No abstract

Cancer cells are metabolically vigorous and are superior in the uptake of nutrients and in the release of the tumor microenvironment (TME)-specific metabolites. They create an acidic, hypoxic, and nutrient-depleted TME that makes it difficult for the cytotoxic immune cells to adapt to the metabolically hostile environment. Since a robust metabolism in immune cells is required for optimal anti-tumor effector functions, the challenges caused by the TME result in severe defects in the invasion and destruction of the established tumors. There have been many recent developments in NK and T cell-mediated immunotherapy, such as engineering them to express chimeric antigen receptors (CARs) to enhance tumor-recognition and infiltration. However, to defeat the tumor and overcome the limitations of the TME, it is essential to fortify these novel therapies by improving the metabolism of the immune cells. One potential strategy to enhance the metabolic fitness of immune cells is to upregulate the expression of nutrient transporters, specifically glucose and amino acid transporters. In particular, the amino acid transporters SLC1A5 and SLC7A5 as well as the ancillary subunit SLC3A2, which are required for efficient uptake of glutamine and leucine respectively, could strengthen the metabolic capabilities and effector functions of tumor-directed CAR-NK and T cells. In addition to enabling the influx and efflux of essential amino acids through the plasma membrane and within subcellular compartments such as the lysosome and the mitochondria, accumulating evidence has demonstrated that the amino acid transporters participate in sensing amino acid levels and thereby activate mTORC1, a master metabolic regulator that promotes cell metabolism, and induce the expression of c-Myc, a transcription factor essential for cell growth and proliferation. In this review, we discuss the regulatory pathways of these amino acid transporters and how we can take advantage of these processes to strengthen immunotherapy against cancer.

SARS-CoV-2 by the direct cytopathic effect or indirectly through the propagation of pro-inflammatory cytokines could cause endothelial dysfunction (ED) and oxidative stress (OS). It has been reported that OS is triggered by various types of viral infections, including SARS-CoV-2. Into the bargain, allopurinol is regarded as a potent antioxidant that acts through inhibition of xanthine oxidase (XO), which is an essential enzyme of purine metabolism. Herein, the present study aimed to find the potential protective effects of allopurinol on the biomarkers of OS and ED in patients with severe Covid-19. This single-center cohort study recruited 39 patients with mild-moderate Covid-19 compared with 41 patients with severe Covid-19. Nineteen patients with severe Covid-19 were on the allopurinol treatment because of underlying chronic gout 3 years ago compared with 22 Covid-19 patients not on this treatment. The recruited patients were allocated into three groups: group I, mild-moderate Covid-19 on the standard therapy ( n = 39); group II, severe Covid-19 patients on the standard therapy only ( n = 22); and group III, severe Covid-19 patients on the standard therapy plus allopurinol ( n = 19). The duration of the study was 3 weeks from the time of hospitalization till the time of recovery. In addition, inflammatory biomarkers (D-dimer, LDH, ferritin, CRP, procalcitonin), neutrophil–lymphocyte ratio (NLR), endothelin-1 (ET-1), uric acid and oxidative stress index (OSI), CT scan score, and clinical score were evaluated at the time of admission and discharge regarding the effect of allopurinol treatment adds to the standard treatment of Covid-19. Allopurinol plus standard treatment reduced LDH, ferritin, CRP, procalcitonin, and ET-1 serum level significantly ( P < 0.05) compared with Covid-19 patients on standard treatment. Besides, neutrophil (%), lymphocyte (%), and neutrophil–lymphocyte ratio (NLR) were reduced in patients with severe Covid-19 on standard treatment plus allopurinol compared with Covid-19 patients on standard treatment alone ( P < 0.01). OSI was higher in patients with severe Covid-19 than mild-moderate Covid-19 patients ( P = 0.00001) at admission. At the time of discharge, the oxidative status of Covid-19 patients was significantly improved compared with that at admission ( P = 0.01). In conclusion, Covid-19 severity is linked with high OS and inflammatory reaction with ED development. High uric acid in patients with severe Covid-19 is correlated with high OS and inflammatory biomarkers. Allopurinol with standard treatment in patients with severe Covid-19 reduced oxidative and inflammatory disorders with significant amelioration of ED and clinical outcomes.

Natural killer (NK) cells are the predominant innate lymphocytes that provide early defense against infections. In the inflammatory milieu, NK cells modify their metabolism to support high energy demands required for their proliferation, activation, and functional plasticity. This metabolic reprogramming is usually accompanied by the upregulation of nutrient transporter expression on the cell surface, leading to increased nutrient uptake required for intense proliferation. The interleukin-1 family members of inflammatory cytokines are critical in activating NK cells during infection; however, their underlying mechanism in NK cell metabolism is not fully elucidated. Previously, we have shown that IL-18 upregulates the expression of solute carrier transmembrane proteins and thereby induces a robust metabolic boost in NK cells. Unexpectedly, we found that IL-18 signaling is dispensable during viral infection in vivo, while the upregulation of nutrient transporters is primarily MyD88-dependent. NK cells from Myd88-/- mice displayed significantly reduced surface expression of nutrient receptors and mTOR activity during MCMV infection. We also identified that IL-33, another cytokine employing MyD88 signaling, induces the expression of nutrient transporters but requires a pre-exposure to IL-12. Moreover, signaling through the NK cell activating receptor, Ly49H, can also promote the expression of nutrient transporters. Collectively, our findings revealed multiple pathways that can induce the expression of nutrient transporters on NK cells while highlighting the imperative role of MyD88 in NK cell metabolism during infection.

