Progress and challenges of developing volatile metabolites from exhaled breath as a biomarker platform.

BACKGROUND: The multitude of metabolites generated by physiological processes in the body can serve as valuable biomarkers for many clinical purposes. They can provide a window into relevant metabolic pathways for health and disease, as well as be candidate therapeutic targets. A subset of these metabolites generated in the human body are volatile, known as volatile organic compounds (VOCs), which can be detected in exhaled breath. These can diffuse from their point of origin throughout the body into the bloodstream and exchange into the air in the lungs. For this reason, breath VOC analysis has become a focus of biomedical research hoping to translate new useful biomarkers by taking advantage of the non-invasive nature of breath sampling, as well as the rapid rate of collection over short periods of time that can occur. Despite the promise of breath analysis as an additional platform for metabolomic analysis, no VOC breath biomarkers have successfully been implemented into a clinical setting as of the time of this review. AIM OF REVIEW: This review aims to summarize the progress made to address the major methodological challenges, including standardization, that have historically limited the translation of breath VOC biomarkers into the clinic. We highlight what steps can be taken to improve these issues within new and ongoing breath research to promote the successful development of the VOCs in breath as a robust source of candidate biomarkers. We also highlight key recent papers across select fields, critically reviewing the progress made in the past few years to advance breath research. KEY SCIENTIFIC CONCEPTS OF REVIEW: VOCs are a set of metabolites that can be sampled in exhaled breath to act as advantageous biomarkers in a variety of clinical contexts.

High-quality identification of volatile organic compounds (VOCs) originating from breath.

INTRODUCTION: Volatile organic compounds (VOCs) can arise from underlying metabolism and are detectable in exhaled breath, therefore offer a promising route to non-invasive diagnostics. Robust, precise, and repeatable breath measurement platforms able to identify VOCs in breath distinguishable from background contaminants are needed for the confident discovery of breath-based biomarkers. OBJECTIVES: To build a reliable breath collection and analysis method that can produce a comprehensive list of known VOCs in the breath of a heterogeneous human population. METHODS: The analysis cohort consisted of 90 pairs of breath and background samples collected from a heterogenous population. Owlstone Medical's Breath Biopsy® OMNI® platform, consisting of sample collection, TD-GC-MS analysis and feature extraction was utilized. VOCs were determined to be "on-breath" if they met at least one of three pre-defined metrics compared to paired background samples. On-breath VOCs were identified via comparison against purified chemical standards, using retention indexing and high-resolution accurate mass spectral matching. RESULTS: 1471 VOCs were present in > 80% of samples (breath and background), and 585 were on-breath by at least one metric. Of these, 148 have been identified covering a broad range of chemical classes. CONCLUSIONS: A robust breath collection and relative-quantitative analysis method has been developed, producing a list of 148 on-breath VOCs, identified using purified chemical standards in a heterogenous population. Providing confirmed VOC identities that are genuinely breath-borne will facilitate future biomarker discovery and subsequent biomarker validation in clinical studies. Additionally, this list of VOCs can be used to facilitate cross-study data comparisons for improved standardization.

Single-Cell-Based High-Throughput Ig and TCR Repertoire Sequencing Analysis in Rhesus Macaques.

Recent advancements in microfluidics and high-throughput sequencing technologies have enabled recovery of paired H and L chains of Igs and VDJ and VJ chains of TCRs from thousands of single cells simultaneously in humans and mice. Despite rhesus macaques being one of the most well-studied model organisms for the human adaptive immune response, high-throughput single-cell immune repertoire sequencing assays are not yet available due to the complexity of these polyclonal receptors. We used custom primers that capture all known rhesus macaque Ig and TCR isotypes and chains that are fully compatible with a commercial solution for single-cell immune repertoire profiling. Using these rhesus-specific assays, we sequenced Ig and TCR repertoires in >60,000 cells from cryopreserved rhesus PBMCs, splenocytes, and FACS-sorted B and T cells. We were able to recover every Ig isotype and TCR chain, measure clonal expansion in proliferating T cells, and pair Ig and TCR repertoires with gene expression profiles of the same single cells. Our results establish the ability to perform high-throughput immune repertoire analysis in rhesus macaques at the single-cell level.

