pinene and Dehydrocostus Lactone caused almost total downregulation of ACT1 whilst minimal changes occurred in expression of HWP1, SAP4, ALS3 and ECE1. CONCLUSIONS: Considering that actin is essential for various cellular processes, including budding, cell shape maintenance, and the formation of filaments in C. albicans, it is a plausible hypothesis that inhibiting ACT1 or disturbing actin's normal functioning could potentially affect the fungus's virulence, which warrants additional research and exploration. This study underscores the potent antifungal and anti-virulence properties of various EO components which effectively cripple C. albicans and reduce its disease-causing ability. This innovative approach holds promise for effective clinical therapies.

Non-monotonic effects of Bisphenol A Dimethacrylate on male mouse reproductive system and fertility leads to impaired conceptive performance.

As an estrogenic agent, Bisphenol A Dimethacrylate (Bis-DMA) may incite alterations in both the reproductive tract and the neuroendocrine axis, and thus have the potential to affect the proper development, maturity and conceptive performance in animals. We investigated the consequences of 14 weeks of exposure to different concentrations of Bis-DMA on male mouse conceptive performance. Male mice were exposed to Bis-DMA (0, 0.1 mg/L, 1.0 mg/L or 10 mg/L) via drinking water, and the effects on fertility, reproductive organ weights, reproductive hormone levels, sperm counts and testicular histology were assessed. We clearly demonstrate that prolonged exposure of male mice to Bis-DMA negatively affects fertility and reproduction causing significant reductions in sperm counts, non-monotonic effects on serum LH and testosterone levels, increased seminal vesicle weights, lower number of embryonic implantations and viable fetuses, as well as, increased embryonal resorptions in females mated by Bis-DMA treated males. Furthermore, Bis-DMA caused abnormalities in testicular infrastructure with atrophic seminiferous tubules exhibiting intraepithelial vacuolization and disorganization, loss and shedding of germ cells into the lumen, and presence of apoptotic cells. Our data collectively suggest that Bis-DMA adversely affects male fertility and reproduction by interference with normal hormone signaling in the testis, inducing changes in testicular infrastructure and ultimately leading to impaired reproductive function and fertility.

The Role of p53 in HIV Infection.

PURPOSE OF REVIEW: This review aims to elucidate the multifaceted role of the tumor suppressor protein p53 in the context of HIV infection. We explore how p53, a pivotal regulator of cellular processes, interacts with various facets of the HIV life cycle. Understanding these interactions could provide valuable insights into potential therapeutic interventions and the broader implications of p53 in viral infections. RECENT FINDINGS: Recent research has unveiled a complex interplay between p53 and HIV. Several reports have highlighted the involvement of p53 in restricting the replication of HIV within both immune and nonimmune cells. Various mechanisms have been suggested to unveil how p53 enforces this restriction on HIV replication. However, HIV has developed strategies to manipulate p53, benefiting its replication and evading host defenses. In summary, p53 plays a multifaceted role in HIV infection, impacting viral replication and disease progression. Recent findings underscore the importance of understanding the intricate interactions between p53 and HIV for the development of innovative therapeutic approaches. Manipulating p53 pathways may offer potential avenues to suppress viral replication and ameliorate immune dysfunction, ultimately contributing to the management of HIV/AIDS. Further research is warranted to fully exploit the therapeutic potential of p53 in the context of HIV infection.

Flow cytometric characterization of cell surface markers to differentiate between fibroblasts and mesenchymal stem cells of different origin.

Introduction: Identification and purification of mesenchymal stem cells (MSCs) expanded in culture for therapeutic use is crucial for improved yield and optimal results. Fibroblasts are the most common cell type in connective tissue and are commonly found as contaminants of MSC cultures, affecting cell yield and potentially causing tumour formation after cell transplantation. In the current study, we wished to identify cell surface markers that can differentiate MSCs of different origins from fibroblasts. Material and methods: Mesenchymal stem cells were isolated from bone marrow, adipose tissue, Wharton's jelly, and placental tissue, and fibroblasts were isolated from foreskin (as a negative control) in order to examine the differences in the expression of a panel of 14 different cell surface markers using multiplex flow cytometry. Results: Our results indicate that the following markers could be useful in differentiating between fibroblasts and MSCs derived from the following: adipose tissue - CD79a, CD105, CD106, CD146, and CD271; Wharton's jelly - CD14, CD56, and CD105; bone marrow - CD105, CD106, and CD146; and placental tissue - CD14, CD105, and CD146. Furthermore, we found that, contradictory to previous studies, CD26 is not fibroblast specific. Conclusions: The results of our study indicate that cell surface markers may prove to be a useful tool in the discrimination between MSCs of different origins and fibroblasts, and thus may be used to authenticate the identity of the isolated cells.

Lower Concentrations of the Glyphosate-Based Herbicide Roundup® Cause Developmental Defects in Artemia salina.

