Ammonium chloride-induced hypothermia is attenuated by transient receptor potential channel vanilloid-1, but augmented by ankyrin-1 in rodents.

AIMS: Systemic administration of ammonium chloride (NH4Cl), an acidifying agent used in human patients and experimental conditions, causes hypothermia in mice, however, the mechanisms of the thermoregulatory response to NH4Cl and whether it develops in other species remained unknown. MAIN METHODS: We studied body temperature (Tb) changes in rats and mice induced by intraperitoneal administration of NH4Cl after blockade of transient receptor potential vanilloid-1 (TRPV1) or ankyrin-1 (TRPA1) channels. KEY FINDINGS: In rats, NH4Cl decreased Tb by 0.4-0.8°C (p < 0.05). The NH4Cl-induced hypothermia also developed in Trpv1 knockout (Trpv1-/-) and wild-type (Trpv1+/+) mice, however, the Tb drop was exaggerated in Trpv1-/- mice compared to Trpv1+/+ controls with maximal decreases of 4.0 vs. 2.1°C, respectively (p < 0.05). Pharmacological blockade of TRPV1 channels with AMG 517 augmented the hypothermic response to NH4Cl in genetically unmodified mice and rats (p < 0.05 for both). In contrast, when NH4Cl was infused to mice genetically lacking the TRPA1 channel, the hypothermic response was significantly attenuated compared to wild-type controls with maximal mean Tb difference of 1.0°C between the genotypes (p = 0.008). Pretreatment of rats with a TRPA1 antagonist (A967079) also attenuated the NH4Cl-induced Tb drop with a maximal difference of 0.7°C between the pretreatment groups (p = 0.003). SIGNIFICANCE: TRPV1 channels limit, whereas TRPA1 channels exaggerate the development of NH4Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular Tb control and careful consideration of NH4Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions.

MiRNAs in Lung Adenocarcinoma: Role, Diagnosis, Prognosis, and Therapy.

Lung cancer has emerged as a significant public health challenge and remains the leading cause of cancer-related mortality worldwide. Among various types of lung malignancies, lung adenocarcinoma (LUAD) stands as the most prevalent form. MicroRNAs (miRNAs) play a crucial role in gene regulation, and their involvement in cancer has been extensively explored. While several reviews have been published on miRNAs and lung cancer, there remains a gap in the review regarding miRNAs specifically in LUAD. In this review, we not only highlight the potential diagnostic, prognostic, and therapeutic implications of miRNAs in LUAD, but also present an inclusive overview of the extensive research conducted on miRNAs in this particular context.

Distinct patterns of serum and urine macrophage migration inhibitory factor kinetics predict death in sepsis: a prospective, observational clinical study.

Macrophage migration inhibitory factor (MIF) has been considered as a biomarker in sepsis, however the predictive value of the pattern of its kinetics in the serum and in the urine has remained unclarified. It is also unclear whether the kinetics of MIF are different between males and females. We conducted a single-center prospective, observational study with repeated measurements of MIF in serum and urine on days 0, 2, and 4 from admission to the intensive care unit (ICU) in 50 adult septic patients. We found that in patients who died within 90 days, there was an increase in serum MIF level from day 0 to 4, whereas in the survivors there was rather a decrease (p = 0.018). The kinetics were sex-dependent as the same difference in the pattern was present in males (p = 0.014), but not in females (p = 0.418). We also found that urine MIF was markedly lower in patients who died than in survivors of sepsis (p < 0.050). Urine MIF levels did not show temporal changes: there was no meaningful difference between day 0 and 4. These results suggest that kinetics of serum MIF during the initial days from ICU admission can predict death, especially in male patients. Additionally, lower urine MIF levels can also indicate death without showing meaningful temporal kinetics.

Microarray data analysis to identify miRNA biomarkers and construct the lncRNA-miRNA-mRNA network in lung adenocarcinoma.

MicroRNAs (miRNAs), regulatory noncoding RNAs, are involved in gene regulation and may play a role in cancer development. The aim of this study was to identify miRNAs involved in lung adenocarcinoma (LUAD) using bioinformatics analysis. MiRNA (GSE135918), mRNA (GSE136043) and lncRNA (GSE130779) microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed miRNAs (DEMis), mRNAs (DEMs), and lncRNA (DELs) in LUAD. We used DEMs for functional enrichment analysis. MiRNA expression quantification from The Cancer Genome Atlas (TCGA) was used to validate DEMis. LncBase Predicted v.2, Targetscan, and MiRBase were used to predict lncRNAs and mRNAs. The LUAD data in TCGA were used for overall survival (OS) analysis. We screened the downregulation of 8 DEMis and upregulation of 6 DEMis, and found that 70 signal pathways changed. We chose 3 relevant signaling pathways in lung cancer development, WNT, PI3K-Akt, and Notch, and scanned for mRNAs involved in them that are potential targets of these miRNAs. Then a lncRNA-miRNA-mRNA network was constructed. We also found 7 miRNAs that were associated with poor OS in LUAD. Low expression level of hsa-miR-30a was highly associated with poor OS in LUAD (P < .001) and the target genes of hsa-miR-30a-3p were abundant in the Wnt and AKT signaling pathways. In addition, our results reported for the first time that hsa-miR-3944 and hsa-miR-3652 were highly expressed in LUAD. And the high expression level of hsa-miR-3944 was associated with poor OS (P < .05). Hsa-miR-30a-3p may suppress the occurrence and progression of lung cancer through Wnt and AKT signaling pathways and become a good biomarker in LUAD. Hsa-miR-3944 and hsa-miR-3652 may serve as new biomarkers in LUAD.