Applications of Hyaluronic Acid in Ophthalmology and Contact Lenses.

Hyaluronic acid (HA) is a glycosaminoglycan that was first isolated and identified from the vitreous body of a bull's eye. HA is ubiquitous in the soft connective tissues of animals and therefore has high tissue compatibility for use in medication. Because of HA's biological safety and water retention properties, it has many ophthalmology-related applications, such as in intravitreal injection, dry eye treatment, and contact lenses. Due to its broad range of applications, the identification and quantification of HA is a critical topic. This review article discusses current methods for analyzing HA. Contact lenses have become a widely used medical device, with HA commonly used as an additive to their production material, surface coating, and multipurpose solution. HA molecules on contact lenses retain moisture and increase the wearer's comfort. HA absorbed by contact lenses can also gradually release to the anterior segment of the eyes to treat dry eye. This review discusses applications of HA in ophthalmology.

The CLAVATA signaling pathway mediating stem cell fate in shoot meristems requires Ca(2+) as a secondary cytosolic messenger.

CLAVATA1 (CLV1) is a receptor protein expressed in the shoot apical meristem (SAM) that translates perception of a non-cell-autonomous CLAVATA3 (CLV3) peptide signal into altered stem cell fate. CLV3 reduces expression of WUSCHEL (WUS) and FANTASTIC FOUR 2 (FAF2) in the SAM. Expression of WUS and FAF2 leads to maintenance of undifferentiated stem cells in the SAM. CLV3 binding to CLV1 inhibits expression of these genes and controls stem cell fate in the SAM through an unidentified signaling pathway. Cytosolic Ca(2+) elevations, cyclic nucleotide (cGMP)-activated Ca(2+) channels, and cGMP have been linked to signaling downstream of receptors similar to CLV1. Hence, we hypothesized that cytosolic Ca(2+) elevation mediates the CLV3 ligand/CLV1 receptor signaling that controls meristem stem cell fate. CLV3 application to Arabidopsis seedlings results in elevation of cytosolic Ca(2+) and cGMP. CLV3 control of WUS was prevented in a genotype lacking a functional cGMP-activated Ca(2+) channel. In wild-type plants, CLV3 inhibition of WUS and FAF2 expression was impaired by treatment with either a Ca(2+) channel blocker or a guanylyl cyclase inhibitor. When CLV3-dependent repression of WUS is blocked, altered control of stem cell fate leads to an increase in SAM size; we observed a larger SAM size in seedlings treated with the Ca(2+) channel blocker. These results suggest that the CLV3 ligand/CLV1 receptor system initiates a signaling cascade that elevates cytosolic Ca(2+), and that this cytosolic secondary messenger is involved in the signal transduction cascade linking CLV3/CLV1 to control of gene expression and stem cell fate in the SAM.

Physiological responses to short-term thermal stress in mayfly (Neocloeon triangulifer) larvae in relation to upper thermal limits.

Understanding species' thermal limits and their physiological determinants is critical in light of climate change and other human activities that warm freshwater ecosystems. Here, we ask whether oxygen limitation determines the chronic upper thermal limits in larvae of the mayfly Neocloeon triangulifer, an emerging model for ecological and physiological studies. Our experiments are based on a robust understanding of the upper acute (∼40°C) and chronic thermal limits of this species (>28°C, ≤30°C) derived from full life cycle rearing experiments across temperatures. We tested two related predictions derived from the hypothesis that oxygen limitation sets the chronic upper thermal limits: (1) aerobic scope declines in mayfly larvae as they approach and exceed temperatures that are chronically lethal to larvae; and (2) genes indicative of hypoxia challenge are also responsive in larvae exposed to ecologically relevant thermal limits. Neither prediction held true. We estimated aerobic scope by subtracting measurements of standard oxygen consumption rates from measurements of maximum oxygen consumption rates, the latter of which was obtained by treating with the metabolic uncoupling agent carbonyl cyanide-4-(trifluoromethoxy) pheylhydrazone (FCCP). Aerobic scope was similar in larvae held below and above chronic thermal limits. Genes indicative of oxygen limitation (LDH, EGL-9) were only upregulated under hypoxia or during exposure to temperatures beyond the chronic (and more ecologically relevant) thermal limits of this species (LDH). Our results suggest that the chronic thermal limits of this species are likely not driven by oxygen limitation, but rather are determined by other factors, e.g. bioenergetics costs. We caution against the use of short-term thermal ramping approaches to estimate critical thermal limits (CTmax) in aquatic insects because those temperatures are typically higher than those that occur in nature.

