Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity.

Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

Differential infection behavior of African swine fever virus (ASFV) genotype I and II in the upper respiratory tract.

African swine fever virus (ASFV) is a substantial threat to pig populations worldwide, contributing to economic disruption and food security challenges. Its spread is attributed to the oronasal transmission route, particularly in animals with acute ASF. Our study addresses the understudied role of nasal mucosa in ASFV infection, using a nasal explant model. The explants remained viable and revealed a discernible ASFV infection in nasal septum and turbinates post-inoculation. Interestingly, more infected cells were found in the turbinates despite its thinner structure. Further analyses showed (i) a higher replication of genotype II strain BEL18 than genotype I strain E70 in the epithelial cell layer, (ii) a preference of ASFV infection for the lamina propria and a tropism of ASFV for various susceptible cell types in different areas in the nasal mucosa, including epithelial cells, macrophages, and endothelial cells. Using porcine respiratory epithelial cells (PoRECs), isolated from nasal tissue, we found a difference in infection mechanism between the two genotypes, with genotype I favoring the basolateral surface and genotype II preferring the apical surface. Moreover, disruption of intercellular junctions enhanced infection for genotype I. This study demonstrated that ASFV may use the respiratory mucosa for entry using different cell types for replication with a genotype difference in their infection of respiratory epithelial cells.

Differential resting-state neurophysiological activity associated with game usage patterns and genres in Internet gaming disorder.

We investigated differences in quantitative electroencephalogram (EEG) patterns associated with game usage patterns and genre among patients with Internet gaming disorder (IGD). Data from 140 participants (76 IGD patients and 64 healthy controls) were analysed. The IGD group was divided into subgroups based on game usage patterns (single game [SG] or multiple games [MGs]) and genre (multiplayer online battle arena, first-person shooter [FPS], or massively multiplayer online role-playing game [MMORPG; hereafter, MMG]). A resting-state, eye-closed quantitative EEG was recorded, and the absolute power and coherence of brain waves were analysed. IGD patients who played SGs showed increased beta activity compared with those who played MGs and controls. Increased absolute beta power was significantly associated with higher tendencies towards behavioural inhibition compared with controls. FPS gamers showed increased delta power in the frontal region compared with controls, which was related to the severity of IGD. Furthermore, decreased intrahemispheric coherence in the left frontoparietal region was observed in the MMG and FPS groups compared with controls. This decreased coherence was observed in the theta (MMG and FPS), delta (MMG), and beta (FPS) bands. These features were related to impairment in visuospatial working memory. Unique neurophysiological features related to preoccupation with an SG may be associated with the inhibition of behavioural changes. The present study suggests that the underlying neurophysiological networks in IGD differ according to game usage patterns and genre.

Duodenal perforation in a puppy with canine parvovirus infection.

A 2-month-old puppy was brought to a veterinary hospital with diarrhea, vomiting, and anorexia. The test for canine parvovirus was positive, and she was hospitalized for supportive care. Her gastrointestinal symptoms initially improved; however, vomiting and lethargy developed again in the second week of hospitalization. Abdominal ultrasonography results were suspicious of a duodenal perforation. Cytology of the abdominal effusion confirmed septic peritonitis; therefore, emergency exploratory laparotomy was performed. The surgery was successful, and the puppy recovered fully. When symptoms recur or deteriorate in patients with parvoviral infection, surgically curable complications may be disregarded if supportive therapy is continued without additional investigative examinations. This report highlights the usefulness of abdominal ultrasound in conjunction with fluid cytology to identify subsequent complications when the clinical signs of parvovirus deteriorate. Key clinical message: This case report demonstrates duodenal perforation as a complication of parvoviral infection. Abdominal ultrasonography and peritoneal fluid cytology can be crucial for the early recognition of intestinal complications requiring immediate successful perioperative treatment.

