Silver nanoparticles' impact on the gene expression of the cytosolic adaptor MyD-88 and the interferon regulatory factor IRF in the gills and digestive gland of mytilus galloprovincialis.

Silver nanoparticles (AgNPs) have been reported as stressors for the bivalves' immune system at different regulatory levels, impacting the detection step and receptors, and other mediators, as well as effector molecules. However, studies on how AgNPs impact the transmission of signals from receptors and whether they have an effect on mediators and transcription factors are still scarce. This study aims to investigate the effect of 12 hours of in vivo exposure to 100 µg/L of AgNPs on the gene expression of the cytosolic adaptor Myeloid, the differentiation protein 88 (MgMyD88-b), and the interferon regulatory factor (Me4-IRF) in the gills and digestive gland of Mytilus galloprovincialis, before and after blocking two major uptake pathways of nanoparticles (clathrin- and caveolae-mediated endocytosis). The results illustrate a tissue-specific gene expression of the MgMyD88-b and the Me4-IRF in the gills and digestive gland of M. galloprovincialis. In the gills, AgNPs did not significantly impact the expression of the two genes. However, blocking the caveolae-mediated endocytosis decreased the expression of Me4-IRF. However, inhibition of clathrin-mediated endocytosis in the digestive gland recorded a significant decrease in the expression of MgMyD88-b. Overall, the inhibition of the AgNPs' uptake routes have highlighted their potential interference with the immune response through the studied mediators' genes, which need to be studied further in future investigations.

Immunological effects of AFM1 in experimental subchronic dosing in mice prevented by lactic acid bacteria.

AIM: Recently, higher contamination by aflatoxin M1 (AFM1) has been detected in many countries. Unfortunately, many tons of contaminated milk and milk byproducts are removed from the food chain to avoid human contamination; as a consequence of higher economic losses. Fewest number of studies are interested to AFM1 detoxification using lactic acid bacteria. MATERIALS AND METHODS: In this study, AFM1-degradation using Lactobacillus paracasei BEJ01 (LPBEJ01) was tested in vitro. The preventive effect of LPBEJ01 against AFM1 immunobiological effects in mice are treated orally during 3 weeks with 100 µg AFM1, LPBEJ01 (2 × 109 CFU/ml∼2 mg/kg p.c.) and a mixture of AFM1 and LPBEJ01. RESULTS: In vitro LPBEJ01 was found able to absorb 98% of AFM1 (100 µg/ml) in liquid medium after 24 h and more than 95% of AFM1 could be eliminated after 24 h in a solid-state fermentation. Animals treated with AFM1 obtained lower body weight than the control ones. The mitogenic response of spleen mononuclear cells (SMCs) in vivo was higher in mice treated with AFM1. The SMC of mice treated with AFM1 produced lower levels of IL-2, higher levels IL-4 and no effect on IL-10 production. The peritoneal macrophages of mice that treated with AFM1 released less H2O2, while mice exposed orally with the mixture of AFM1 and LPBEJ01 produced higher levels. CONCLUSION: LPBEJ01 was safe and it did not have any sign of toxicity. It can be used as an additive for AFM1-detoxification contamination in the food chain in countries suffering from this problem.

Antimicrobial peptides Pep19-2.5 and Pep19-4LF inhibit Streptococcus mutans growth and biofilm formation.

With this study, we investigated the effect of synthetic antimicrobial peptides Pep19-2.5 and Pep194LF alone or in combination with antibiotics on S. mutans growth and biofilm formation/disruption. We also examined the cytotoxic effect of each peptide on monocytes. S. mutans was cultured in the presence of different concentrations of each peptide. We showed that Pep19-2.5 and Pep19-4LF were able to significantly (p ≤ 0.01) inhibit the growth of S. mutans. The synthetic peptides also decreased biofilm formation by S. mutans. Furthermore, both peptides reduced the viability of S. mutans in already formed biofilms. The combination of each peptide with antibiotics (penicillin/streptomycin, P/S) produced additive interactions which inhibited S. mutans growth and biofilm formation. Pep19-2.5 and Pep19-4LF were nontoxic, as they did not decrease monocyte viability and did not increase the lactate dehydrogenase activity of the exposed cells. In conclusion, synthetic peptides Pep19-2.5 and Pep19-4LF did inhibit S. mutans growth and its capacity to form biofilm. Both peptides were found to be nontoxic to monocytes. These data provide new insight into the efficacy of synthetic peptides Pep19-2.5 and Pep19-4LF against S. mutans. These peptides may thus be useful in controlling the adverse effects of this cariogenic bacterium in human.