Roundup® is the most used glyphosate-based herbicide. During agricultural use it may directly contaminate existing aquatic ecosystems, posing severe concerns for the safety of nontarget terrestrial and aquatic organisms. We investigated the outcome of exposure to different concentrations of glyphosate in Roundup on cyst hatchability, toxicity, and teratogenic effects in the aquatic crustacean Artemia salina that inhabits diverse types of salt waters and, as a filter feeder, carries a greater risk of being exposed to pollutants. We found that exposure to 144 and 288 µg/ml glyphosate in Roundup resulted in cysts unable to complete diapause, and hatchability was completely inhibited during all exposure times tested (17-48 h). A glyphosate concentration of 288 µg/ml in Roundup was lethal to A. salina nauplii, and the lower concentrations (9, 18, 36, 72 µg/ml) had no significant effects on viability. In addition, sublethal and environmentally safe concentrations of glyphosate (0.72 µg/ml) in Roundup affected the early development of A. salina nauplii, with significantly decreased body lengths and reduced widths of the tail, abdomen, and head. The increased level of catalase activity observed in nauplii exposed to 0.72 µg/ml glyphosate for 24 h and those exposed to 7.2 and 72 µg/ml glyphosate for 48 h may be linked to excessive reactive oxygen species levels that had been induced by Roundup. In conclusion, Roundup containing >72 µg/ml glyphosate totally inhibited hatching of cysts and exerted toxic effects on A. salina nauplii. The increased prevalence of developmental defects in the nauplii observed at 0.72 µg/ml glyphosate signifies possible teratogenicity of Roundup exposure even at environmentally relevant concentrations of glyphosate, possibly due to disturbance of the antioxidant defenses, which needs further investigation. Environ Toxicol Chem 2023;42:1586-1594. © 2023 SETAC.

The role of IL-1ß during human immunodeficiency virus type 1 infection.

Interleukin (IL)-1ß is a key innate cytokine that is essential for immune activation and promoting the inflammatory process. However, abnormal elevation in IL-1ß levels has been associated with unwanted clinical outcomes. IL-1ß is the most extensively studied cytokine among the IL-1 family of cytokines and its role in pathology is well established. During the course of human immunodeficiency virus type 1 (HIV-1) infection, the level of this proinflammatory cytokine is increased in different anatomical compartments, particularly in lymphatic tissues, and this elevation is associated with disease progression. The aim of this review is to address the pathological roles play by IL-1ß in the light of enhancing HIV-1 replication, driving immune cell depletion, and chronic immune activation. The role of IL-1ß in HIV-1 transmission (sexually or vertically 'from mother-to-child') will also be discussed. Additionally, the impact of the available antiretroviral therapy regimens on the levels of IL-1ß in HIV-1 treated patients is also discussed. Finally, we will provide a glance on how IL-1ß could be targeted as a therapeutic strategy.

The clinical and prognostic significance of CMTM6/PD-L1 in oncology

The recent discovery of CMTM6 and to a lesser extent CMTM4, two members of the chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family, as master positive regulators of PD-L1 expression, the primary ligand of programmed cell death 1 (PD-1), on tumor and immune cells has opened new horizons for investigating the role of CMTM6/CMTM4 in different aspects of oncology including their clinical and prognostic values in different cancer types. The absence of a specific review article addressing the available results about the clinical and prognostic roles of CMTM6 alone and/or in combination with PD-L1 in cancer has encouraged us to write this paper. (AU)

T-cell evasion and invasion during HIV-1 infection: The role of HIV-1 Tat protein.

T-cell-mediated immune responses play indispensable roles in the defense against infectious pathogens including human immunodeficiency virus type 1 (HIV-1) which can establish a persistent infection that leads to many alterations in T-cell-mediated immunity. The latter include T-cell hyperactivation and depletion, both of which are essential for disease progression. Determining the factors and mechanisms pathways that lead to such abnormalities in T-cell mediated immunity during HIV-1 infection and ascertaining how the virus is able to evade immune responses elicited by T cells are critical for understanding the pathophysiology of HIV-1 infection, which in turn, could lead to new insights that may accelerate the development of novel and effective therapeutic strategies. To this end, we addressed the roles played by HIV-1 Tat protein, one of the first proteins to be expressed, in the pathogenesis of HIV-1 infection, focusing on the pathological effects of this protein in the cellular adaptive immune response in which T cells are intimately involved.

The clinical and prognostic significance of CMTM6/PD-L1 in oncology.

The recent discovery of CMTM6 and to a lesser extent CMTM4, two members of the chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family, as master positive regulators of PD-L1 expression, the primary ligand of programmed cell death 1 (PD-1), on tumor and immune cells has opened new horizons for investigating the role of CMTM6/CMTM4 in different aspects of oncology including their clinical and prognostic values in different cancer types. The absence of a specific review article addressing the available results about the clinical and prognostic roles of CMTM6 alone and/or in combination with PD-L1 in cancer has encouraged us to write this paper.