Effect of the surface chemistry of insulin fibrils on the aggregation rate.

Structure transition cascade: Insulin fibrils undergo a secondary structural transition-from the α-rich to the ß-rich form-upon progressively increasing the incubation time from 0.5 to ten hours. Atomic force microscopy measurements show that the fibril surface chemistry changes from hydrophilic to hydrophobic and the aggregation rate increases fivefold.

Transoral Ultrasound-Guided Core Biopsy for Minimally Invasive Sampling of Hard-to-Access Oropharyngeal Cancers.

Pathological diagnosis plays a pivotal role in risk classification and personalized treatment planning for patients with oropharyngeal cancers. However, challenges arise in cases involving trismus and tumors with submucosal spread, hindering traditional endoscopic biopsies and open incisional biopsies. In this study, we examined the clinical and pathological data of patients with trismus who underwent transoral ultrasound-guided core biopsy (USCB) for their oropharyngeal tumors, comparing this method with existing diagnostic approaches. Seventeen patients presenting with oropharyngeal tumors and trismus underwent transoral USCB for diagnosis. Of these, 14 patients were diagnosed with squamous cell carcinoma, while the remaining 3 were diagnosed with lymphoma. The procedure resulted in minimal wound size and effective bleeding control through compression, without encountering any complications. In conclusion, transoral USCB emerges as a precise diagnostic tool for patients with oropharyngeal tumors and trismus, offering a valuable adjunct to conventional open and endoscopic biopsies.

Establishing breath as a biomarker platform-take home messages from the Breath Biopsy Conference 2023.

The annual Breath Biopsy Conference hosted by Owlstone Medical gathers together the leading experts, early career researchers, and physicians working with breath as a biomarker platform for clinical purposes. The current topics in breath research are discussed and presented, and an overarching topical theme is identified and discussed as part of an expert panel to close the conference. The profiling of normal breath composition and the establishment of standards for analyzing breath compared to background signal were two important topics that were major focuses of this conference, as well as important innovative progress that has been made since last year, including the development of a non-invasive breath test for lung cancer and liver disease. This meeting report offers an overview of the key take-home messages from the various presentations, posters, and discussions from the conference.

Human long noncoding RNA, VILMIR, is induced by major respiratory viral infections and modulates the host interferon response.

Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic datasets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus inducible lncRNA modulator of interferon response (VILMIR), that was consistently upregulated after in vitro influenza infection across multiple human epithelial cell lines and influenza A virus subtypes. VILMIR was also upregulated after SARS-CoV-2 and RSV infections in vitro. We experimentally confirmed the response of VILMIR to influenza infection and interferon-beta (IFN-ß) treatment in the A549 human epithelial cell line and found the expression of VILMIR was robustly induced by IFN-ß treatment in a dose and time-specific manner. Single cell RNA-seq analysis of bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients uncovered that VILMIR was upregulated across various cell types including at least five immune cells. The upregulation of VILMIR in immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-ß treatment. Finally, we found that knockdown of VILMIR expression reduced the magnitude of host transcriptional responses to IFN-ß treatment in A549 cells. Together, our results show that VILMIR is a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.

Clinical outcomes and patient-reported outcomes after oncoplastic breast surgery in breast cancer patients: A matched cohort study.