STAT1 and STAT6 Act as Antagonistic Regulators of PPARγ in Diabetic Patients with and without Cardiovascular Diseases.

BACKGROUND: The processes that mediate an inflammatory environment and increase atherosclerosis in diabetes are not well understood. Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) and atherosclerosis. PPARγ promotes changes in lipid metabolism, especially in fatty acid (FA) trafficking, and the activity of PPARγ could be modulated by diabetes phenotype patients. Fatty acid translocase CD36 is one of the advanced PPARγ targets to arbitrate this action. In the current study, we investigated the potential role of signal transducer and activator of transcription STAT1 and STAT6 signaling linked to PPARγ and its implication in the modulation of lipid metabolism. METHODS: Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to quantify target genes in Peripheral Blood Mononuclear Cells (PBMCs) isolated from two diabetic groups: diabetic patients with cardiovascular diseases (D.CVD) and without cardiovascular diseases (D). RESULTS: We demonstrated that PPARγ and CD36 mRNA expressions were downregulated along D.CVD compared to D (p = 0.002; p = 0.04; respectively). Decreased CD36 was accompanied by elevated levels of plasma triglyceride (TG) concentrations, 0.83 ± 0.29 vs. 2.46 ± 0.22), respectively. Furthermore, STAT1 was significantly more expressed in D.CVD (p = 0.01). On the other hand, we demonstrated that STAT6 induces a significant level of PPARγ mRNA expression in D patients (p = 0.01). CONCLUSIONS: Our results suggest that the expression and activity of PPARγ mediates CD36 in PBMCs and varies with respect to STAT6 and STAT1 trafficking in diabetic patients with and without cardiovascular diseases.

Effect of exposure time, particle size and uptake pathways in immune cell lysosomal cytotoxicity of mussels exposed to silver nanoparticles.

Cytotoxicity evaluation of hemocytes (lysosomal membrane stability [LMS] assay) from Mytilus galloprovincialis Lamarck, exposed to a sublethal dose (100 µg/L) of two size of silver nanoparticles (AgNPs: <50 nm and <100 nm) - prior to and after inhibition of potential uptake pathways (i.e., clathrin- and caveolae-mediated endocytosis) within different times of exposure (3, 6, 12 h) - showed that there was a significant cytotoxic effect on immune cells of mussels exposed for different times to either AgNP size (p < 0.01); the greater effect was with the smaller size. However, hemocytes seemed more sensitive to the larger AgNP after clathrin-mediated endocytosis was blocked (p < 0.01); this was not so with inhibition of caveolae-mediated endocytosis. Dimethyl-sulfoxide (DMSO) did not impart a carrier-mediated effect despite an enhanced cytotoxicity when DMSO was present with AgNP. From these results, it is concluded that the immunotoxicity of AgNP in mussels was size-dependent as well as length of exposure-dependent. It was also clear that nanoparticles (NP) internalization mechanisms were a major factor underlying any toxicity.

The extracellular matrix of the oleolytic biofilms of Marinobacter hydrocarbonoclasticus comprises cytoplasmic proteins and T2SS effectors that promote growth on hydrocarbons and lipids.

