Type 1/type 2 inflammatory cytokines correlate with olfactory function in patients with chronic rhinosinusitis.

BACKGROUND: Olfactory dysfunction secondary to chronic rhinosinusitis (CRS) has been highly associated with impaired quality of life. Asian CRS patients showed a distinct inflammatory profile, with less type 2 endotype compared with European and North American. This study aimed to explore the pattern of the inflammatory cytokines in CRS patients from China and their association with olfactory function. METHODS: Institutional review board-approved prospective study in which the olfactory function of 71 CRS patients was assessed with Sniffin' Sticks before the nasal endoscopic surgery. A set of cytokines and inflammatory mediators including type 1 and type 2 inflammatory cytokines were measured in nasal mucus by using a multiplex flow cytometric bead assay (CBA). Baseline characteristics in CRS patients were collected and the Spearman r statistic was performed to assess the association of olfactory function with cytokines and inflammatory mediators. RESULTS: A total of 71 nasal mucus samples of CRS patients, including 25 chronic rhinosinusitis without nasal polyposis (CRSsNP) patients and 46 chronic rhinosinusitis with nasal polyposis (CRSwNP) patients, were evaluated in this study. The nasal mucus levels of type 1 inflammatory cytokine IFN-γ (interferon-γ), type 2 inflammatory cytokines including IL-4, IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) and anti-inflammatory cytokine IL-10 were significantly and inversely correlated with olfactory function in total patients with CRS (r = -0.308, p = 0.009; r = -0.250, p = 0.036; r = -0.399, p = 0.001; r = -0.269, p = 0.023; r = -0.273, p = 0.021, respectively). In CRSsNP, the olfactory function was inversely correlated with levels of type 1 inflammatory cytokine TNF-α (tumor necrosis factor-α) (r = -0.637, p = 0.001) and IL-10 (r = -0.468, p = 0.018). Nevertheless, the olfactory function in CRSwNP was inversely correlated with type 2 inflammatory cytokines including IL-4 (r = -0.303, p = 0.041) and IL-5 (r = -0.383, p = 0.009). CONCLUSION: Both type 1 and type 2 inflammatory cytokines may contribute to the pathogenesis of CRS-associated olfactory dysfunction in the Chinese population.

Correlation of tissue eosinophil count and chemosensory functions in patients with chronic rhinosinusitis with nasal polyps after endoscopic sinus surgery.

PURPOSE: To investigate the correlation of tissue eosinophil count and chemosensory functions in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) after endoscopic sinus surgery (ESS). METHODS: This was a cross-sectional study including 40 patients with a history of ESS for CRSwNP recruited consecutively. Visual analog scale score and the Lund-Kennedy endoscopic score were recorded. Biopsies of the ethmoidal sinus mucosal were performed and evaluated. Chemosensory functions were measured by Sniffin' Sticks and chemosensory event-related potentials (CSERP). The associations between chemosensory functions and tissue eosinophil count were analyzed using Spearman correlation and partial correlation after adjusting the confounding factors. Kendall's tau-b correlation was performed between sneezing score and CSERP with ethyl alcohol (EAL) stimulation. RESULTS: Olfactory and trigeminal nerve function was successfully evaluated using CSERP. Postoperative tissue eosinophil count was correlated with threshold (T) score (partial correlation coefficient r = - 0.460, p = 0.012) and CSERP peak latency for olfactory (N1: partial r = 0.471, p = 0.010; P2: partial r = 0.487, p = 0.007) and mixed olfactory-trigeminal (N1: partial r = - 0.516, p = 0.008; P2: partial r = - 0.590, p = 0.002). There were also correlations between T score and N1 latency with phenyl ethyl alcohol (PEA) (partial r = - 0.560, p < 0.001), between sneezing score and N1 latency with EAL (Kendall's tau-b = - 0.40, p = 0.005). CONCLUSIONS: Postoperative tissue eosinophilia is significantly associated with postoperative olfactory disorders as assessed by Sniffin' Sticks and CSERP peak latency. Furthermore, olfaction as measured by T score correlates with olfactory ERP latency in inflammation-associated olfactory dysfunction. Trigeminal sensitivity also appears to relate to tissue eosinophilia, indicating mucosal inflammation can affect both sensory systems in the nose.

