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In the midst of resurging COVID-19 cases, the second NIH/FDA virtual COVID-19 and Cytokines symposium was held on 1 December 2020, focusing on longitudinal studies of COVID-19 immunity, including long-term consequences, potential associations with autoimmunity and the multisystem inflammatory syndrome in children (MIS-C).

“The role of cytokines in COVID-19” online symposium was presented on 18 June 2020 by the NIH/FDA Immunology and Cytokine Interest Groups and was purposed to discuss our rapidly changing understanding of COVID-19-related cytokine responses in different stages of infection, including the etiologies, downstream consequences and possible mitigation strategies. The recording is available at https://nci.rev.vbrick.com/sharevideo/03106730-66cc-47ba-870b-f6e6274a998a .

Key events in the pathogenesis of Sjӧgren syndrome (SS) include the change of salivary gland epithelial cells into antigen-presenting cell-like phenotypes and focal lymphocytic sialadenitis (FLS). However, what triggers these features in SS is unknown. Dysbiosis of the gut and oral microbiomes is a potential environmental factor in SS, but its connection to the etiopathogenesis of SS remains unclear. This study aimed to characterize the oral microbiota in SS and to investigate its potential role in the pathogenesis of SS. Oral bacterial communities were collected by whole mouthwash from control subjects (14 without oral dryness and 11 with dryness) and primary SS patients (8 without oral dryness and 17 with dryness) and were analyzed by pyrosequencing. The SS oral microbiota was characterized by an increased bacterial load and Shannon diversity. Through comparisons of control and SS in combined samples and then separately in non-dry and dry conditions, SS-associated taxa independent of dryness were identified. Three SS-associated species and 2 control species were selected and used to challenge human submandibular gland tumor (HSG) cells. Among the selected SS-associated bacterial species, Prevotella melaninogenica uniquely upregulated the expression of MHC molecules, CD80, and IFNλ in HSG cells. Concomitantly, P. melaninogenica efficiently invaded HSG cells. Sections of labial salivary gland (LSG) biopsies from 8 non-SS subjects and 15 SS patients were subjected to in situ hybridization using universal and P. melaninogenica-specific probes. Ductal cells and the areas of infiltration were heavily infected with bacteria in the LSGs with FLS. Collectively, dysbiotic oral microbiota may initiate the deregulation of SGECs and the IFN signature through bacterial invasion into ductal cells. These findings may provide new insights into the etiopathogenesis of SS.

Invariant natural killer T ( i NKT) cells are thymus-generated innate-like αβ T cells that undergo terminal differentiation in the thymus. Such a developmental pathway differs from that of conventional αβ T cells, which are generated in the thymus but complete their functional maturation in peripheral tissues. Multiple subsets of i NKT cells have been described, among which IL-17-producing i NKT cells are commonly referred to as NKT17 cells. IL-17 is considered a proinflammatory cytokine that can play both protective and pathogenic roles and has been implicated as a key regulatory factor in many disease settings. Akin to other i NKT subsets, NKT17 cells acquire their effector function during thymic development. However, the cellular mechanisms that drive NKT17 subset specification, and how i NKT cells in general acquire their effector function prior to antigen encounter, remain largely unknown. Considering that all i NKT cells express the canonical Vα14-Jα18 TCRα chain and all i NKT subsets display the same ligand specificity, i.e., glycolipid antigens in the context of the nonclassical MHC-I molecule CD1d, the conundrum is explaining how thymic NKT17 cell specification is determined. Mapping of the molecular circuitry of NKT17 cell differentiation, combined with the discovery of markers that identify NKT17 cells, has provided new insights into the developmental pathway of NKT17 cells. The current review aims to highlight recent advances in our understanding of thymic NKT17 cell development and to place these findings in the larger context of i NKT subset specification and differentiation. Immunology: Investigating a subset of natural killer T cells A subset of white blood cells called invariant natural killer T ( i NKT) cells secrete the cell-signaling molecule interleukin 17 (IL-17) which promotes immune reactions that can be either protective or damaging to the organism. i NKT cells can eliminate diseased cells, including cancer cells or pathogen-infected cells. NKT17 cells are the IL-17-producing subset of i NKT cells. Nurcin Liman and Jung-Hyun Park at the US National Cancer Institute, Bethesda, review recent advances in understanding how NKT17 cells undergo development in the thymus to acquire differing functions and phenotypes. The authors consider insights and distinct hypotheses focused on the key question of how and when the development of NKT17 cells diverges from that of other subsets of i NKT cells, which has implications in understanding their effector functions and roles among different tissues.