The assimilation of the nearly water insoluble substrates hydrocarbons and lipids by bacteria entails specific adaptations such as the formation of oleolytic biofilms. The present article reports that the extracellular matrix of an oleolytic biofilm formed by Marinobacter hydrocarbonoclasticus at n-hexadecane-water interfaces is largely composed of proteins typically cytoplasmic such as translation factors and chaperones, and a lesser amount of proteins of unknown function that are predicted extra-cytoplasmic. Matrix proteins appear to form a structured film on hydrophobic interfaces and were found mandatory for the development of biofilms on lipids, alkanes and polystyrene. Exo-proteins secreted through the type-2 secretion system (T2SS) were shown to be essential for the formation of oleolytic biofilms on both alkanes and triglycerides. The T2SS effector involved in biofilm formation on triglycerides was identified as a lipase. In the case of biofilm formation on n-hexadecane, the T2SS effector is likely involved in the mass transfer, capture or transport of alkanes. We propose that M. hydrocarbonoclasticus uses cytoplasmic proteins released by cell lysis to form a proteinaceous matrix and dedicated proteins secreted through the T2SS to act specifically in the assimilation pathways of hydrophobic substrates.

Histopathological indices and inflammatory response in the digestive gland of the mussel Mytilus galloprovincialis as biomarker of immunotoxicity to silver nanoparticles.

BACKGROUND: Histopathological assessments approaches in bivalves have become an important tool in environmental toxicology. This study seeks to develop a quantitative histopathological index (Ih) and inflammation score as biomarkers in the aim to assess the health status of nanoparticles exposed mussels. METHODS: Digestive gland hematoxylin and eosin (H&E) stained sections from Mytilus galloprovincialis were assessed after in vivo exposure (for 3, 6 and 12 h) to silver nanoparticles (Ag-NPs < 50 nm and Ag-NPs < 100 nm) prior and after manipulating the potential uptake pathways (clathrin- and caveolae-mediated endocytosis) using amantadine and nystatin as blockers. Quantitative models evaluate the impacts of nanoparticles size, as well as their uptake routes within different time of exposure on the inflammation intensity, the digestive tubules histomorphometry and the histopathological indices. RESULTS: Silver nanoparticles clearly induced histopathological alterations in digestive gland (maximum inflammation 2.75 with AgNP < 100 nm [p < 0.05]; significant Ih with AgNP < 50 nm and AgNP < 100 nm at different time-points [p < 0.05]). Significant Ih were recorded after uptake routes were blockade: AgNP < 50 nm + nystatin and AgNP < 100 nm + amantadine; [p < 0.05] all time-points. CONCLUSIONS: Histopathological assessments showed to be promising tool in nanotoxicity which seems to depend on nanoparticles size, exposure time and interestingly to uptake routes. It was not clear: is it the length of exposure or the size of particles is more impactful.

Histopathology and analyses of inflammation intensity in the gills of mussels exposed to silver nanoparticles: role of nanoparticle size, exposure time, and uptake pathways.

Environmentally induced perturbation of health parameters lead to morphological changes associated to the inflammatory response. Hematoxyline and eosin (H&E)-stained gill filaments sections were examined for such changes and inflammation intensity was scored according to a quantitative model in order to evaluate the health status of in vivo exposed (for 3, 6, and 12 h) mussels to silver nanoparticles (Ag-NPs <50 nm and Ag-NPs <100 nm) prior and after the inhibition of two potential uptake pathways (clathrin- and caveolae-mediated endocytosis) with the aid of pharmaceutical inhibitors (amantadine and nystatin). The impacts of the nanoparticles (NPs) size, as well as their uptake routes within different time of exposure on the inflammatory response were assessed. The results showed that Ag-NPs clearly induced morphological changes associated to the inflammatory response in gill tissues (Mann-Whitney p values were <.05). It is also clear that the length of the exposure as well as the NP size highly impacted inflammation intensity (highest histopathological indices recorded with Ag-NPs <100 nm). Also, the routes of NPs entry noticed to be major factor underlying inflammatory response (significant inflammation intensity reported with Ag-NPs <50 nm after blockade of uptake routes; p <.05). Throughout, it was concluded that inflammation intensity was related to NPs size and exposure time. Overall, uptake routes are shown to be the major factor underlying nanotoxicity.

PSMA-PSA clones controlled by full Akt phosphorylation (T308+,S473+) recapitulate molecular features of human prostate cancer.