Exhausted signature and regulatory network of NK cells in myasthenia gravis.

Introduction: NK cells are dysfunctional in myasthenia gravis (MG), but the mechanism is unclear. This study aims to measure associations and underlying mechanisms between the NK cells and the development of MG. Methods: Twenty healthy controls (HCs) and 53 MG patients who did not receive glucocorticoids and immunosuppressants were collected. According to the Myasthenia Gravis Foundation of America (MGFA) classification, MG patients were categorized into MGFA I group (n = 18) and MGFA II-IV group (n = 35). Flow cytometry, cell sorting, ELISA, mRNA-sequencing, RT-qPCR, western blot, and cell culture experiments were performed to evaluate the regulatory mechanism of exhausted NK cells. Results: Peripheral NK cells in MGFA II-IV patients exhibit exhausted phenotypes than HCs, marked by the dramatic loss of total NK cells, CD56dimCD16- NK cells, elevated PD1 expression, reduced NKG2D expression, impaired cytotoxic activity (perforin, granzyme B, CD107a) and cytokine secretion (IFN-γ). Plasma IL-6 and IL-21 are elevated in MG patients and mainly derived from the aberrant expansion of monocytes and Tfh cells, respectively. IL-6/IL-21 cooperatively induced NK-cell exhausted signature via upregulating SOCS2 and inhibiting the phosphorylation of STAT5. SOCS2 siRNA and IL-2 supplement attenuated the IL-6/IL-21-mediated alteration of NK-cell phenotypes and function. Discussion: Inhibition of IL-6/IL-21/SOCS2/STAT5 pathway and recovery of NK-cell ability to inhibit autoimmunity may be a new direction in the treatment of MG.

From mitochondria to tumor suppression: ACAT1's crucial role in gastric cancer.

Acetyl CoA acetyltransferase 1 (ACAT1), a mitochondrial enzyme, is mainly involved in the formation and decomposition of ketones, isoleucine, and fatty acids. Previous clinical studies showed that mutations in the ACAT1 gene lead to ketoacidosis, Notably the role of ACAT1 in human cancer' pathogenesis varies depending on cancer type, and its specific role in gastric cancer remains largely unknown. In the current study, we found that the expression of ACAT1 in primary late-stage gastric cancer tumor tissues was significantly lower than in early-stage tumors. This observation was further confirmed in high-grade gastric cancer cell line MKN45. The expression of CD44 and OCT4 was decreased, while CD24 expression was increased by overexpressing ACAT1 in MKN45 gastric cancer cells. Moreover, the ability of gastric cancer cells to form colonies on soft agar was also reduced by ACAT1 overexpression. Likewise, overexpression of ACAT1 inhibited epithelial mesenchymal transition (EMT) in gastric cancer cells evidenced by increased expression of the epithelial marker E-Cadherin, decreased expression of mesenchymal marker vimentin, and decreased expression levels of SNAI 1/3. In addition, ACAT1 overexpression inhibited cell migration and invasion, improved the response to 5-Fluorouracil (5-FU) and etoposide. In contrast, inhibition of ACAT1 activity promoted the proliferation of gastric cancer cells. The xenotransplantation results in nude mice showed that overexpression of ACAT1 in gastric cancer cells inhibited tumor growth in vivo. In addition, the low expression of ACAT1 in gastric cancer was further validated by searching public databases and conducting bioinformatic analyses. Mechanistically, bioinformatic analysis found that the inhibitory effect of ACAT1 in gastric cancer may be related to the Adipocytokine Signaling Pathway, Ppar Signaling Pathway, Propanoate Metabolism and P53 Signaling Pathway. Correlation analysis indicated ACAT1 mRNA expression was correlated with immune infiltrates. Collectively, our data show that ACAT1 induces pronounced inhibitory effects on gastric cancer initiation and development, which may impact future strategies to treat this aggressive cancer.

Disturbed microbiota-metabolites-immune interaction network is associated with olfactory dysfunction in patients with chronic rhinosinusitis.