BACKGROUND: Surgery is the recommended treatment for breast cancer, the most common cancer in women in Taiwan and the leading cause of cancer-related deaths. Although breast-conserving surgery (BCS) has good prognosis, in some cases, BCS may cause more significant deformities and interfere with the patient's psychosocial well-being. Oncoplastic breast surgery (OBS) is the treatment option in these cases. This study aimed to determine the outcomes of OBS and BCS regardless of clinical and patient-reported esthetic outcomes. METHODS: Between 2015 and 2020, 50 patients who underwent OBS at our hospital after complete treatment were enrolled. With 1:2 matched ratios, 100 patients were enrolled in the BCS control group. Clinical outcomes were analyzed. The BREAST-Q questionnaire was then assessed 6 months after the completion of treatment for subjective patient-reported outcomes. RESULTS: Due to the matching process, no difference was noted between the two groups in terms of demographic data such as age, comorbidities, or tumor characteristics. There were no significant differences in the local recurrence rate, disease-free survival, overall survival, positive margin rate, rewide excision rate, conversion to mastectomy rate, or complication rate (major or minor) between both groups. However, the OBS group showed higher satisfaction with breasts in the BREAST-Q questionnaire ( p < 0.001). The mean follow-up time was 38.77 ± 14.70 months in the BCS group and 29.59 ± 14.06 months in the OBS group. CONCLUSION: OBS seems to be a safe and feasible surgery in breast cancer patients because clinical outcomes are compatible with BCS. Moreover, the OBS group had better patient-reported outcomes in terms of satisfaction.

Metabolic insights at the finish line: deciphering physiological changes in ultramarathon runners through breath VOC analysis.

Exhaustive exercise can induce unique physiological responses in the lungs and other parts of the human body. The volatile organic compounds (VOCs) in exhaled breath are ideal for studying the effects of exhaustive exercise on the lungs due to the proximity of the breath matrix to the respiratory tract. As breath VOCs can originate from the bloodstream, changes in abundance should also indicate broader physiological effects of exhaustive exercise on the body. Currently, there is limited published data on the effects of exhaustive exercise on breath VOCs. Breath has great potential for biomarker analysis as it can be collected non-invasively, and capture real-time metabolic changes to better understand the effects of exhaustive exercise. In this study, we collected breath samples from a small group of elite runners participating in the 2019 Ultra-Trail du Mont Blanc ultra-marathon. The final analysis included matched paired samples collected before and after the race from 24 subjects. All 48 samples were analyzed using the Breath Biopsy Platform with GC-Orbitrap™ via thermal desorption gas chromatography-mass spectrometry. The Wilcoxon signed-rank test was used to determine whether VOC abundances differed between pre- and post-race breath samples (adjustedP-value < .05). We identified a total of 793 VOCs in the breath samples of elite runners. Of these, 63 showed significant differences between pre- and post-race samples after correction for multiple testing (12 decreased, 51 increased). The specific VOCs identified suggest the involvement of fatty acid oxidation, inflammation, and possible altered gut microbiome activity in response to exhaustive exercise. This study demonstrates significant changes in VOC abundance resulting from exhaustive exercise. Further investigation of VOC changes along with other physiological measurements can help improve our understanding of the effect of exhaustive exercise on the body and subsequent differences in VOCs in exhaled breath.

A Novel Technique for Autograft Preparation Using Patient-Specific Instrumentation (PSI) Assistance in Total Hip Arthroplasty in Developmental Dysplasia of Hip (DDH).

Due to the change in the structure of the proximal femur and acetabulum in patients with developmental dysplasia of the hip, total hip arthroplasty (THA) was difficult to perform for surgeons. To elevate the acetabular coverage rate, we developed a technique in the use of a patient-specific instrumentation (PSI) graft in patients with developmental dysplasia of hip (DDH) undergoing surgery. This study aims to evaluate the peri-operative outcomes of THA with PSI graft in patients with DDH. This study recruited 6 patients suffering from Crowe I DDH with secondary Grade IV osteoarthritis. All the patients underwent THA with PSI graft performed by a well-experienced surgeon. Perioperative outcomes included surgical procedures, blood loss during operation, the volume of blood transfusion, length of hospitalization, complications, and the mean difference in hemoglobin levels before and after surgery. All the outcomes analyzed were assessed by mean and standard deviation. The average duration of the surgical procedure was found to be 221.17 min, with an SD of 19.65 min. The mean blood loss during the operation was 733.33 mL, with an SD of 355.90 mL. The mean length of hospital stay was calculated to be 6 days, with an SD of 0.89 days. Furthermore, the mean difference between the pre- and postoperative hemoglobin levels was 2.15, with an SD of 0.99. A total of three patients received 2 units of leukocyte-poor red blood cells (LPR) as an accepted blood transfusion. There were no reported complications observed during the admission and one month after the operation. This study reported the peri-operative outcomes in the patients with DDH who underwent THA with PSI graft. We found that THA with PSI graft would provide a safe procedure without significant complications. We assumed that the PSI graft in THA may increase the coverage rate of the acetabulum, which may increase the graft union rates. Further cohort studies and randomized controlled trials were needed to confirm our findings.

