Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation.

The molecular mediator and functional significance of meal-associated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-sympathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, which is sensed in the brain and promotes satiation. Chronic infusion of a modified human secretin transiently elevates energy expenditure in diet-induced obese mice. Clinical trials with human subjects showed that thermogenesis after a single-meal ingestion correlated with postprandial secretin levels and that secretin infusions increased glucose uptake in BAT. Collectively, our findings highlight the largely unappreciated function of BAT in the control of satiation and qualify BAT as an even more attractive target for treating obesity.

Chronic viral infection impairs immune memory to a different pathogen.

Chronic viral infections cause T cell dysfunction in both animal models and human clinical settings, thereby affecting the ability of the host immune system to clear viral pathogens and develop proper virus-specific immune memory. However, the impact of chronic viral infections on the host's immune memory to other pathogens has not been well described. In this study, we immunized mice with recombinant Listeria monocytogenes expressing OVA (Lm-OVA) to generate immunity to Lm and allow analysis of OVA-specific memory T (Tm) cells. We then infected these mice with lymphocytic choriomeningitis virus (LCMV) strain Cl-13 which establishes a chronic infection. We found that chronically infected mice were unable to protect against Listeria re-challenge. OVA-specific Tm cells showed a progressive loss in total numbers and in their ability to produce effector cytokines in the context of chronic LCMV infection. Unlike virus-specific T cells, OVA-specific Tm cells from chronically infected mice did not up-regulate the expression of inhibitory receptors, a hallmark feature of exhaustion in virus-specific T cells. Finally, OVA-specific Tm cells failed to mount a robust recall response after bacteria re-challenge both in the chronically infected and adoptively transferred naïve hosts. These results show that previously established bacteria-specific Tm cells become functionally impaired in the setting of an unrelated bystander chronic viral infection, which may contribute to poor immunity against other pathogens in the host with chronic viral infection.

Bactericidal and sterilizing activity of sudapyridine-clofazimine-TB47 combined with linezolid or pyrazinamide in a murine model of tuberculosis.

As an obligate aerobe, Mycobacterium tuberculosis relies on its branched electron transport chain (ETC) for energy production through oxidative phosphorylation. Regimens targeting ETC exhibit promising potential to enhance bactericidal activity against M. tuberculosis and hold the prospect of shortening treatment duration. Our previous research demonstrated that the bacteriostatic drug candidate TB47 (T) inhibited the growth of M. tuberculosis by targeting the cytochrome bc1 complex and exhibited synergistic activity with clofazimine (C). Here, we found synergistic activities between C and sudapyridine (S), a structural analog of bedaquiline (B). S has shown similar anti-tuberculosis efficacy and may share a mechanism of action with B, which inhibits ATP synthesis and the energy metabolism of bacteria. We evaluated the efficacy of SCT in combination with linezolid (L) or pyrazinamide (Z) using a well-established murine model of tuberculosis. Compared to the BPa(pretomanid)L regimen, SCT and SCTL demonstrated similar bactericidal and sterilizing activities. There was no significant difference in activity between SCT and SCTL. In contrast, SCZ and SCTZ showed much higher activities, with none of the 15 mice experiencing relapse after 2 months of treatment with either SCZ or SCTZ. However, T did not contribute to the activity of the SCZ. Our findings emphasize the efficacy and the potential clinical significance of combination therapy with ETC inhibitors. Additionally, cross-resistance exists not only between S and B but also between S/B and C. This is supported by our findings, as spontaneous S-resistant mutants exhibited mutations in Rv0678, which are associated with cross-resistance to B and C.

Analysis of the epidemiology and clinical characteristics of Epstein-Barr virus infection.