Natural Killer (NK) cells are lymphocytes of the innate immune response that play a vital role in controlling infections and cancer. Their pro-inflammatory role has been well-established; however, less is known about the regulatory functions of NK cells, in particular, their production of the anti-inflammatory cytokine IL-10. In this study, we investigated the immunoregulatory function of NK cells during MCMV infection and demonstrated that NK cells are major producers of IL-10 during the early stage of infection. To investigate the effect of NK cell-derived IL-10, we have generated NK cell-specific IL-10-deficient mice (NKp46-Cre-Il10fl/fl) displaying no signs of age-related spontaneous inflammation, with NK cells that show no detectable IL-10 production upon in vitro stimulation. In NKp46-Cre-Il10fl/fl mice, the levels of IL-10 and IFNγ, viral burdens and T cell activation were similar between NKp46-Cre-Il10fl/fl mice and their control littermates, suggesting that NK cell-derived IL-10 is dispensable during acute MCMV infection in immunocompetent hosts. In perforin-deficient mice that show a more sustained infection, NK cells produce more sustained levels of IL-10. By crossing NKp46-Cre-Il10fl/fl mice with perforin-deficient mice, we demonstrated that NK cell-derived IL-10 regulates T cell activation, prevents liver damage, and allows for better disease outcome. Taken together, NK cell-derived IL-10 can be critical in regulating the immune response during early phases of infection and therefore protecting the host from excessive immunopathology.

The Moroccan flora abounds and is an important reserve of medicinal plants. Nigella sativa and Lepidium sativum are plants that are widely used in traditional medicine for their multiple therapeutic properties. The current study aims to highlight the biological activities that can justify and valorize the use of these plants. Flavonoids, total phenols, condensed tannins, and sugars were determined. The biological activities tested were antioxidant by determining the IC50 (defined as the concentration of an antioxidant required to decrease the initial concentration by 50%; inversely related to the antioxidant capacity), hemagglutination, and hemolytic activities. Phytochemical quantification of the seed extracts indicated that the total phenol content was largely similar for both plants and in the order of 10 mg GAE (Gallic acid equivalent)/g. On the other hand, L. sativum seeds registered a higher content of flavonoids (3.09 ± 0.04 mg QE (quercetin equivalent)/g) as compared to Nigella saliva (0.258 ± 0.058). Concerning condensed tannins, N. saliva seeds present a higher amount with a value of 7.2 ± 0.025 mg/g as compared to L. sativum (1.4 ± 0.22 mg/g). Concerning the total sugar content, L. sativum shows a higher content (67.86 ± 0.87 mg/g) as compared to N. sativa (58.17 ± 0.42 mg/g); it is also richer in mucilage with a content of 240 mg as compared to 8.2 mg for N. saliva. Examination of the antioxidant activity using a DPPH (2.2-diphenyl 1-pycrilhydrazyl) test revealed that the EButOH (n-butanol extract) and EAE (ethyl acetate extract) extracts were the most active, with IC50 values of 48.7 and 50.65 μg/mL for the N. sativa extracts and 15.7 and 52.64 μg/mL for the L. sativum extracts, respectively. The results of the hemagglutination activity of the different extracts of the two plants prepared in the PBS (phosphate-buffered saline) medium showed significant agglutination for the L. sativum extract (1/50) compared to the N. sativa extract (1/20). An evaluation of the hemolytic effect of the crude extract of the studied seeds on erythrocytes isolated from rat blood incubated in PBS buffer compared to the total hemolysis induced by distilled water showed a hemolysis rate of 54% for Nigella sativa and 34% for L. sativum. In conclusion, the two plants studied in the current work exhibited high antioxidant potential, which could explain their beneficial properties.

Background SARS-CoV-2 pandemic continues to threaten the human population with millions of infections and deaths worldwide. Vaccination campaigns undertaken by several countries have resulted in a notable decrease in hospitalization and deaths. However, with the emergence of new virus variants, it is critical to determine the longevity and the protection efficiency provided by the current authorized vaccines. Aim The aims of this study are to provide data about the magnitude of immune responses in individuals fully vaccinated against COVID-19 in Riyadh province of Saudi Arabia. Also, to evaluate the continuity of specific IgG levels and compare the titers in individuals who have been received two doses of the matched and mixed vaccines, including Pfizer and AstraZeneca against SARS-CoV-2 during the period of three to six months. Moreover, we analyze the current state of immune response in terms of antibody responses in thepopulation postvaccination using homogenous or hetrogenous vaccine regimen. Methods A total of 141 healthy volunteers were recruited to our study; blood (n=63) and the saliva samples (n=78) and were collected from fully vaccinated individuals in Riyadh city. We employed a specific ELISA assay in plasma and saliva of fully vaccinated individuals. Results IgG levels varied with age groups with the highest concentration in the age group 19–29 years, but the age group (≥50) had the lowest IgG concentration. The IgG levels in both serum and saliva were higher after three months and start to wane after six months. Individuals who received mixed types of vaccines had significantly better response than Pfizer vaccine alone. Conclusion The current study investigates the status of humoral responses in different age groups, in terms of antibody measurements. These data will help to evaluate the need for further COVID-19 vaccine doses and to what extent a two-dose regimen will protect vaccinated individuals.

Natural killer (NK) cells are predominant innate lymphocytes that initiate the early immune response during infection. NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection. Tumor necrosis factor-alpha (TNFα) is a well-known inflammatory cytokine that enhances NK cell function; however, the mechanism underlying NK cell proliferation in response to TNFα is not well established. Here, we demonstrated that upon infection/inflammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity, and effector function. Notably, IL-18 can induce TNFR2 expression in NK cells, augmenting their sensitivity toward TNFα. Mechanistically, TNFα-TNFR2 signaling upregulates the expression of CD25 (IL-2Rα) and nutrient transporters in NK cells, leading to a metabolic switch toward aerobic glycolysis. Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice. Accordingly, our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation, glycolysis, and effector function.