Analgesic efficacy of collagen peptide in knee osteoarthritis: a meta-analysis of randomized controlled trials.

BACKGROUND: The management of knee osteoarthritis involves various treatment strategies. It is important to explore alternative therapies that are both safe and effective. Collagen peptides have emerged as a potential intervention for knee osteoarthritis. This study aims to evaluate the analgesic effects and safety of collagen peptide in patients diagnosed with knee osteoarthritis. METHODS: We conducted a systematic literature search following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Multiple databases including PubMed, Scopus, EMBASE, Web of Science, Cochrane, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) published up to 27 May 2023 that focused on the analgesic outcomes and adverse events associated with collagen peptides or hydrolyzed collagen in patients with osteoarthritis. We assessed the quality of the included studies and the strength of evidence using the Cochrane ROB 2.0 tool and Grading of Recommendations, Assessment, Development, and Evaluations. RESULTS: Four trials involving 507 patients with knee osteoarthritis were included and analyzed using the random-effects model. All these trials were considered to have a high risk of bias. Our results revealed a significant difference in pain relief between the collagen peptide group and the placebo group in patients with knee osteoarthritis (standardized mean difference: - 0.58; 95% CI - 0.98, - 0.18, p = 0.004; I2: 68%; quality of evidence: moderate). However, there was no significant difference in the risk of adverse events between collagen peptide and placebo (odds ratio: 1.66; 95% CI 0.99, 2.78, p = 0.05; I2: 0%; quality of evidence: very low). CONCLUSIONS: Our findings demonstrate significant pain relief in patients with knee osteoarthritis who received collagen peptides compared to those who received placebo. In addition, the risk of adverse events did not differ significantly between the collagen peptide group and the placebo group. However, due to potential biases and limitations, well-designed randomized controlled trials are needed to validate and confirm these findings.

Calsarcin-2 May Play a Compensatory Role in the Development of Obese Sarcopenia.

Although obese sarcopenia is a major public health problem with increasing prevalence worldwide, the factors that contribute to the development of obese sarcopenia are still obscure. In order to clarify this issue, a high-fat-diet-induced obese sarcopenia mouse model was utilized. After being fed with a high-fat diet for 24 weeks, decreased motor functions and muscle mass ratios were found in the C57BL/6 mice. In addition, the expression of calsarcin-2 was significantly increased in their skeletal muscle, which was determined by a microarray analysis. In order to clarify the role of calsarcin-2 in muscle, lentiviral vectors containing the calsarcin-2 gene or short hairpin RNA targeted to calsarcin-2 were used to manipulate calsarcin-2 expressions in L6 myoblasts. We found that an overexpression of calsarcin-2 facilitated L6 myoblast differentiation, whereas a calsarcin-2 knockdown delayed myoblast differentiation, as determined by the expression of myogenin. However, the calsarcin-2 knockdown showed no significant effects on myoblast proliferation. In addition, to clarify the relationship between serum calsarcin-2 and sarcopenia, the bilateral gastrocnemius muscle mass per body weight in mice and appendicular skeletal muscle mass index in humans were measured. Although calsarcin-2 facilitated myoblast differentiation, the serum calsarcin-2 concentration was negatively related to skeletal muscle mass index in mice and human subjects. Taken together, calsarcin-2 might facilitate myoblast differentiation and appear to play a compensatory role in sarcopenia.

Growth differentiation factor-15 is independently associated with metabolic syndrome and hyperglycemia in non-elderly subjects.