Perforation duodénale chez un chiot infecté par le parvovirus canin. Un chiot de 2 mois a été amené dans un hôpital vétérinaire avec de la diarrhée, des vomissements et de l'anorexie. Le test de dépistage du parvovirus canin était positif et l'animal a été hospitalisé pour des soins de soutien. Ses symptômes gastro-intestinaux se sont initialement améliorés; cependant, des vomissements et une léthargie se sont à nouveau développés au cours de la deuxième semaine d'hospitalisation. Les résultats de l'échographie abdominale étaient suspects d'une perforation duodénale. La cytologie de l'épanchement abdominal a confirmé une péritonite septique; par conséquent, une laparotomie exploratrice d'urgence a été réalisée. L'opération a été un succès et le chiot s'est complètement rétabli. Lorsque les symptômes réapparaissent ou s'aggravent chez les patients atteints d'une infection parvovirale, les complications soignables chirurgicalement peuvent être ignorées si le traitement de soutien est poursuivi sans examens d'investigation supplémentaires. Ce rapport souligne l'utilité de l'échographie abdominale en conjonction avec la cytologie du liquide péritonéal pour identifier les complications ultérieures lorsque les signes cliniques associés au parvovirus se détériorent.Message clinique clé :Ce rapport de cas démontre une perforation duodénale comme complication d'une infection parvovirale. L'échographie abdominale et la cytologie du liquide péritonéal peuvent être cruciales pour la détection précoce des complications intestinales nécessitant un traitement per-opératoire immédiat réussi.(Traduit par Dr Serge Messier).

Isolation and characterization of a new population of nasal surface macrophages and their susceptibility to PRRSV-1 subtype 1 (LV) and subtype 3 (Lena).

Sialoadhesin (Sn) and CD163 have been recognized as two important mediators for porcine reproductive and respiratory syndrome virus (PRRSV) in host macrophages. Recently, it has been demonstrated that the highly virulent Lena strain has a wider macrophage tropism than the low virulent LV strain in the nasal mucosa. Not only CD163+Sn+ macrophages are infected by Lena but also CD163+Sn- macrophages. This suggests that an alternative receptor exists for binding and internalization of PRRSV Lena in the CD163+Sn- macrophages. Further investigation to find the new entry receptor was hampered by the difficulty of isolating these macrophages from the nasal mucosa. In the present study, a new population of CD163+Sn- cells has been identified that is specifically localized in the nasal lamina propria and can be isolated by an intranasal digestion approach. Isolated nasal cells were characterized using specific cell markers and their susceptibility to two different PRRSV-1 strains (LV and Lena) was tested. Upon digestion, 3.2% (flow cytometry)-6.4% (confocal microscopy) of the nasal cells were identified as CD163+ and all (99.7%) of these CD163+ cells were Sn-. These CD163+Sn- cells, designated as "nasal surface macrophages", showed a 4.9 times higher susceptibility to the Lena strain than to the LV strain. Furthermore, the Lena-inoculated cell cultures showed an upregulation of CD163. These results showed that our new cell isolation system is ideal for the further functional and phenotypical analysis of the new population of nasal surface macrophages and further research on the molecular pathogenesis of PRRSV in the nose.

Computed tomographic lymphangiography of the thoracic duct by subcutaneous iohexol injection into the metatarsal region.

OBJECTIVE: To evaluate the efficacy of subcutaneous iohexol injection into the metatarsal region for thoracic duct lymphangiography in dogs and to determine the minimum effective dose. STUDY DESIGN: Experimental study and clinical report. ANIMALS: Five healthy beagle dogs and one dog with chylothorax. METHODS: For the experimental study, iohexol was injected subcutaneously into the metatarsal region of five dogs at three doses (0.5, 0.75, and 1 mL/kg), and the injection sites were massaged gently. Computed tomography (CT) was performed 1, 3, 5, 7, 10, 15, and 20 minutes after iohexol injection. Subjective quality was assessed, and Hounsfield unit values were measured at several regions of interest (T1, T4, T8, T13, and L3). In the dog with chylothorax, iohexol (1.0 mL/kg) was injected into the right metatarsal region prior to CT. RESULTS: The thoracic duct was visualized and enhanced by contrast in all dogs after injection of 0.75 and 1.0 mL/kg of iohexol, and in two dogs after injection of 0.5 mL/kg at 3, 5, and 7 minutes. The thoracic duct was gradually attenuated with increasing doses of iohexol. In the dog with chylothorax, the entire thoracic duct was well enhanced and dilated, and tortuous cranial mediastinal lymphatics were detected. CONCLUSION: The thoracic duct was visualized when at least 0.75 mL/kg of iohexol was injected subcutaneously into the metatarsal region of dogs. CLINICAL SIGNIFICANCE: Subcutaneous injection of iohexol into the metatarsal region offers a simple alternative to conventional thoracic duct lymphangiography.

Computed tomographic bronchial collapsibility values over 50% may be detected in healthy dogs.

