Anti-inflammatory potential of aspergillus unguis SP51-EGY: TLR4-dependent effects & chemical diversity via Q-TOF LC-HRMS.

Inflammation serves as an intricate defense mechanism for tissue repair. However, overactivation of TLR4-mediated inflammation by lipopolysaccharide (LPS) can lead to detrimental outcomes such as sepsis, acute lung injury, and chronic inflammation, often associated with cancer and autoimmune diseases. This study delves into the anti-inflammatory properties of "Aspergillus unguis isolate SP51-EGY" on LPS-stimulated RAW 264.7 macrophages. Through real-time qPCR, we assessed the expression levels of pivotal inflammatory genes, including iNOS, COX-2, TNF-α, and IL-6. Remarkably, our fungal extracts significantly diminished NO production and showed noteworthy reductions in the mRNA expression levels of the aforementioned genes. Furthermore, while Nrf2 is typically associated with modulating inflammatory responses, our findings indicate that the anti-inflammatory effects of our extracts are not Nrf2-dependent. Moreover, the chemical diversity of the potent extract (B Sh F) was elucidated using Q-TOF LC-HRMS, identifying 54 compounds, some of which played vital roles in suppressing inflammation. Most notably, compounds like granisetron, fenofibrate, and umbelliprenin were found to downregulate TNF-α, IL-1ß, and IL-6 through the NF-κB signaling pathway. In conclusion, "Aspergillus unguis isolate SP51-EGY", isolated from the Red Sea, Egypt, has been unveiled as a promising TLR4 inhibitor with significant anti-inflammatory potentials, presenting novel insights for their potential therapeutic use in inflammation.

Combination of Searches for Higgs Boson Pair Production in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector.

This Letter presents results from a combination of searches for Higgs boson pair production using 126-140 fb^{-1} of proton-proton collision data at sqrt[s]=13 TeV recorded with the ATLAS detector. At 95% confidence level (CL), the upper limit on the production rate is 2.9 times the standard model (SM) prediction, with an expected limit of 2.4 assuming no Higgs boson pair production. Constraints on the Higgs boson self-coupling modifier κ_{λ}=λ_{HHH}/λ_{HHH}^{SM}, and the quartic HHVV coupling modifier κ_{2V}=g_{HHVV}/g_{HHVV}^{SM}, are derived individually, fixing the other parameter to its SM value. The observed 95% CL intervals are -1.2<κ_{λ}<7.2 and 0.6<κ_{2V}<1.5, respectively, while the expected intervals are -1.6<κ_{λ}<7.2 and 0.4<κ_{2V}<1.6 in the SM case. Constraints obtained for several interaction parameters within Higgs effective field theory are the strongest to date, offering insights into potential deviations from SM predictions.

CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB.

The regulatory circuits dictating CD8+ T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating antigen-specific PD-1+ TCF-1- CD8+ T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8+ T cells prolongs CD8+ T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1+ CD8+ T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8+ T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2-expressing CD8+ T cells, when compared to Fgl2-deficient CD8+ T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8+ T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1+ CD8+ T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.

Efficacy of Dietary Supplementation with Zinc-Chromium Mixture, Organic Selenium, or Their Combinations on Growth Performance, Carcass Traits, and Blood Profiles of Broilers under Heat Stress Conditions.