BACKGROUND: (PSMA+,PSA+) and (PSMA+,PSA-) are the two most individual clones that we have previously identified during prostate cancer (PC) progression. However, molecular signatures associated with these distinct PSMA-PSA prostate clones and their specific correlation with disease outcome is yet to be defined. AIM: Since Akt is a major pathway involved in the critical activating events that leads to malignant form of the disease, we studied the involvement of full Akt activation (T308+,S473+) connected with serum PSA levels, tissue PSMA expression and angiogenic activity on the emergence of (PSMA+,PSA+) and (PSMA+,PSA-) PC clones. METHODS: The study was carried out in 6 normal prostate, 25 benign prostate hyperplasia (BPH) and 23 (PC). Immunohistochemical analysis was performed to study the expression of PSMA, PSA, pAkt(T308), pAkt(S473) and CD34 in prostate tissues. The evaluation of angiogenesis was made by CD34 immune marker. Serum levels of PSA were assayed by Immulite autoanalyser. RESULTS: The most relevant result showed that, among PC patients with pAkt (T308+,S473+) profile, patients that exhibit the (PSMA+,PSA+) clone have .higher serum PSA levels, tissue PSMA expression and angiogenic activity than those with (PSMA+,PSA-) clone. Although have the same (PSMA+,PSA+) prostate clone, BPH patients have distinct molecular-biological features compared to PC patients among pAkt (T308+,S473+) profile. In fact, among patients with maximal Akt activation, the (PSMA+,PSA+) PC clone is characterized by higher serum PSA levels, tissue PSMA production and intensive angiogenic activity than (PSMA+,PSA+) BPH clone. CONCLUSION: These findings emphasize the potential role of the full Akt activation (T308+,S473+) in expansion of several PSMA-PSA prostate clones capable of driving both human PC initiation as well as progression to a metastatic phenotype. Pinpoint patients according to PSMA-PSA clones could recapitulate the histological and molecular features of human PC and may offer a novel approach for controlling metastasis.

PSMA/PSA ratio evaluated by immunohistochemistry may improve diagnosis of prostate cancer.

Prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) measured in serum are not fully satisfactory as biomarkers of prostate cancer (PC). Results obtained in this article indicated that PSMA/PSA ratio evaluated by immunohistochemistry in normal prostate (NP), benign prostatic hyperplasia (BPH), and PC at the individual level could be a useful tool for diagnosis and prognosis of PC. PSMA and PSA were equally expressed in NP and the PSMA/PSA ratio was 1.22 ± 0.15. Data also indicated that PSMA/PSA ratio fluctuates in BPH and PC compared to NP. In BPH, the PSMA/PSA ratio was around 0.47 ± 0.02, whereas it's significantly increased in PC, about 4.95 ± 0.83. In parallel, the highest PSMA/PSA ratio was associated with high intratumoral angiogenesis in PC patients with (PSMA+,PSA+) profile.

Comparison of long-term anti-RBD SARS-CoV-2 antibody response following different vaccination schemes in Tunisia.

AIM: The study aimed to compare long-term vaccine-induced humoral immunity following different vaccines regimens. METHODS: Anti-S-RBD total antibody levels were measured in blood samples of 167 participants nearly 6 months post-vaccination. Participants had received one; two or four doses of Pfizer vaccine or who received a third dose of mRNA vaccine (Pfizer) and primed with mRNA (Pfizer/Moderna), adenoviral (AstraZeneca/Jonson & Jonson) or inactivated (CoronaVac/Sinopharm) vaccine. RESULTS: Among all vaccination regimens, fourth dose of Pfizer achieved the highest S-RBD antibody titers. Nevertheless, the third dose of mRNA vaccine primed with adenoviral vaccine achieved the lowest titers of S-RBD antibody. Notably, the group that received a third dose of mRNA primed with two doses of mRNA vaccine exhibited higher S-RBD antibody compared to groups inoculated with a third dose of mRNA and primed with inactivated or adenovirus vaccine. CONCLUSION: Our data showed the superiority of three mRNA vaccinations compared to third heterologous vaccine (inactivated of adenoviral) including mRNA as booster in terms of humoral immunogenicity. Our findings supporting the use of additional booster shot from a more potent vaccine type such as mRNA vaccines. Nevertheless, due to the limited number of subjects, it is difficult to extrapolate the results of our study to the whole of Tunisian population. Future studies should investigate a larger cohort and other potential correlates of protection, such as cellular immunity and how it is affected by different vaccination schemes after long-term post-vaccination.