Stereolithography 3D Printing of a Heat Exchanger for Advanced Temperature Control in Wire Myography.

We report the additive manufacturing of a heat-exchange device that can be used as a cooling accessory in a wire myograph. Wire myography is used for measuring vasomotor responses in small resistance arteries; however, the commercially available devices are not capable of active cooling. Here, we critically evaluated a transparent resin material, in terms of mechanical, structural, and thermal behavior. Tensile strength tests (67.66 ± 1.31 MPa), Charpy impact strength test (20.70 ± 2.30 kJ/m2), and Shore D hardness measurements (83.0 ± 0.47) underlined the mechanical stability of the material, supported by digital microscopy, which revealed a glass-like structure. Differential scanning calorimetry with thermogravimetry analysis and thermal conductivity measurements showed heat stability until ~250 °C and effective heat insulation. The 3D-printed heat exchanger was tested in thermophysiology experiments measuring the vasomotor responses of rat tail arteries at different temperatures (13, 16, and 36 °C). The heat-exchange device was successfully used as an accessory of the wire myograph system to cool down the experimental chambers and steadily maintain the targeted temperatures. We observed temperature-dependent differences in the vasoconstriction induced by phenylephrine and KCl. In conclusion, the transparent resin material can be used in additive manufacturing of heat-exchange devices for biomedical research, such as wire myography. Our animal experiments underline the importance of temperature-dependent physiological mechanisms, which should be further studied to understand the background of the thermal changes and their consequences.

Dietary supplementation of transient receptor potential vanilloid-1 channel agonists reduces serum total cholesterol level: a meta-analysis of controlled human trials.

Abnormal cholesterol level is a major risk factor in the development of atherosclerosis, which is a fundamental derangement in cardiovascular diseases. Any efforts should be undertaken to lower blood cholesterol levels. Among dietary interventions, capsaicinoid supplementation is also considered as a novel cholesterol-lowering approach, but human studies concluded contradictory results about its effectiveness. The present meta-analysis aimed at determining the effects of capsaicinoids on serum lipid profile in humans. We searched the PubMed, EMBASE, and CENTRAL databases from inception to February 2021. We included 10 controlled studies, which involved 398 participants. We found that dietary capsaicinoid supplementation alone or in combination with other substances significantly (p = 0.004 and 0.001, respectively) reduced serum total cholesterol level compared to controls with an overall standardized mean difference of -0.52 (95% confidence interval: -0.83, -0.21). Capsaicinoids also decreased low-density lipoprotein level significantly (p = 0.035), whereas no effect was observed on serum levels of high-density lipoprotein and triglycerides. Our findings provide novel quantitative evidence for the efficacy of dietary capsaicin supplementation in lowering serum total cholesterol and low-density lipoprotein levels in humans. To validate our conclusion, further randomized controlled trials in a diverse population of adult humans receiving dietary capsaicinoid supplementation are warranted.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice.

Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1-/-) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5-1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1-/- mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.

Assessment of clinical data on urocortins and their therapeutic potential in cardiovascular diseases: A systematic review and meta-analysis.

Heart failure (HF) and cardiovascular diseases present public health challenges. Although great progress was achieved in their treatment, there is continuous need for new therapies. Urocortins of the corticotropin neuropeptide family were reported to exert beneficial effects in animal models of HF and cardiovascular diseases. We aimed to assess the available clinical evidence on the potential role of urocortins in HF and other cardiovascular diseases. We explored MEDLINE, Embase, CENTRAL, and Scopus databases. Twenty-seven studies were included in the qualitative and 15 studies (2005 patients) in the quantitative syntheses. Available data allowed us to meta-analyze the blood pressure (BP) lowering and heart rate (HR) increasing effects of urocortin 2 in HF with reduced ejection fraction. We applied meta-regression to explore the association between left ventricular ejection fraction and serum urocortin 1 and urocortin 2 levels. Short-term urocortin 2 infusion decreased mean arterial pressure in chronic HF with reduced ejection fraction (mean difference = -9.161 mmHg, 95% confidence interval [CI] -12.661 to -5.660 mmHg, p < 0.001). Such infusions increased HR mildly (mean difference = 5.629 beats/min, 95% CI 1.612 to 9.646 beats/min, p = 0.006). Although some studies reported increased urocortin 1 and urocortin 2 levels in HF with growing severity, our meta-regressions failed to confirm associations between blood urocortin levels and left ventricular ejection fraction. Clinical evidence confirms short-term BP lowering effects of urocortin 2, whereas individual studies report additional beneficial effects. Further clinical investigations are necessary to confirm the latter and the long-term value of these peptides in cardiovascular diseases. Review protocol: CRD42020163203.