The Epstein-Barr virus (EBV) is responsible for a spectrum of human diseases and demonstrates a considerable prevalence among various populations. Advances in molecular epidemiological research have enhanced our comprehension of EBV-related pathologies. In this study, our objective was to examine the epidemiological profile and clinical features of EBV infection in Chongqing, China. We enrolled patients suspected of EBV-related diseases who were admitted to the First Affiliated Hospital of Chongqing Medical University between May 2013 and November 2022. Inclusion criteria were based on those who underwent EBV-specific immunofluorescence or plasma EBV-DNA testing. Among 13 584 inpatients, the overall seropositivity rates for EBNA-1-IgG, EBV-VCA-IgM, EBV-EA-IgG, EBV-EA-IgA, EBV-VCA-IgA, and EBV-DNA were 91.89%, 7.22%, 18.00%, 16.19%, 30.78%, and 18.00%, respectively. The seropositivity rate for EBNA-1-IgG steadily increased with age. The seropositivity rate for VCA-IgM, an indicator of acute EBV infection, was highest in patients aged 11-20 years at 26.41%, decreasing to 2%-6% in older patients. Additionally, among 205 outpatients, the EBV-DNA positivity rate was 14.15%. In 3670 individuals from health check-up centers, the seropositivity rates for EBV-EA-IgA and EBV-VCA-IgA were 11.96% and 28.09%, respectively, and the EBV-DNA positivity rate was 11.92%, all of which were lower than those in inpatients. Among the 762 EBV-DNA positive inpatients, adults aged 31-40 years were the least affected, with a seropositivity rate of 12.00%, which increased with age. The most common diseases associated with primary EBV infection were infectious mononucleosis (IM) (35.49%), followed by EBV infection (14.15%) and pneumonia (7.19%). The most common diseases associated with EBV reactivation were pneumonia (16.80%), nasopharyngeal carcinoma (NPC) (11.02%), and autoimmune diseases (7.04%). Patients with hemophagocytic lymphohistiocytosis (HLH) had the highest viral load, significantly higher than those with NPC, pneumonia, and liver cirrhosis. This large-scale retrospective study explores the epidemiological characteristics and disease spectrum of EBV infection across all age groups. The findings contribute to the improvement of diagnostic and management strategies for EBV infection.

NMNATs expression inhibition mediated NAD+ deficiency plays a critical role in doxorubicin-induced hepatotoxicity in mice.

Doxorubicin (DOX) is one of the most widely used antineoplastic drugs with known cardiotoxicity while other organ toxicity, such as hepatotoxicity is not well defined. This study was to explore the role of nicotinamide adenine dinucleotide (NAD+) in DOX-induced hepatotoxicity. DOX (20 mg/kg) induced acute liver injury and oxidative stress in C57BL/6 J mice at 48 h. Notably, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H dehydrogenase quinone 1 (NQO1) were downregulated. NAD+ deficiency was confirmed due to DOX exposure. Mechanistically, the downregulation of nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1), NMNAT2 and NMNAT3, while no alteration of nicotinamide phosphoribosyl transferase was proved. As a consequence of NAD+ deficiency, the expression of poly-ADP-ribose polymerase1 (PARP1), CD38 and Sirtuin1 (SIRT1) were reduced. Furthermore, supplementation of NAD+ (200 mg/kg/day) or its precursor nicotinamide mononucleotide (NMN) (500 mg/kg/day) alleviated liver injury, attenuated oxidative stress, and elevated the downregulation of Nrf2 and NQO1. More importantly, compromised expression of NMNAT1-3, PARP1, CD38 and SIRT1 were improved by NAD+ and NMN. In conclusion, NAD+ deficiency due to NMNATs expression inhibition may attribute to the pathogenesis of DOX-induced hepatotoxicity, thus providing new insights for mitigating DOX side effects.

An FUO patient diagnosed as appendicitis: a case report.