Metabolic syndrome (MetS) is a major health issue worldwide accompanied by cardiovascular comorbidities. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine expressed in cardiomyocytes, adipocytes, macrophages, and endothelial cells. Previous research in elderly subjects revealed that GDF-15 levels were associated with the MetS. However, the association between GDF-15 levels and MetS or its components in the non-elderly subjects remains unclear. In this study, a total of 279 subjects younger than 65-year-old with (n = 84) or without (n = 195) MetS were recruited. MetS was defined according to modified NCEP/ATP III criteria. The GDF-15 levels were measured by an enzyme-linked immunosorbent assay. A multiple linear regression analysis was conducted to identify factors independently associated with GDF-15 levels. Subjects with MetS had higher GDF-15 levels than those without MetS (median (interquartile range), 1.72 ng/mL (1.38, 2.26) vs. 1.63 ng/mL (1.27, 2.07), P = 0.037). With the number of MetS components increased, the GDF-15 levels increased significantly (P for trend = 0.005). Multiple linear regression analysis revealed that the presence of MetS was positively associated with the GDF-15 levels (ß = 0.132, P = 0.037). When substituting MetS with its components, only the presence of hyperglycemia was positively associated with the GDF-15 levels after adjustment for covariates (ß = 0.193, P = 0.003). Taken together, the presence of the MetS in non-elderly was associated with higher GDF-15 levels. Among the MetS components, only hyperglycemia was significantly associated with the GDF-15 levels. Future longitudinal studies will be needed to explore whether GDF-15 has the potential to be a biomarker of gluco-metabolic dysfunction in non-elderly subjects.

Serum Cardiotrophin-1 Concentration Is Negatively Associated with Controlled Attenuation Parameters in Subjects with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Since non-alcoholic fatty liver disease (NAFLD) is highly associated with obesity, cardiovascular disease, and diabetes, biomarkers for the diagnosis of NAFLD have become an important issue. Although cardiotrophin-1 (CT-1) has a protective effect on the liver in NAFLD animal models, the serum levels of CT-1 in human subjects with NAFLD were still unknown. OBJECTIVE: The present study aimed to investigate the relationship between the circulating concentration of CT-1 and the severity of hepatic steatosis graded by the value of the controlled attenuation parameter (CAP) in humans. DESIGN AND METHODS: The study was designed as a cross-sectional study, and a total of 182 subjects were enrolled. Hepatic steatosis measurement was carried out with a Firoscan® device and recorded by CAP. The enrolled study subjects were categorized into CAP < 238 dB/m, 238 ≤ CAP ≤ 259 dB/m, 260 ≤ CAP ≤ 290 dB/m, and CAP > 290 dB/m. Serum CT-1 concentrations were determined by enzyme-linked immunosorbent assay. The association between the serum CT-1 concentration and NAFLD was examined by multivariate linear regression analysis. RESULTS: Body mass index, percentage of body fat, systolic and diastolic blood pressure, alanine aminotransferase (ALT), cholesterol, triglyceride, hemoglobin A1c and homeostatic model assessment for insulin resistance (HOMA-IR) were significantly increased in groups with higher CAP value, whereas high-density lipoprotein cholesterol was significantly decreased. In addition, serum CT-1 concentrations were significantly decreased in subjects with higher CAP values. In multivariate linear regression models, including age, sex, body fat percentage, CAP, high sensitivity- C reactive protein, uric acid, creatinine, ALT, total cholesterol, and HOMA-IR, only age, CAP and uric acid independently associated with CT-1 levels. Moreover, having NAFLD was independently associated with CT-1 after adjustment for sex, obesity and type 2 diabetes. CONCLUSIONS: Serum CT-1 concentrations are decreased in subjects with NAFLD and negatively associated with CAP.

Dietary fatty acids differentially affect secretion of pro-inflammatory cytokines in human THP-1 monocytes.