A novel regulation of PSMA and PSA expression by Q640X AR in 22Rv1 and LNCaP prostate cancer cells.

We have investigated the expression of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) transcripts in androgen-dependent (LNCaP) and androgen-independent (22Rv1) prostate cancer cell lines. We also enquired whether Q640X CTE-truncated androgen receptor (AR) has an impact on transcription of mRNA for PSMA and PSA in transfected androgen-sensitive prostate cancer LNCaP cells. Wild type LNCaP, 22Rv1 prostate cancer cells, prostate stromal cells (PrSC) and LNCaP cells transfected with p-Q640X AR, p-WT AR or p-C3 empty plasmids were studied. The expression of PSMA and PSA were detected by real-time PCR after transfection for 4 and 7 days. Expression of mRNAs for PSA was sixfold greater than PSMA in wild type LNCaP cells. In contrast, the wild type androgen refractory 22Rv1 cell line reacted almost exactly the opposite way reverse to LNCaP cells, since the transcription of mRNA for PSMA almost twofold greater than PSA. Non-transfected human PrSC responded similarly to PSMA mRNA and PSA mRNA was not detected in these cells. Q640X AR transfected LNCaP cells downregulated the expression of PSMA and PSA genes after 7 days. Our results demonstrate that Q640X mutated AR may have an important regulatory role in mediating the PSMA and PSA genes expression during the progression of prostate cancer from androgen-dependence to androgen-independence. Understanding their functional properties and mechanisms by which ARs involved in regulation of PSMA and PSA expression will allow the identification of new target therapies for the treatment of hormone-resistant prostate cancer.

Lactobacillus paracasei BEJ01 prevents immunotoxic effects during chronic zearalenone exposure in Balb/c mice.

BACKGROUND AND AIM: Zearalenone (ZEN) is an estrogenic mycotoxin produced by numerous Fusarium species in pre- or post-harvest cereals. ZEN displays a potent estrogenicity in livestock and also causes severe immunological problems. The aims of this study were to isolate a new ZEN-degrading micro-organism for biological detoxification, to examine its ability to degrade ZEN in liquid medium, and to evaluate its potential for in vivo preventitive effects against ZEN (as would occur with contaminated feed)-induced immunomodulation in mice. MATERIALS AND METHODS: Lactobacillus paracasei BEJ01 (LP) isolated from Tunisian artisanal butter was found to display significant binding ability to ZEN in phosphate-buffered saline (i.e. 96.6%) within 24 h of incubation. The in vivo study was conducted using Balb/c mice that received either vehicle (control), LP only (at 2 × 10(9 )cfu/l, ∼2 mg/kg BW), ZEN alone (at 40 mg/kg BW), or ZEN + LP daily for 15 d. RESULTS: Compared to control mice, ZEN treatment led to significantly decreased body weight gains and decrements in all immune parameters assessed. The addition of LP to ZEN strongly reduced the adverse effects of ZEN on each parameter. In fact, mice receiving ZEN + LP co-treatment displayed no significant differences in the assayed parameters as compared to the control mice. The exposures to the bacteria alone had no adverse effects in the mice. CONCLUSION: From these data, we conclude that LP bacteria could be beneficial in human and animals for protection against immunotoxicity from ZEN at high levels and during chronic exposures.

Cellular distribution and heterogeneity of Psa and Psma expression in normal, hyperplasia and human prostate cancer.