BACKGROUND: The diagnosis and management of fever of unknown origin pose significant challenges in the field of infectious diseases, as it is influenced by various factors. Infectious diseases have long been recognized as the primary etiology of fever of unknown origin. However, not all infectious diseases can definitively identify the causative pathogen and infection sites. CASE PRESENTATION: we present a case report of an individual with fever, nausea, and anorexia but did not report any abdominal pain. Physical examination revealed no signs of abdominal tenderness. Repeated imaging studies including enhanced CT and color US of the appendix, only one color US suggested the possibility of appendicitis. Despite effective anti-infective treatment, the patient continued to experience low-grade fever, leading to the decision for laparoscopic exploration and subsequent appendectomy. Pathological findings confirmed the presence of appendicitis. After the surgical procedure, the patient's temperature and infectious markers returned to within normal range, ultimately leading to a diagnosis of appendicitis. CONCLUSIONS: The atypical symptoms and signs, along with the negative imaging results, contribute to the under diagnosis of appendicitis and the progression of fever of unknown origin, thereby exacerbating the physical, mental, and economic burden on patients. Consequently, there are valuable insights to be gained regarding the management of both appendicitis and fever of unknown origin.

Surviving winter on the Qinghai-Tibetan Plateau: Pikas suppress energy demands and exploit yak feces to survive winter.

The Qinghai-Tibetan Plateau, with low precipitation, low oxygen partial pressure, and temperatures routinely dropping below -30 °C in winter, presents several physiological challenges to its fauna. Yet it is home to many endemic mammalian species, including the plateau pika (Ochotona curzoniae). How these small animals that are incapable of hibernation survive the winter is an enigma. Measurements of daily energy expenditure (DEE) using the doubly labeled water method show that pikas suppress their DEE during winter. At the same body weight, pikas in winter expend 29.7% less than in summer, despite ambient temperatures being approximately 25 °C lower. Combined with resting metabolic rates (RMRs), this gives them an exceptionally low metabolic scope in winter (DEE/RMRt = 1.60 ± 0.30; RMRt is resting metabolic rate at thermoneutrality). Using implanted body temperature loggers and filming in the wild, we show that this is achieved by reducing body temperature and physical activity. Thyroid hormone (T3 and T4) measurements indicate this metabolic suppression is probably mediated via the thyroid axis. Winter activity was lower at sites where domestic yak (Bos grunniens) densities were higher. Pikas supplement their food intake at these sites by eating yak feces, demonstrated by direct observation, identification of yak DNA in pika stomach contents, and greater convergence in the yak/pika microbiotas in winter. This interspecific coprophagy allows pikas to thrive where yak are abundant and partially explains why pika densities are higher where domestic yak, their supposed direct competitors for food, are more abundant.

Insight into the underlying molecular mechanism of dilated cardiomyopathy through integrative analysis of data mining, iTRAQ-PRM proteomics and bioinformatics.

BACKGROUND: DCM is a common cardiomyopathy worldwide, which is characterized by ventricular dilatation and systolic dysfunction. DCM is one of the most widespread diseases contributing to sudden death and heart failure. However, our understanding of its molecular mechanisms is limited because of its etiology and underlying mechanisms. Hence, this study explored the underlying molecular mechanism of dilated cardiomyopathy through integrative analysis of data mining, iTRAQ-PRM proteomics and bioinformatics METHODS: DCM target genes were downloaded from the public databases. Next, DCM was induced in 20 rats by 8 weeks doxorubicin treatment (2.5 mg/kg/week). We applied isobaric tags for a relative and absolute quantification (iTRAQ) coupled with proteomics approach to identify differentially expressed proteins (DEPs) in myocardial tissue. After association analysis of the DEPs and the key target genes, subsequent analyses, including functional annotation, pathway enrichment, validation, were performed. RESULTS: Nine hundred thirty-five genes were identified as key target genes from public databases. Meanwhile, a total of 782 DEPs, including 348 up-regulated and 434 down-regulated proteins, were identified in our animal experiment. The functional annotation of these DEPs revealed complicated molecular mechanisms including TCA cycle, Oxidative phosphorylation, Cardiac muscle contraction. Moreover, the DEPs were analyzed for association with the key target genes screened in the public dataset. We further determined the importance of these three pathways. CONCLUSION: Our results demonstrate that TCA cycle, Oxidative phosphorylation, Cardiac muscle contraction played important roles in the detailed molecular mechanisms of DCM.

LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis.

The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos-regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.

iTRAQ and PRM-Based Comparative Proteomic Profiling of the Hippocampus in Rat Models of Epilepsy.

BACKGROUND: Epilepsy is a disease caused by paroxysmal abnormal supersynchronous electrical activity of brain neurons, and it is also one of the most common illnesses in neurology. Among the causes, hippocampal sclerosis may be one of the main causes of temporal lobe epilepsy. However, the pathogenesis of hippocampal sclerosis in epilepsy remains unclear. METHODS: We established an epilepsy model by intraperitoneal injection of pentetrazol (PTZ) into Sprague-Dawley rats, and applied isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify differentially expressed proteins (DEPs) in the hippocampus. We quantified a total of 3782 proteins. DEPs were defined as proteins with a fold change >1.2 (or <0.83) and a Q value (p-adjusted) <0.05. RESULTS: Comparing the epilepsy group and the control group, we identified 170 DEPs, comprising 109 upregulated and 61 downregulated proteins. According to bioinformatics analysis, the DEPs were primarily involved in long-term potentiation, the calcium signalling pathway, aldosterone synthesis and secretion, carbon metabolism, and dopaminergic synapses. Four of these proteins were validated using parallel reaction monitoring (PRM), including Glud1, Atp1a2, Prkcg and Arpc3. CONCLUSIONS: Our research results may provide further insight into the molecular pathology of hippocampal injury in epilepsy.

A case of unexpected death due to primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (PACNS) is a rare and fatal cerebral vasculitis mainly involving the arteriole of the pia mater, cerebral cortex, and spinal cord. It has an insidious onset atypical symptoms. In this paper, we reported an unexpected death due to cerebral hemorrhage caused by PACNS. According to the typical clinical manifestations (headache, dizziness, weakness of the limbs, temporary blurred vision, etc.) and pathological examination (wide degeneration and fibrinoid necrosis of blood vessel walls with inflammatory cell infiltration), as well as hematoxylin-eosin staining, immunohistochemistry for CD15 + and gram staining, we finally determined that the patient died due to cerebral vascular rupture and hemorrhage caused by PACNS. This case illustrates the value and key points of autopsy in evaluating sudden deaths.

Case report: sudden death following the administration of CAR-NK cells for lung cancer immunotherapy.

Lung cancer is a high degree of malignancy. Although surgery, radiotherapy, and chemotherapy have made significant progress and become general methods of clinical treatment, the overall survival rate is still low. In recent years, targeted therapy and immunotherapy have a rapid development in the clinical treatment of tumors. Among them, natural killer (NK) cells have the advantages of rapid killing of diseased cells and low risk of graft-versus-host reaction. It is considered a great vector for chimeric antigen receptors (CARs), making them have good application prospects in tumor immunotherapy. However, its clinical application in lung cancer needs further research. Herein, we reported a case of a lung cancer patient undergoing CAR-NK cell immunotherapy after resection, which caused a cytokine storm and sudden death after the fourth treatment. This case report provides a reference for the forensic examination of cadavers that died after immunotherapy and challenges the clinical application of cell immunotherapy.

A case of cardiac tamponade caused by T4N2M1 lung squamous cell carcinoma invading the aorta.

In patients with known lung squamous cell carcinoma, it is necessary to be alert to the presence of cancer cell infiltration in the large blood vessels and the heart. In this report, we report a case of a 49-year-old man who was previously diagnosed with squamous cell carcinoma of the lung, underwent autoimmune cell therapy, and was diagnosed posthumously with lung cancer invading the aorta and heart, resulting in severe cardiac tamponade. This case illustrates the value and key points of autopsy in evaluating sudden deaths.