CMTM6 as a master regulator of PD-L1.

Immune checkpoint proteins, such as programmed cell death receptor 1 (PD-1) and its ligand (PD-L1), play critical roles in the pathology of chronic inflammatory pathological conditions, particularly cancer. In addition, the activation of PD-1/PD-L1 pathway is involved in mediating resistance to certain anti-cancer chemo- and immuno-therapeutics. Unfortunately, targeting the PD-1/PD-L1 pathway by the available anti-PD-1/PD-L1 drugs can benefit only a small proportion of cancer patients. Thus, studying the factors that regulate the expression of these immune checkpoint proteins is of central importance in this context. Recent investigations have identified CMTM6 and, to a lesser extent, CMTM4, as master regulators of PD-L1 expression in various cancer cells. Understanding the mechanisms by which such proteins upregulate the expression of PD-L1 in tumor cells, and determining the potential regulators of CMTM6 expression in different types of cancers will accelerate the development of new therapeutic targets and/or lead to the enhancement of the currently available PD-1/PD-L1 blockade therapies.

Anatomical Distribution of Myeloid-Derived Suppressor Cells During HIV Infection.

In recent years, expansion of myeloid-derived suppressor cells (MDSCs) has been reported to play a detrimental role in the pathogenesis of human immunodeficiency virus (HIV) infection. Much effort has been focused to comprehend the mechanisms and factors that regulate the expansion of such unwanted immune cell populations. Of particular interest has been the mechanisms by which MDSCs could contribute to the pathogenesis of HIV infection. So far, the studies have been restricted to MDSCs in the circulatory system of HIV patients, but not in other tissue compartments. In fact, lymphatic tissues/organs are the primary sites where HIV replication and immune depletion/dysfunction occur during the course of HIV infection. Therefore, investigating the anatomical distribution of MDSCs in such compartments is essential to understand the role that they play in the pathogenesis of HIV infection. Hence, we aim to shed light on the available literature about the anatomical distribution of MDSCs during HIV infection and compare it with the distribution of MDSCs in other pathological conditions, mainly cancer.

Myeloid-derived suppressor cells and the pathogenesis of human immunodeficiency virus infection.

There are several mechanisms by which human immunodeficiency virus (HIV) can mediate immune dysfunction and exhaustion during the course of infection. Chronic immune activation, after HIV infection, seems to be a key driving force of such unwanted consequences, which in turn worsens the pathological status. In such cases, the immune system is programmed to initiate responses that counteract unwanted immune activation, for example through the expansion of myeloid-derived suppressor cells (MDSCs). Although the expansion of immune suppressor cells in the setting of systemic chronic immune activation, in theory, is expected to contain immune activation, HIV infection is still associated with a remarkably high level of biomarkers of immune activation. Paradoxically, the expansion of immune suppressor cells during HIV infection can suppress potent anti-viral immune responses, which in turn contribute to viral persistence and disease progression. This indicates that HIV hijacks not only immune activation but also the immune regulatory responses to its advantage. In this work, we aim to pave the way to comprehend how such unwanted expansion of MDSCs could participate in the pathology of acute/primary and chronic HIV infection in humans, as well as simian immunodeficiency virus infection in rhesus macaques, according to the available literature.

The impact of MDSCs on the efficacy of preventive and therapeutic HIV vaccines.

In spite of four decades of research on human immunodeficiency virus (HIV), the virus remains a major health problem, affecting tens of millions of people around the world. As such, developing an effective preventive/protective and therapeutic vaccines against HIV are essential to prevent/limit the continuous spread of the virus as well as to control the disease progression and to completely eradicate the virus from HIV infected patients, respectively. There are several factors that have impeded the development of such vaccines, and we need to gain further insight into these factors in order to enhance our knowledge concerning the proper immune activation pathways in the hope of accelerating the development of the highly sought-after vaccine. Recently, new immune cell populations, namely the myeloid-derived suppressor cells (MDSCs), were added to the battle of HIV infection. Indeed, MDSCs seem to play a central role in determining the efficacy of therapeutic and preventive vaccines, especially because vaccines, in general, enhance immune responses, while as a potent immunosuppressor cell population, MDSCs, in turn, subvert and limit the activation of immune responses. Hence, in this work, we sought to address the role of MDSCs in the context of preventive/protective, as well as, therapeutic HIV vaccines.

Recent advances in myeloid-derived suppressor cell biology.