Monocytes are a major population of circulating immune cells that play a crucial role in producing pro-inflammatory cytokines in the body. The actions of monocytes are known to be influenced by the combinations and concentrations of certain fatty acids (FAs) in blood and dietary fats. However, systemic comparisons of the effects of FAs on cytokine secretion by monocytes have not be performed. In this study, we compared how six saturated FAs (SFAs), two monounsaturated FAs (MUFAs), and seven polyunsaturated FAs (PUFAs) modulate human THP-1 monocyte secretion of TNF, IL-1ß, and IL-6 in the absence or presence of lipopolysaccharide. SFAs generally stimulated resting THP-1 cells to secrete pro-inflammatory cytokines, with stearic acid being the most potent species. In contrast, MUFAs and PUFAs inhibited lipopolysaccharide-induced secretion of pro-inflammatory cytokines. Interestingly, the inhibitory potentials of MUFAs and PUFAs followed U-shaped (TNF and IL-1ß) or inverted U-shaped (IL-6) dose-response curves. Among the MUFAs and PUFAs that were analyzed, docosahexaenoic acid (C22:6 n-3) exhibited the largest number of double bonds and was found to be the most potent anti-inflammatory compound. Together, our findings reveal that the chemical compositions and concentrations of dietary FAs are key factors in the intricate regulation of monocyte-mediated inflammation.

Compensatory Increase of Serum Hepassocin Protects Hyperthyroidism-Induced Hepatic Dysfunction.

Hepatic dysfunction is commonly observed in subjects with hyperthyroidism. Hepassocin is a hepatokine playing an important role in metabolic diseases and exhibiting a hepatic protective effect. Nevertheless, the relationship between hepassocin and hyperthyroidism was still unknown. In the present study, a total of 36 subjects with Graves' disease were enrolled, and we found that the alanine aminotransferase (ALT) levels were significantly decreased in parallel with the decrement in serum hepassocin concentrations at 6 months after standard treatment for hyperthyroidism. In addition, HepG2 cell line was used to investigate the role of hepassocin in hyperthyroidism-induced hepatic dysfunction. Treatment of hepassocin recombinant protein in HepG2 cells dose-dependently decreased triiodothyronine (T3)-induced ALT and aspartate aminotransferase (AST) elevation. Moreover, hepassocin significantly increased the expression of phosphoenolpyruvate carboxykinase (PEPCK) in a dose-dependent manner. Deletion of hepassocin in HepG2 cells reversed the effects of T3 on PEPCK expressions. Furthermore, we found that T3 increased the expression of hepassocin through a hepatocyte nuclear factor 1α-dependent pathway. Taken together, these results indicated a compensatory increase in serum hepassocin might have a protective role in hyperthyroidism-induced hepatic dysfunction.

Associations between GDF15 levels and pre-diabetes in non-obese subjects.

Growth differentiation factor 15 (GDF15) is a stress-response cytokine which belongs to the transforming growth factor ß superfamily. Although GDF15 was initially found to have a role in metabolic diseases, the association between GDF15 and dysglycemic status remains inconclusive. Thus, the aim of this study was to examine the relationships between GDF15 and different glycemic statuses in non-obese subjects. We enrolled 502 non-obese subjects, among individuals who had normal glucose tolerance (NGT; n=125), isolated impaired fasting glucose (IFG; n=116), isolated impaired glucose tolerance (IGT; n=106), IFG plus IGT (n=27), and newly diagnosed diabetes (NDD; n=128). A multivariate linear regression analysis of GDF15 levels was used to find independent predictors. The median (IQR) GDF15 levels were 1641.0 (1187.0-1985.5) pg/mL, 1656.1 (1226.8-2379.7) pg/mL, 1487.8 (1145.9-1987.2) pg/mL, 1722.2 (1172.9-1939.0) pg/mL, and 2204.5 (1767.4-2919.1) pg/mL in NGT, IFG, IGT, IFG plus IGT, and NDD groups, respectively. The NDD group had significantly higher GDF15 levels than those with NGT, IFG, IGT, and IFG plus IGT. The IFG group had a significantly higher GDF15 value than the NGT group. In multivariate linear regression analysis, IFG (beta=0.145, 95% CI 192.487 to 740.937, p=0.001), NDD (beta=0.227, 95% CI 390.459 to 888.145, p<0.001), and high-sensitivity C reactive protein (beta=0.105, 95% CI 3.276 to 27.768, p=0.013) were independently associated with GDF15 levels. Non-obese subjects with isolated IFG and NDD had significantly higher GDF15 levels than those with NGT. In addition, A1C was independently associated with GDF15 levels. IFG and NDD, but not isolated IGT or IFG plus IGT, were positively associated with GDF15 levels.