Purpose: Olfactory dysfunction (OD) is a debilitating symptom frequently reported by patients with chronic rhinosinusitis (CRS) and it is associated with a dysregulated sinonasal inflammation. However, little information is available about the effect of the inflammation-related nasal microbiota and related metabolites on the olfactory function in these patients. Therefore, the current study aimed to investigate the nasal microbiota-metabolites-immune interactions and their role in the pathogenesis of OD in CRS patients. Methods: 23 and 19 CRS patients with and without OD, respectively, were enrolled in the present study. The "Sniffin' Sticks" was used to measure the olfactory function, while the metagenomic shotgun sequencing and the untargeted metabolite profiling were performed to assess the differences in terms of the nasal microbiome and metabolome between the two groups. The levels of nasal mucus inflammatory mediators were investigated by a multiplex flow Cytometric Bead Array (CBA). Results: A decreased diversity in the nasal microbiome from the OD group compared to the NOD group was evidenced. The metagenomic analysis revealed a significant enrichment of Acinetobacter johnsonii in the OD group, while Mycoplasma arginini, Aeromonas dhakensis, and Salmonella enterica were significantly less represented (LDA value > 3, p < 0.05). The nasal metabolome profiles were significantly different between the OD and NOD groups (P < 0.05). The purine metabolism was the most significantly enriched metabolic subpathway in OD patients compared with NOD patients (P < 0.001). The expressions of IL-5, IL-8, MIP-1α, MCP-1, and TNF were statistically and significantly increased in the OD group (P < 0.05). All these data, including the dysregulation of the nasal microbiota, differential metabolites, and elevated inflammatory mediators in OD patients demonstrated a clear interaction relationship. Conclusion: The disturbed nasal microbiota-metabolite-immune interaction networks may be implicated in the pathogenesis of OD in CRS patients and the underlying pathophysiological mechanisms need to be further investigated in future studies.

The Critical Role of microRNA-21 in Non-alcoholic Fatty Liver Disease Pathogenesis.

Nonalcoholic fatty liver disease (NAFLD) has received worldwide scientific attention because of its rapidly increasing prevalence, and it has emerged as a serious public health problem in end-stage liver disease. Many factors are involved in the multifactorial development and progression of liver disease by influencing multiple signaling and metabolic pathways. Currently, many studies have demonstrated the critical role of microRNA- 21 (miR-21) in NAFLD pathogenesis. In addition, many studies have found that miR-21 is highly expressed in inflammatory bowel disease, which is associated with intestinal barrier dysfunction and altered gut microbiota. In this paper, we focus on the regulatory role of miR-21 in the progression of NAFLD and its effect on the gut microbiota, summarize the involvement of miR-21 through a variety of signaling pathways and metabolic pathways, as well as discuss some predicted miR-21 target genes and miR-21 pathways for future experimental identification.

The Regulatory Role of Lipid Metabolism in Endometrial Cancer.

Endometrial cancer is the 6th most common carcinoma as well as the 2nd most common malignancy worldwide in women. It is closely related to fat content, and dyslipidemia is among the most significant metabolic changes in this cancer. Therefore, further understanding of the regulation mechanism in lipid metabolism of endometrial cancer is conducive to the development of better therapeutic strategies and methods. Here, we systematically review the signaling pathways that regulate lipid metabolism in endometrial cancer and the research progress of drugs and targeted therapies that act on lipid metabolism by retrieving relevant articles. The underlying mechanism of occurrence and development of endometrial cancer is relatively clear and comprehensively reviewed here. But following more research studies will help to illuminate more specific regulatory roles of lipid metabolism in endometrial cancer and explore new possible mechanisms, prognostic and therapeutic targets, and subsequent drugs. Our review will provide a full view for the following investigation of lipid metabolism in endometrial cancer.

Chemosensory Functions in Patients with Inflammatory Bowel Disease and Their Association with Clinical Disease Activity.