BACKGROUND: As promising targets for in vivo diagnostic,prognostic and therapeutic approaches, the distribution and staining pattern of prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) in tumors are of significant interest. AIMS: To compare the cellular distribution and heterogeneity of PSA and PSMA expression in normal prostate (NP), benign prostatic hyperplasia (BPH) and primary prostatic tumors and to analyze their relation with the angiogenic activity according to Gleason grade (low, medium and high) in primary PC. METHODS: The study was carried out in 6 NP, 44 BPH and 39 PC. Immunohistochemical analysis was performed. Monoclonal antibodies 3E6 and ER-PR8 were used to assess PSMA and PSA expression respectively. The evaluation of angiogenesis was made by CD34 immune marker. RESULTS: In our study we noticed differences in the intracellular localization of the PSMA immunostaining which seem to be related to the normal and pathological context. A significant number of primary tumors presented with apical pattern of PSMA (28/39); whereas a relevant part of NP samples and BPH samples showed cytoplasmic localization (4/6 and 30/44,respectively) in luminal epithelial cells. Compared to PSMA, PSA was preferentially localized in cytoplasmic compartment in all type of prostate. A direct correlation between histological grade, PSMA expression and angiogenic activity could be demonstrated in primary PC. CONCLUSIONS: Simultaneous stains with PSA and PSMA in individual prostate tissue will greatly improve the detection rate and identify a high risk PC that could progress to metastatic phenotype. Our findings clearly support the feasibility but also direct the potential of PSMA-targeted in vivo therapeutic approaches in PC patients rather than PSA especially those with poorly differentiated adenocarcinoma.

SMAD3, Cell proliferation and lymph nodes metastasis in breast cancer hormone-dependent.

INTRODUCTION: Tumor Growth Factor-ß (TGF-ß) is a multifunctional cytokine that plays a crucial role in various biological processes. TGF-ß is also involved in various pathologies including breast cancer (BC). BC is strongly dependent on hormone receptors such as Estrogen receptors (ERa, ERb) and Progesterone Receptor (PR). AIM: To audit the potential cross-talk between TGF-ß and the molecular distribution of hormone receptors (ERs and PR). METHODS: The current study analyzes the expression patterns of SMAD3, ERα, ERß and PR in 40 breast tumor tissues using qRT-PCR. Furthermore, the Ki-67 and HER2/neu status have been detected by Immunohistochemistry. RESULTS: Our results show a decrease in the SMAD3 expression in 27 of the 40 cases while its expression is increased in the remaining 13 cases (p=0.003). The over-expression of SMAD3 is associated with high tumor grades. Moreover, there is a significant positive correlation between SMAD3+ with a high proliferative index and metastases (p=0.001 and p=0.01respectevely). The SMAD3 expression relative to (ERα, ERß) subgroups shows a significant association of SMAD3+ with the (ERα+, ERß+) subgroups (p=0.009). The same is true for PR, our results show a significant association of SMAD3+ with PR+ (p=0.02). Moreover, analysis of the expression of molecular subgroups (SMAD3+, ERα+, ERß+) and (SMAD3+, PR+) compared to clinical and pathological information shows a significant association with high grade tumors, a high proliferation index (p=0.02, p= 0.01 respectively) and lymph node infiltration. CONCLUSION: It is concluded that SMAD3 can promote cell proliferation and metastases in (ERα+, ERß+) and PR+ breast cancer.

Immunometabolism mRNA expression phenotypes and reprogramming of CD14 in T2DM with or without CVD.