Expression of airway smooth muscle contractile proteins in children with acute interstitial pneumonia.

The purpose of the present study was to investigate the expression of α-SMA and SM22α in airway smooth muscle (ASM) of bronchioles from children younger than 14 years who died of acute interstitial pneumonia (AIP). This is based upon the hypothesis that as contractile marker proteins α-SMA and SM22α can serve as an index of the overcontractile phenotype of ASM that is seen in AIP. Lung tissue samples of children were obtained from autopsies and divided into the AIP group (55.9% male and 44.1% female, between 0.4 and 132 months old, n = 34) and the control group (60% male and 40% female, between 2 and 156 months old, n = 10). We recorded the post-mortem interval (PMI), height, clinical symptoms and abdominal fat thickness (AFT) of each case. Haematoxylin-and-eosin-stained sections were used to examine the luminal area and observe the morphological changes in the bronchioles. Immunohistochemistry and Masson's trichrome staining were used to detect the expression of contractile marker proteins and the degree of pulmonary fibrosis respectively. Compared with the control group, the luminal areas of bronchioles in the AIP group were smaller (p < .001). The expression differences in α-SMA and SM22α between the two groups were statistically significant (p = .01 and p = .02 respectively). Also, there was no significant correlation of the contractile marker proteins expression with PMI, height, clinical symptoms and AFT. The collagen deposition difference in lung between the two groups was not statistically significant (p = .224). These findings suggest that enhancement of ASM contractile function appears to be involved in the death mechanism of children with AIP, which affords more insights into the understanding of AIP.

Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent.

Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).

A case of brucellosis-induced Guillain-Barre syndrome.

BACKGROUND: Guillain-Barre syndrome (GBS) is a rare neurological complication of brucellosis, and neurobrucellosis is the most common, but they have many similarities in clinical manifestations. Many clinicians are accustomed to merely explaining the manifestations of nervous system involvement with neurobrucellosis, but they ignore the possibility of GBS, and this leads to misdiagnosis, untimely treatment, and serious consequences. CASE PRESENTATION: A 55-year-old male patient was admitted to The First Affiliated Hospital of Harbin Medical University for intermittent fever, fatigue, and waist pain more than three months. Brucellosis was diagnosed from the blood test. Although anti-brucella treatment was given at the time of diagnosis, the disease continued to progress. At the time of the cerebrospinal fluid systematic physical examination and the neuroelectrophysiological test, acute motor sensory axonal neuropathy was diagnosed. The patient was given immediately administered immunoglobulin therapy. After three months of systemic treatment, the patient's muscle strength of the distal limbs gradually recovered. The numbness of the limbs eased slowly, and urination function and respiratory function returned to normal. He could sit by himself. CONCLUSIONS: The possibility of GBS should be closely monitored for when a brucellosis patient shows typical clinical manifestations of progressive muscle weakness, protein-cell separation of the cerebral spinal fluid, and typical demyelinating sensorimotor polyneuropathy.

Bariatric Surgery is Effective and Safe for Obese Patients with Compensated Cirrhosis: A Systematic Review and Meta-Analysis.