Treating female canine mammary gland tumors is crucial owing to their propensity for rapid progression and metastasis, significantly impacting the overall health and well-being of dogs. Mitoquinone (MitoQ), an antioxidant, has shown promise in inhibiting the migration, invasion, and clonogenicity of human breast cancer cells. Thus, we investigated MitoQ’s potential anticancer properties against canine mammary gland tumor cells, CMT-U27 and CF41.Mg. MitoQ markedly suppressed the proliferation and migration of both CMT-U27 and CF41.Mg cells and induced apoptotic cell death in a dose-dependent manner. Furthermore, treatment with MitoQ led to increased levels of pro-apoptotic proteins, including cleaved-caspase3, BAX, and phospho-p53. Cell cycle analysis revealed that MitoQ hindered cell progression in the G1 and S phases in CMT-U27 and CF41.Mg cells. These findings were supported using western blot analysis, demonstrating elevated levels of cleaved caspase-3, a hallmark of apoptosis, and decreased expression of cyclin-dependent kinase (CDK) 2 and cyclin D4, pivotal regulators of the cell cycle. In conclusion, MitoQ exhibits in vitro antitumor effects by inducing apoptosis and arresting the cell cycle in canine mammary gland tumors, suggesting its potential as a preventive or therapeutic agent against canine mammary cancer.

Berberine (BBR), a natural plant product, has been shown to have antidiabetic, cholesterol-reducing effects. To investigate the action of BBR as appetite suppressants, two experimental protocols were performed. In the first experiment, the mice were fed either a normal-chow diet or a high-fat diet (HF). The mice received daily intraperitoneal injections of BBR (10 mg/kg or saline at 1 ml/kg) for 3 weeks. To determine the antiobesity effects of BBR, the food consumption, body weight, fat contents, serum leptin, and glucose level were investigated. In the second experiment, we set out to validate the effect of BBR on central neuropeptide Y (NPY) stimulated rats. Experiments were carried out in 24-hour fasted rats, and then food intake and glucose level were subsequently recorded for 1 hour. The experimental groups were subdivided into the intra-3rd ventricular microinjections of ACSF (artificial cerebrospinal fluid), neuropeptide Y (NPY; 100 nM), NPY+BBR (10 nM), and NPY+BBR (100 nM) group. And then the blood glucose level was examined. In the first experiment, treatment with BBR in the HF diet mice reduced food intake, body weight, fat contents, serum leptin, and glucose level. In the second experiment, the NPY-injected group increased food intake by 39.3%, and food intake was reduced in the BBR group by 47.5%, compared with the ACSF-injected group. Also, the serum glucose level in the NPY+BBR (100 nM) group was significantly lower than that in the NPY (100 nM) group. The results suggest that BBR improved lipid dysregulation in obesity by controlling the central obesity related pathway.

Vascular smooth muscle cells (VSMCs) plays an important role in maintaining vascular function by responding to various vasoactive stimuli within blood vessels. Far-infrared (FIR) rays has been shown to possess a variety of physiological effects including vasodilation, while the underlying molecular mechanism remains elusive. Here, we explored the molecular mechanism by which FIR irradiation suppresses vascular contraction using rat VSMCs and aortas. FIR irradiation enhanced the transport of intracellular Ca 2+ from the cytosol to the sarcoendoplasmic reticulum (SER) via activation of sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA), which accompanied a decrease in intracellular ATP levels. Pretreatment with thapsigargin (TG), a specific SERCA inhibitor, or knockdown of SERCA2 gene expression reversed FIR irradiation-induced translocation of Ca 2+ into the SER. Notably, FIR irradiation promoted the dissociation of SERCA2 and phospholamban (PLN), an endogenous SERCA inhibitor, without altering their total protein expression levels. The array of effects elicited by FIR irradiation was not observed under hyperthermic conditions (39°C). Moreover, FIR irradiation, but not hyperthermal condition, decreased the phosphorylation of myosin light chain (MLC) at Ser19, which was restored by pretreatment with TG or the knockdown of SERCA2 gene expression. FIR irradiation attenuated phenylephrine-induced vessel contraction in endothelium-deprived rat aortas. Consistent with the in vitro results, the reduction in MLC phosphorylation caused by FIR irradiation was reversed following pretreatment with TG in isolated aortas. Additionally, FIR irradiation increased blood flow in the carotid arteries of mice. Collectively, these results suggest that FIR irradiation activates SERCA2 by promoting its dissociation from PLN, independent of hyperthermic effects. This activation lowers cytosolic Ca²⁺ and ATP levels, reducing MLC phosphorylation and vascular smooth muscle contraction. These findings provide scientific evidence for the therapeutic potential of FIR therapy in the treatment and prevention of arterial narrowing conditions such as pathological vasospasm, and peripheral artery disease.