BACKGROUND/AIM: Type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) have a significant impact on the expression of genes in peripheral blood mononuclear cells (PBMCs). The primary objective of this study was to investigate the role of two signaling pathways, STAT1/6, and two important modulators of immunometabolism, leptin and PPARs, in the development of T2DM with and without CVD. Furthermore, the study aimed to assess the correlation between these factors and the dynamics of CD14 in PBMCs. This research was conducted within the context of a growing body of literature on the complex pathophysiology of T2DM and its association with CVD. Prior studies have indicated that T2DM is characterized by an imbalance in immunometabolism and the involvement of various signaling pathways. MATERIALS AND METHODS: Blood samples were collected from a total of 47 subjects, including 7 healthy volunteers, 20 individuals diagnosed with diabetes and cardiovascular disease (D.CVD) and another 20 individuals diagnosed with diabetes only (D). PBMCs were isolated from these samples, and the expression levels of leptin, PPARγ, PPARα, and CD14 genes were measured using Real-Time PCR. RESULTS: The most relevant result showed that diabetic patients with CVD had significantly higher levels of leptin expression, which was positively correlated with STAT1 (r = 0.7497, p = 0.0001). On the other hand, diabetic patients without CVD had elevated PPARγ expression, which was strongly correlated with STAT6 (r = 0.8437, p = 0.0001). Interestingly, we found a significant increase in the PPARγ/ PPARα ratio in the D.CVD group compared to the D group (4.273 ± 0.9531; 7.52 ± 3.556, p = 0.0479). Moreover, CD14 expression was significantly reduced in this group compared to diabetic patients without CVD. CONCLUSION: These findings suggested that the immunometabolic imbalance in T2DM was driven by a STAT1/Leptin phenotype in diabetic patients with CVD and by a STAT6/PPARγ phenotype in diabetic patients without CVD. Taking into account STAT1/Leptin and STAT6/PPARγ profiling could help clinicians identify novel therapeutic targets for T2DM and other related diseases.

Differences in leucocytes and inflammation-based indices among critically ill patients owing to SARS-CoV-2 variants during several successive waves of COVID-19 pandemic.

BACKGROUND/AIM: Inflammatory indices are useful informative markers in assessing the severity of the COVID-19 disease course; however, their involvements during series waves of SARS-CoV-2 virus outbreaks in critical patients with COVID-19 remain unclear. Hence, we aimed to ascertain the changing dynamics of the combined inflammatory indices (NLR, dNLR, CLR, LMR, PLR, SII, and SIRI) and their associations with clinical outcomes in severe COVID-19 patients during serial waves of SARS-CoV-2. PATIENTS AND METHODS: We retrospectively enrolled 163 severe COVID-19 patients admitted to the ICU during six SARS-CoV-2 waves. RESULTS: We found that most of patients admitted to the ICU were from the fourth wave. Patients in the fourth wave were considerably younger and had the highest percentage of ARDS than other waves. The highest CRP was found in the first wave, while the lowest in patients admitted in the sixth wave. Although most of the COVID-19 waves were marked with leukocytosis, neutrophilia, and lymphocytopenia, the lowest of both NLR and dNLR were found in the fourth wave "Delta wave" and the lowest of both CLR and SII were observed in "Omicron wave". Interestingly, during most of the COVID-19 waves, the derived combined inflammatory ratio NLR, dNLR, CLR, SII and SIRI were sustained at high levels in fatal cases at the last day of hospitalization, while these indices declined in the alive group at the end of ICU hospitalization. No major difference was identified in lymphocyte count between admission and the last day of hospitalization in both deceased and recovered COVID-19 patients during Delta and Omicron waves. Moreover, patients admitted in the Omicron wave had less severe disease compared to those admitted in the Delta wave. The Kaplan-Meier analysis revealed no significant difference in survival rates or the probability of respiratory failure between six successive COVID-19 waves. CONCLUSION: Taken together, our results showed marked differences in the alteration of nonspecific inflammation and damage in the adaptive immune response during the six serial SARS-CoV-2 waves. Considering the inflammatory response of infectious diseases, embedding inflammatory indices informative markers into routine clinical testing offers the potential to mitigate the impact of future pandemics of COVID-19 and other infectious diseases.

Involvement of interleukin-1ß mediated nuclear factor κB signalling pathways to down-regulate prostate-specific antigen and cell proliferation in LNCaP prostate cancer cells.