To determine the effects of organic selenium (0.0-0.6 mg and 0.9 mg Se/Kg diet) and Zn-Cr mixture (100 mg Zn/Kg diet plus 1.5 mg Cr/Kg diet) on broiler chicken performance, carcass traits, blood hematology, and biochemistry under heat stress conditions, this study was conducted. Under temperatures between 30.21 to 31.82 °C, 240 broiler chickens (Ross-308), which were 7-day-old, were randomly assigned to one of six treatments: T1 (control), T2 (100 mg Zn per kg of diet and 1.5 mg Cr per kg of diet), T3 (0.6 mg Se per kg of diet), T4 (0.9 mg Se per kg of diet), T5 (100 mg Zn, 1.5 mg Cr and (LSe), and T6 (100 mg Zn, 1.5 mg Cr and (HSe)). At 35 days old, the chicks fed a diet containing Zn-Cr with low or high organic selenium (organic-Se) outweighed the control group in terms of live body weight, weight gain, and feed conversion ratio (p < 0.05). In comparison to the control treatment, birds fed diets supplemented with Zn-Cr or organic-Se (LSe, HSe) significantly increased their serum levels of total protein and total antioxidant capacity. However, these additives resulted in a decrease (p < 0.01) in their serum levels of triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, creatinine, and uric acid. Together, it was found that trace elements (Zn-Cr and organic-Se) may greatly lessen the impacts of heat stress on broilers by promoting growth performance and boosting metabolic processes.

Cytotoxic and Antioxidative Effects of Geranium Oil and Ascorbic Acid Coloaded in Niosomes against MCF-7 Breast Cancer Cells.

Geranium oil (GO) has antiproliferative, antiangiogenic, and anti-inflammatory properties. Ascorbic acid (AA) is reported to inhibit the formation of reactive oxygen species, sensitize cancer cells, and induce apoptosis. In this context, AA, GO, and AA-GO were loaded into niosomal nanovesicles to ameliorate the physicochemical properties of GO and improve its cytotoxic effects using the thin-film hydration technique. The prepared nanovesicles had a spherical shape with average diameters ranging from 200 to 300 nm and exhibited outstanding surface negative charges, high entrapment efficiencies, and a controlled sustained release over 72 h. Entrapping AA and GO in niosomes resulted in a lower IC50 value than free AA and GO when tested on MCF-7 breast cancer cells. In addition, flow cytometry analysis showed higher apoptotic cells in the late apoptotic stage upon treating the MCF-7 breast cancer cells with AA-GO niosomal vesicles compared to treatments with free AA, free GO, and AA or GO loaded into niosomal nanovesicles. Assessing the antioxidant effect of the free drugs and loaded niosomal nanovesicles showed enhanced antioxidant activity of AA-GO niosomal vesicles. These findings suggest the AA-GO niosomal vesicles as a potential treatment strategy against breast cancer, possibly through scavenging free radicals.

Terfezia boudieri and Terfezia claveryi inhibit the LPS/IFN-γ-mediated inflammation in RAW 264.7 macrophages through an Nrf2-independent mechanism.

Desert truffles have been used as traditional treatments for numerous inflammatory disorders. However, the molecular mechanisms underlying their anti-inflammatory effects in RAW 264.7 macrophages have yet to be fully elucidated. The present study investigated the anti-inflammatory activities of two main desert truffles, Terfezia boudieri and T. claveryi, and the underlying mechanisms associated with their anti-inflammatory activities in RAW 264.7 macrophages stimulated with lipopolysaccharide/interferon-gamma (LPS/IFN-γ). Our results demonstrated that treatment with T. boudieri and T. claveryi extracts effectively suppressed the inflammatory response in LPS/IFN-γ-stimulated RAW 264.7 macrophages. Specifically, T. boudieri extract was found to reduce the production of nitric oxide and inhibit the expression of various pro-inflammatory markers, including inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor-α, and interleukin-6 (IL-6) at both the mRNA and protein levels. Similarly, T. claveryi extract exhibited comparable inhibitory effects, except for the expression of IL-6 and COX-2 at the protein level, where no significant effect was observed. Moreover, both studied extracts significantly downregulated the microRNA expression levels of miR-21, miR-146a, and miR-155, suggesting that T. boudieri and T. claveryi suppress the inflammatory response in LPS/IFN-γ-stimulated RAW 264.7 cells through an epigenetic mechanism. Furthermore, our study reveals a new mechanism for the anti-inflammatory properties of desert truffle extracts. We show for the first time that Terfezia extracts do not rely on the nuclear factor erythroid 2-related factor 2 pathway, previously linked to anti-inflammatory responses. This expands our understanding of natural product anti-inflammatory mechanisms and could have important implications for developing new therapies. To account for differences in truffle effects, extracts prepared were subjected to secondary metabolites profiling using UPLC-MS. UPLC-MS led to the annotation of 87 secondary metabolites belonging to various classes, including amino acids, carbohydrates, alkaloids, amides, fatty acids, sterols, and phenolic compounds. Therefore, these results indicate that T. boudieri and T. claveryi exhibit anti-inflammatory activities through suppressing multiple inflammatory mediators and cytokines and may be potential anti-inflammatory agents.