BACKGROUND: With the global pandemic of obesity and nonalcoholic fatty liver disease (NAFLD), the incidence of cirrhosis associated with nonalcoholic steatohepatitis (NASH) has greatly increased. This study aimed to evaluate the efficacy and safety of bariatric surgery in obese cirrhotic patients. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for relevant studies. Effectiveness outcomes were weight loss, remission of comorbidities, and improvement in liver function. Safety outcomes were procedural complications and mortality. RESULTS: A total of 15 studies were included in this meta-analysis. Patients with compensated cirrhosis lost weight significantly after surgery, and the percentage of excess weight loss was 60.44 (95% CI, 44.34 to 76.55). Bariatric surgery resulted in remission of NAFLD in 57.9% (95% CI, 27.5% to 88.3%), T2DM in 58.4% (95% CI, 48.4% to 68.4%), hypertension in 53.1% (95% CI, 43% to 63.3%), dyslipidemia in 59.8% (95% CI, 41.1% to 78.5%) of patients with cirrhosis. Bariatric surgery reduced the levels of alanine aminotransferase and aspartate aminotransferase. The incidence of surgical complications in patients with cirrhosis was about 19.2% (95% CI, 11.7% to 26.6%), which was higher than that in patients without cirrhosis (OR 2.67 [95% CI, 1.26 to 5.67]). Patients with cirrhosis had an overall mortality rate of 1.3%, and the mortality rates for compensated cirrhosis and decompensated cirrhosis were 0.9% and 18.2%, respectively. CONCLUSIONS: Bariatric surgery is effective for weight loss, remission of comorbidities, and reversal of liver damage. Although cirrhotic patients have a higher risk of complications and death, bariatric surgery is relatively safe for well-compensated cirrhosis.

Uncoupling Protein 1 Does Not Produce Heat without Activation.

Mitochondrial uncoupling protein 1 (UCP1) is the crucial mechanistic component of heat production in classical brown fat and the newly identified beige or brite fat. Thermogenesis inevitably comes at a high energetic cost and brown fat, ultimately, is an energy-wasting organ. A constrained strategy that minimizes brown fat activity unless obligate will have been favored during natural selection to safeguard metabolic thriftiness. Accordingly, UCP1 is constitutively inhibited and is inherently not leaky without activation. It follows that increasing brown adipocyte number or UCP1 abundance genetically or pharmacologically does not lead to an automatic increase in thermogenesis or subsequent metabolic consequences in the absence of a plausible route of concomitant activation. Despite its apparent obviousness, this tenet is frequently ignored. Consequently, incorrect conclusions are often drawn from increased BAT or brite/beige depot mass, e.g., predicting or causally linking beneficial metabolic effects. Here, we highlight the inherently inactive nature of UCP1, with a particular emphasis on the molecular brakes and releases of UCP1 activation under physiological conditions. These controls of UCP1 activity represent potential targets of therapeutic interventions to unlock constraints and efficiently harness the energy-expending potential of brown fat to prevent and treat obesity and associated metabolic disorders.

Uncoupling protein-1 expression does not protect mice from diet-induced obesity.

We studied the metabolic phenotype of a novel Ucp1-LUC-iRFP713 knock-in reporter gene mouse model originally generated to monitor endogenous Ucp1 gene expression. Both reporter mice and reporter cells reliably reflected Ucp1 gene expression in vivo and in vitro. We here report an unexpected reduction in UCP1 content in homozygous knock-in (KI) reporter mice. As a result, the thermogenic capacity of KI mice stimulated by norepinephrine was largely blunted, making them more sensitive to an acute cold exposure. In return, these reporter mice with reduced UCP1 expression enabled us to investigate the physiological role of UCP1 in the prevention of weight gain. We observed no substantial differences in body mass across the three genotypes, irrespective of the type of diet or the ambient temperature, possibly due to the insufficient UCP1 activation. Indeed, activation of UCP1 by daily injection of the selective ß3-adrenergic receptor agonist CL316,243 resulted in significantly greater reduction of body weight in wild-type mice than in KI mice. Taken together, we conclude that the intact expression of UCP1 is essential for cold-induced thermogenesis but the presence of UCP1 per se does not protect mice from diet-induced obesity.NEW & NOTEWORTHY To study the functional role of UCP1-dependent brown adipose tissue thermogenesis for energy balance, new animal models are needed. By metabolic phenotyping of a novel mouse model with low UCP1 levels in brown fat, we demonstrate that the susceptibility to diet-induced obesity is not increased despite impaired cold-induced thermogenic capacity. Brown fat requires pharmacological activation to promote negative energy balance in diet-induced obese mice.

Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans.

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.