In recent years, studying the role of myeloid-derived suppressor cells (MDSCs) in many pathological inflammatory conditions has become a very active research area. Although the role of MDSCs in cancer is relatively well established, their role in non-cancerous pathological conditions remains in its infancy resulting in much confusion. Our objectives in this review are to address some recent advances in MDSC research in order to minimize such confusion and to provide an insight into their function in the context of other diseases. The following topics will be specifically focused upon: (1) definition and characterization of MDSCs; (2) whether all MDSC populations consist of immature cells; (3) technical issues in MDSC isolation, estimation and characterization; (4) the origin of MDSCs and their anatomical distribution in health and disease; (5) mediators of MDSC expansion and accumulation; (6) factors that determine the expansion of one MDSC population over the other; (7) the Yin and Yang roles of MDSCs. Moreover, the functions of MDSCs will be addressed throughout the text.

Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine.

Chronic immune activation and inflammation are unwanted consequences of many pathological conditions, since they could lead to tissue damage and immune exhaustion, both of which can worsen the pathological condition status. In fact, the immune system is naturally equipped with immunoregulatory cells that can limit immune activation and inflammation. However, chronic activation of downregulatory immune responses is also associated with unwanted consequences that, in turn, could lead to disease progression as seen in the case of cancer and chronic infections. Myeloid-derived suppressor cells (MDSCs) are now considered to play a pivotal role in the pathogenesis of different inflammatory pathological conditions, including different types of cancer and chronic infections. As a potent immunosuppressor cell population, MDSCs can inhibit specific and non-specific immune responses via different mechanisms that, in turn, lead to disease persistence. One such mechanism by which MDSCs can activate their immunosuppressive effects is accomplished by secreting copious amounts of immunosuppressant molecules such as interleukin-10 (IL-10). In this article, we will focus on the pathological role of MDSC expansion in chronic inflammatory conditions including cancer, sepsis/infection, autoimmunity, asthma and ageing, as well as some of the mechanisms by which MDSCs/IL-10 contribute to the disease progression in such conditions.

Blue light emitting diodes enhance the antivirulence effects of Curcumin against Helicobacter pylori.

Introduction. Growing concern about the increasing frequency of resistance of Helicobacter pylori to the available antimicrobial agents worldwide has encouraged the search for new strategies in treating and eradicating H. pylori infections. Endoscopic blue-light therapy has been used in patients with H. pylori gastritis with limited success due to subsequent repopulation with H. pylori. Clinical trials using Curcumin could not eradicate infection either.Aim. We studied the effect of blue light emitting diodes (LEDs) in conjunction with Curcumin on H. pylori, since this has not been previously reported.Methodology. We examined the effect of Curcumin with and without irradiation with blue LEDs on the viability of H. pylori and four key factors important for colonization and establishment of H. pylori infection, namely urease production, motility, adhesion and biofilm formation.Results. We found that a combination of Curcumin and blue LEDs caused significant reductions in viability, urease production, motility, haemagglutination activity, as well as increased disruption of mature preformed biofilms of H. pylori, in comparison to Curcumin alone (P<0.0001), at sublethal concentrations of Curcumin.Conclusion. Targeting the virulence factors of H. pylori with blue LED photoactivated Curcumin would theoretically cripple this pathogen from colonizing and causing tissue damage and perhaps overcome the problem of repopulation with H. pylori that often occurs following endoscopic blue-light therapy.

Biocompatibility evaluation of Jordanian Portland cement for potential future dental application.

BACKGROUND: The demand for novel Portland cement (PC)-based formulations to be used in dental applications is ever increasing in viewing the foregoing knowledge on the favorable effects of these formulations on cellular proliferation and healing, leading to treatment success. AIM: This study investigated the effect of white and gray mineral trioxide aggregate (W-MTA and G-MTA) and white and gray Jordanian PC (W-PC and G-PC) in their raw state on the viability of Balb/C 3T3 fibroblasts using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MATERIALS AND METHODS: Materials were prepared in the form of disks, with a diameter of 5 mm and a thickness of 2 mm. In the first experiment, Balb/C 3T3 fibroblasts were cultured with the material disks using culture plate inserts. In the second experiment, material elutes were added to cultured cells. The elutes were prepared by adding 2 ml serum-free media to 10 disks of each material and then incubated at 37°C for different time intervals. Material elutes were analyzed using ion chromatography for traces of calcium. The data were analyzed using analysis of variance followed by Dunnett test (α = 0.05) or Tukey test (α = 0.05). RESULTS: In response to material disks, G-PC had a proliferative effect on cells at day 1 and day 2 with a significant difference from the control at day 1. G-MTA reduced cell viability with a significant difference from the control level at day 2. Elutes of PC showed biocompatible and even proliferative effects on Balb/C 3T3 fibroblasts. Calcium ions were found to leach continuously over the measurement period for all the materials tested in this work. CONCLUSION: Jordanian PC in its raw state was found to be biocompatible, and the results of this work give promise of its wider use as a base for further development to improve the physiochemical and mechanical properties of the material.