Bronchomalacia and bronchial collapse are important causes of chronic coughing in dogs. The current reference standard diagnostic tests for these problems are flexible bronchoscopy and biopsy. Previous human studies have also supported inspiration/expiration computed tomography (CT) as a diagnostic test. The current prospective, pilot study aimed to determine whether inspiration/expiration CT is also a feasible test for quantifying bronchial collapsibility in dogs. Thoracic CT images were acquired using a 64-row multidetector CT for 10 healthy Beagle dogs during maximal inspiration and expiration. For each scan, one observer measured transverse sectional areas of the mainstem and lobar bronchi, and the dorsal and ventral segmental bronchi of the left cranial lobar bronchus. Diameters for each bronchus were also measured in transverse, sagittal, and dorsal planes. Bronchial collapsibility (%) was calculated as the difference between inspiration/expiration transverse sectional areas divided by the inspiration transverse sectional areas. Mean bronchial collapsibility of all bronchi was 38.20 ± 15.17%. A collapsibility of over 50% was found in the dorsal (n = 7) and ventral (n = 4) segmental bronchi of the left cranial lobar bronchus, and the left caudal (n = 5) and right middle (n = 2) lobar bronchus. Bronchial collapsibility measurements were greater in the dorsal and ventral segmental bronchi of the left cranial lobar bronchus and the left caudal lobar bronchus (P < 0.001). Findings supported inspiration/expiration CT as a modality to noninvasively assess bronchial collapse in dogs and a bronchial collapsibility value greater than 50% for detecting pathologic bronchial collapse in clinically affected dogs.

Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance.

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.

GPR105 ablation prevents inflammation and improves insulin sensitivity in mice with diet-induced obesity.

GPR105, a G protein-coupled receptor for UDP-glucose, is highly expressed in several human tissues and participates in the innate immune response. Because inflammation has been implicated as a key initial trigger for type 2 diabetes, we hypothesized that GPR105 (official gene name: P2RY14) might play a role in the initiation of inflammation and insulin resistance in obesity. To this end, we investigated glucose metabolism in GPR105 knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD). We also examined whether GPR105 regulates macrophage recruitment to liver or adipose tissues by in vivo monocyte tracking and in vitro chemotaxis experiments, followed by transplantation of bone marrow from either KO or WT donors to WT recipients. Our data show that genetic deletion of GPR105 confers protection against HFD-induced insulin resistance, with reduced macrophage infiltration and inflammation in liver, and increased insulin-stimulated Akt phosphorylation in liver, muscle, and adipose tissue. By tracking monocytes from either KO or WT donors, we found that fewer KO monocytes were recruited to the liver of WT recipients. Furthermore, we observed that uridine 5-diphosphoglucose enhanced the in vitro migration of bone marrow-derived macrophages from WT but not KO mice, and that plasma uridine 5-diphosphoglucose levels were significantly higher in obese versus lean mice. Finally, we confirmed that insulin sensitivity improved in HFD mice with a myeloid cell-specific deletion of GPR105. These studies indicate that GPR105 ablation mitigates HFD-induced insulin resistance by inhibiting macrophage recruitment and tissue inflammation. Hence GPR105 provides a novel link between innate immunity and metabolism.

Case report: Magnetic resonance imaging features with postoperative improvement of atypical cervical glioma characterized by predominant extramedullary distribution in a dog.

Introduction: Intramedullary cord tumors present diagnostic and therapeutic challenges. Furthermore, spinal cord tumors can move across compartments, making antemortem diagnosis difficult, even with advanced imaging. This report presents a rare case of a cranial cervical spinal glioma, confirmed by surgical histopathology, with postoperative improvement in a dog. Case description: A 9-year-old female Maltese dog presented with kyphotic posture, progressive left hemiparesis, and decreased appetite. Neurological examination revealed neck pain and decreased proprioception in the left limbs along with intact deep pain perception. Two days later, the patient developed non-ambulatory tetraparesis. Magnetic resonance imaging (MRI) revealed an ovoid, well-defined mass with homogeneously marked contrast enhancement in the second cervical spinal cord that severely compressed the spinal cord. This mass was heterogeneously hyperintense on T2-weighted images and iso-to-hypointense on T1-weighted images, showing an appearance resembling the "golf-tee" and "dural tail" signs. The MRI findings suggested an intradural extramedullary tumor. Intraoperatively, a well-demarcated mass which was locally adherent to the spinal meninges was removed. Both histopathological and genomic tumor tests were indicative of a glioma. Approximately 2 weeks postoperatively, the patient's neurological signs returned to normal. Conclusion: This case report describes an atypical cervical glioma with complicated MR characteristics in a dog, where MRI helped guide surgical intervention.

Development of chimeric antigen receptor (CAR)-T cells targeting A56 viral protein implanted by oncolytic virus.