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Modulatory Effects of Arctostaphylos uva-urs Extract In Ovo Injected into Broiler Embryos Contaminated by Aflatoxin B1.

In ovo injection of nutrients can modulate the embryo's physiological responses against aflatoxin B1 (AFB1) embryotoxicity. This hypothesis was tested using in ovo injection of Arctostaphylos uva-ursi (Ar. uu.) methanolic extract. The total polyphenols, total flavonoids, total antioxidant capacity, and GC-MS analysis were all assessed in the Ar. uu. methanolic extract. A total of 180 ten-day-old embryonated eggs were distributed into six groups of 30 replicates each. The first group was used as a control (non-injected), and the second, third, fourth, fifth, and sixth groups were injected with 10 µ double-distilled water (DDW), 500 µL methanol, 0.01 g Ar. uu./500 µL methanol, 50 ng AFB1/10 µL DDW, and 50 ng AFB1 in 10 µ DDW + 0.01 g Ar. uu./500 µL methanol, respectively. The relative embryo weight, residual yolk sac weight, tibia length and weight, and survival were recorded. Total and differential leukocytes, oxidative stress, and humoral immune responses were observed. The residual yolk sac was lower (p < 0.05) in the Ar. uu. group than other groups. The embryonic growth (tibia weight and length) was enhanced in AFB1 + Ar. uu.-injected embryos compared with those injected with AFB1 alone. In conclusion, in ovo injection of Arctostaphylos uva-ursi could modulate AFB1-induced toxicity in chicken embryos.

Effect of maternal nicotine/thiocyanate exposure during gestational period upon pituitary, thyroid and parathyroid function/morphology of 1-month-old rat offspring.

INTRODUCTION: Impact of in utero exposure to nicotine, on the structure of the thyroid-pituitary axis and the parathyroid glands have been examined in 1-month-old rats and compared with that of thiocyanate. MATERIALS AND METHODS: Three pregnant female groups were used; control, nicotine and thiocyanate. Treatment started from gestation day (4-20) and the specimens were harvested from the male offspring of all groups at the age of 1 month and processed for light, electronmicroscopic and immunohistochemical examination. Total triiodothyronine (tT3), total thyroxine (tT4) and total thyrotropin (TSH) were quantitatively determined in serum. RESULTS: Both nicotine and thiocyanate activated the thyroid follicular cells, with an increase in height (about 30 %) and a negative feedback on the pituitary thyrotrophs which revealed a reduction in the number of cytoplasmic secretory granules, particularly the thiocyanate group. However, in thiocyanate group there was signs of impaired secretory activity of the thyroid gland. The arbitrary area of parathyroid chief cells, increased (about 45 %) particularly in nicotine group, with signs of reduced activity and a positive feedback on the parafollicular cells which revealed hypertrophy, proliferation (25 %) and increased intensity of positive immunohistochemical reaction for calcitonin. CONCLUSION: Nicotine impaired chief parathyroid cells activity and consequently activated parafollicular cells. Thiocyanate reduced pituitary thyrotrophs activity, whereas both nicotine and thiocyanate increased thyroid follicular cells activity. This impact of in utero exposure persisted for 1-month postnatal.