Involvement of NF-κB (nuclear factor κB) mediated by IL-1ß (interleukin-1ß) on cell proliferation and PSA (prostate-specific antigen) production of LNCaP prostate cell lines and the possible cross-talk with Akt (also known as protein kinase B) signalling pathway has been investigated. NF-κB and Akt were analysed by Western blotting from LNCaP cells treated by IL-1ß before proliferation and PSA production were measured. IL-1ß inhibited proliferation and decreased PSA production. The Akt pathway was not sensitive, whereas NF-κB phosphorylation occurred as a result of treatment. PSA production and proliferation of LNCaP cells were down-regulated by NF-κB mediated by IL-1ß promoting anti-apoptotic signalling and co-suppressor factors of PSA expression. IL-1ß through NF-κB activation provides a rationale for therapeutic approaches in the anticancer treatment of prostate.

Interaction of Lactobacillus plantarum MON03 with Tunisian montmorillonite clay and ability of the composite to immobilize Zearalenone in vitro and counteract immunotoxicity in vivo.

BACKGROUND AND AIM: The present study was conducted to determine the abilities of the living Lactobacillus plantarum MON03 (LP) cells, Tunisian montmorillonite clay and their composites to accumulate Zearalenone (ZEA) from a liquid medium and elucidate the preventive effect of their composite in ZEA-contaminated balb/c mice showing immunotoxicity disorders. MATERIALS AND METHODS: In the in vitro study, LP (2 × 10(9) CFU/mL), TM (0.5 mg) and LP+TM were incubated with 50 µg mL(-1) ZEA for 0, 12 and 24 h. For the in vivo study, the composite MT+LP was evaluated also for possible protection regarding ZEA-immunotoxicity in Balb/c mice as a sensitive model. RESULTS: Results indicated that TM and LP+TM had a high capacity of adsorbing ZEA 87.2 ± 2.1 and 94.2 ± 2.1%, respectively. However, LP alone able to remove only 78% after 24 h of incubation. The quantity of adsorbed ZEA by LP, TM and LP+TM were 39, 43,5 and 47 µg mL(-1) of PBS, respectively. The in vivo results indicated that mice orally exposed to ZEA- (40 mg/kg bw) for 2 weeks showed severe immunotoxicity typical of fusarotoxicosis regarding thymocytes and splenocytes cell viability count, IFN-γ, IL-12, TNF-α production and B-cell activation. Mice treated with LP and TM alone, and LP+MT in combination with ZEA were comparable to the control. CONCLUSION: Both LP and TM are safe by themselves and their composite succeeded to exert a potential prevention by counteracting ZEA-immunotoxicity and can be implicated in the biotechnology of ZEA removal in human food and animal feed.

Correlation between ebv co-infection and HPV16 genome integrity in Tunisian cervical cancer patients.

Infection with high risk Human papillomavirus (HR-HPV) is necessary but not sufficient to cause cervical carcinoma. This study explored whether multiple HR-HPV or coinfection with Epstein-Barr virus (EBV) influence the integration status of HPV16 genome. The presence and typing of HPV in a series of 125 cervical specimens were assessed by polymerase chain reaction (PCR) using the specific primers for the HPV L1 region. As for EBV infection, the viral EBNA1 gene was used for its detection through PCR amplification. Disruption of the HPV E2 gene was assessed by amplification of the entire E2 gene with single set of primers, while E2 transcripts were evaluated by a reverse transcription PCR method (RT-PCR). The overall prevalence of HPVDNA was of 81.8% in cervical cancers versus 26.9% in benign lesions. In HPV positive cases, HPV16 and HPV18 were the most prevalent types, followed by HPV types 33, 31. EBV EBNA1 prevalence was statistically more frequent in cervical carcinomas than in benign lesions (29.5%, vs 9.6%; P=0.01). No viral infection was detected in healthy control women. The uninterrupted E2 gene was correlated with the presence of E2 transcripts originating from the HPV episomal forms. It was observed that integration was more common in HPV18 and EBV coinfection. The presence of EBV caused a five-fold [OR= 5; CI= 1.15-21.8; P = 0.04] increase in the risk of HPV16 genome integration in the host genome. This study indicates that EBV infection is acting as a cofactor for induction of cervical cancer by favoring HPVDNA integration.