Chemotherapy is used for childhood cancer but may lead to infertility in patients. Spermatogonia stem cells are present in the testes of prepubertal boys, although they do not produce sperm at this age. Herein, we evaluated the toxicity of cisplatin, a known medicine for cancer treatment, in neonatal mouse testes using in vitro organ culture. Mouse testicular fragments (MTFs) derived from 5.5-d postpartum mouse testes were exposed to 1–10 μg/mL cisplatin. The results showed that cisplatin significantly downregulated the expression of germ cell marker genes, including differentiated and undifferentiated, in a dose-dependent manner. In particular, a high dose of cisplatin (10 μg/mL) led to germ cell depletion. In addition, the expression levels of the Sertoli cell marker gene, the number of SOX9+ Sertoli cells, and the levels of SOX9 protein were markedly decreased in cisplatin-treated MTFs compared to controls. The mRNA expression of steroidogenic enzyme-related genes significantly increased in cisplatin-treated MTFs, except for estrogen receptor 1 (Esr1). Consistently, 3β-hydroxysteroid dehydrogenase protein was also observed in the interstitial regions of cisplatin-treated MTFs. Altogether, our findings showed a significant impairment in germ cell development, Sertoli cell survival, and steroidogenesis in the MTFs of cisplatin-treated mice.

Zearalenone (ZEN), a widely known mycotoxin, is mainly produced by various Fusarium species, and it is a potent estrogenic metabolite that affects reproductive health in livestock and humans. In this study, the molecular mechanisms of toxicity and cell damage induced by ZEN in GC-1 spermatogonia (spg) cells were evaluated. Our results showed that cell viability decreased and apoptosis increased in a dose-dependent manner when GC-1 spg cells were exposed to ZEN. In addition, the key proteins involved in apoptosis, cleaved caspase-3 and -8, BAD, BAX, and phosphorylation of p53 and ERK1/2, were significantly increased in ZEN-exposed GC-1 spg cells for 24 h, and cytochrome c was released from mitochondria by ZEN. Interestingly, ZEN also triggered autophagy in GC-1 spg cells. The expression levels of the autophagy-related genes Atg5, Atg3, Beclin 1, LC3, Ulk1, Bnip 3, and p62 were significantly higher in ZEN-treated GC-1 spg cells, and the protein levels of both LC3A/B and Atg12 were remarkably increased in a dose-dependent manner in ZEN-exposed GC-1 spg cells compared to the control. In addition, immunostaining results showed that ZEN-treated groups showed a remarkable increase in LC 3A/B positive puncta as compared to the control in a dose-dependent manner based on confocal microscopy analysis in GC-1 spg cells. Our findings suggest that ZEN has toxic effects on tGC-1 spg cells and induces both apoptosis and autophagy.

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy characterized by high invasiveness and poor prognosis. This study investigated the anticancer mechanisms of eupatilin, a pharmacologically active flavonoid derived from species, in human OSCC YD-10B cells. Eupatilin significantly reduced cell viability in a dose-dependent manner, with an IC of approximately 50 μM. Flow cytometric analysis revealed G0/G1 phase arrest accompanied by downregulation of Cyclin D1 and CDK2, and upregulation of p21. Annexin V/Propidium Iodide staining and Western blotting confirmed apoptosis induction through activation of Bax, cleaved caspase-3/9, and poly ADP-ribose polymerase (PARP) cleavage, alongside suppression of Bcl-2. Furthermore, eupatilin markedly decreased both the mRNA expression and enzymatic activities of matrix metalloproteinases (MMP)-2 and MMP-9, indicating its potential to inhibit cancer cell invasion. Collectively, these findings demonstrate that eupatilin exerts potent antiproliferative and anti-invasive effects on OSCC cells via cell-cycle modulation and mitochondrial-mediated apoptosis. This study provides the first evidence of eupatilin's therapeutic potential against OSCC, suggesting its promise as a natural compound for the development of safer and more effective treatments for oral cancer.