Purpose: Decreased olfactory and gustatory functions are present in various systemic autoimmune diseases. However, little is known about the chemosensory functions of patients with inflammatory bowel disease (IBD). The present study aimed to investigate olfactory and gustatory functions in patients with IBD and their correlation with clinical disease activity. Methods: A total of 103 patients with IBD were included (52 men, 51 women, mean age 40.3 ± 1.2 years) in the present study. Chemosensory functions were assessed utilizing the "Sniffin' Sticks" olfactory function test and "taste sprays" gustatory function test. The clinical disease activity of patients was graded as remission, mild, and moderate−severe. In addition, inflammatory markers (fecal calprotectin, C-reactive protein and blood leucocyte count) were recorded. Results: In total, 70% of IBD patients were normosmic, 30% were hyposmic, and none of them was functionally anosmic; 6% of the patients showed signs of hypogeusia. Patients with moderate−severe IBD reached a higher olfactory threshold score compared with patients with remission (p = 0.011) and mild IBD (p < 0.001). The BMI of IBD patients was inversely correlated with their olfactory threshold (r = −0.25, p = 0.010). Olfactory and gustatory function in IBD patients did not correlate with duration of disease, blood leucocyte count, CRP level, or fecal calprotectin level. However, patients' olfactory function significantly increased after 4 months of TNF-α inhibitor treatment (p = 0.038). Conclusions: IBD patients are more likely to present with hyposmia. Olfactory thresholds were mainly affected. They were significantly associated with clinical disease activity and BMI. As shown in a subgroup, treatment with TNF-α inhibitors appeared to improve olfactory function.

Machine Learning-Based Prediction Method for Tremors Induced by Tacrolimus in the Treatment of Nephrotic Syndrome.

Tremors have been reported even with a low dose of tacrolimus in patients with nephrotic syndrome and are responsible for hampering the day-to-day work of young active patients with nephrotic syndrome. This study proposes a neural network model based on seven variables to predict the development of tremors following tacrolimus. The sensitivity and specificity of this algorithm are high. A total of 252 patients were included in this study, out of which 39 (15.5%) experienced tremors, 181 patients (including 32 patients who experienced tremors) were randomly assigned to a training dataset, and the remaining were assigned to an external validation set. We used a recursive feature elimination algorithm to train the training dataset, in turn, through 10-fold cross-validation. The classification performance of the classifer was then used as the evaluation criterion for these subsets to find the subset of optimal features. A neural network was used as a classification algorithm to accurately predict tremors using the subset of optimal features. This model was subsequently tested in the validation dataset. The subset of optimal features contained seven variables (creatinine, D-dimer, total protein, calcium ion, platelet distribution width, serum kalium, and fibrinogen), and the highest accuracy obtained was 0.8288. The neural network model based on these seven variables obtained an area under the curve (AUC) value of 0.9726, an accuracy of 0.9345, a sensitivity of 0.9712, and a specificity of 0.7586 in the training set. Meanwhile, the external validation achieved an accuracy of 0.8214, a sensitivity of 0.8378, and a specificity of 0.7000 in the validation dataset. This model was capable of predicting tremors caused by tacrolimus with an excellent degree of accuracy, which can be beneficial in the treatment of nephrotic syndrome patients.

CPAP is associated with decreased risk of AF recurrence in patients with OSA, especially those younger and slimmer: a meta-analysis.

PURPOSE: Obstructive sleep apnea (OSA) is associated with the management of atrial fibrillation (AF). This manuscript aims to discuss the effects of continuous positive airway pressure (CPAP) in patients with rhythm control strategies and patients with different ages, weights and length of follow-up. METHODS: We searched Embase, PubMed, Cochrane, Web of Science and Ovid for relevant studies (from inception to 7 July 2019; English). The primary outcome was documented AF recurrence in CPAP users and nonusers. We assessed pooled data by use of a random-effects model. RESULTS: Nine prospective cohort studies with a total of 2134 participants met the inclusion criteria. Results showed that complementary CPAP therapy reduced AF recurrence (RR = 0.63; 95% CI, 0.56-0.72). In subgroup analyses, the benefits of CPAP were stronger in patients younger than 60 years old (< 60 years old: RR, 0.59; 95% CI, 0.50-0.68 vs. ≥ 60 years old: RR, 0.73; 95% CI, 0.59-0.91), with a body mass index (BMI) of less than 30 (< 30: RR, 0.53; 95% CI, 0.37-0.77 vs. ≥ 30: RR, 0.65; 95% CI, 0.55-0.77) or with less follow-up time (≤ 1 year: RR, 0.57; 95% CI, 0.42-0.79 vs. > 1 year: RR, 0.64; 95% CI, 0.53-0.78). CONCLUSIONS: Complementary CPAP therapy reduces the risk of AF recurrence in OSA patients with rhythm control strategies. In addition to weight control and early AF intervention, CPAP compliance should be recommended along with periodic adjustments as necessary.