To address the challenge of solid tumor targeting in CAR-T therapy, we utilized the A56 antigen, which is uniquely expressed on a diverse range of cancer cells following the systemic administration of an oncolytic vaccinia virus (OVV). Immunohistochemical assays precisely confirmed exclusive localization of A56 to tumor tissues. In vitro studies demonstrated a distinct superiority of A56-dependent CAR-T cytotoxicity across multiple cancer cell lines. Building on these in vitro observations, we strategically administered A56 CAR-T cells, OVV, and hydroxyurea (HU) combination in HCT-116 tumor-bearing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, leading to a significant reduction in tumor size and an extended time to progression. Consequently, A56-targeting combinatorial immunotherapy provides the benefit of reducing inadvertent CAR-T effects on normal cells while preserving its effectiveness against cancer cells. Furthermore, our approach of implanting A56 via OVV on tumors facilitates a wide therapeutic application of CAR-T cells across various solid tumors.

Selection and validation of reference genes for RT-qPCR normalization of porcine alveolar macrophages (PAMs) for PRRSV studies.

Porcine alveolar macrophages (PAMs) are widely used for in vitro studies of porcine respiratory viruses. Gene expression in these cells is altered by viral infection and cellular immune response. Real-time reverse transcription polymerase chain reaction (RT-qPCR) is a powerful technique for analyzing these changes. In order to obtain reliable quantitative RT-qPCR data and come to sound conclusions, stable reference genes are needed for normalization of target gene expression. In the present study, we evaluated the expression stability of nine reference genes in PAMs during cultivation and upon porcine reproductive and respiratory syndrome virus (PRRSV) inoculation. Using geNorm and NormFinder algorithms, we identified PSAP and GAPDH as the most stable reference genes under all experimental conditions. The selected reference genes were used for the normalization of CD163 expression under different conditions. This study demonstrates that selection of appropriate reference genes is essential for normalization and validation of RT-qPCR data across all experimental conditions. This study provides a new set of stable reference genes for future studies with porcine respiratory viruses in PAMs.

Susceptibility of perivenous macrophages to PRRSV-1 subtype 1 LV and PRRSV-1 subtype 3 Lena using a new vein explant model.

Vessel pathology such as increased permeability and blue discoloration is frequently observed with highly pathogenic PRRSV strains. However, data concerning the viral replication in the environment of blood vessels are absent. In the present study, ex vivo models with swine ear and hind leg vein explants were established to study the interaction of PRRSV-1 subtype 1 reference strain LV and highly pathogenic subtype 3 strain Lena with perivenous macrophages. The replication characteristics of these two strains were compared in vein explants by immunofluorescence analysis. The explants maintained a good viability during 48 hours of in vitro culture. We found that CD163-positive macrophages were mainly present around the veins and their number gradually decreased with increasing distance from the veins and longer incubation time. More CD163+Sn- cells than CD163+Sn+ cells (6.6 times more) were observed in the vein explants. The Lena strain demonstrated a higher replication level than the LV strain, with approximately 1.4-fold more infected cells in the surrounding areas of the ear vein and 1.1-fold more infected cells in the leg vein explants at 48 hours post inoculation. In both LV and Lena inoculated vein explants, most infected cells were identified as CD163+Sn+ (> 94%). In this study, an ex vivo vein model was successfully established, and our findings will contribute to a better understanding of the vein pathology during viral infections (e.g., PRRS, classical and African swine fever).

Postoperative Computed Tomographic Assessment of the Complete Resection of an Infiltrative Lipoma Compressing the Spinal Cord in a Dog.

Infiltrative lipomas, which are locally invasive tumors composed of well-differentiated adipocytes, are histologically identical to lipomas but have a tendency to infiltrate adjacent muscle and fibrous tissue without metastasis, such as muscle; connective tissue; bone; and, in rare cases, peripheral nerves and the spinal cord. They differ from liposarcomas yet also exhibit neoplastic cell infiltration and often recur despite surgical removal. A 10-year-old spayed Maltese female dog presented with hindlimb paresis and back pain for two months. Computed tomography and magnetic resonance imaging revealed an extensive fatty mass impinging on the vertebral canal, compressing the spinal cord, and extending into the surrounding muscle layers and thoracic cavity. The mass was surgically removed, and subsequent postoperative computed tomography confirmed complete removal of the mass using Vitrea® advanced visualization fat measurement. Histopathological analysis confirmed that the mass was an infiltrative lipoma. The patient's symptoms completely resolved after surgery, with no recurrence reported at the 2-year follow-up. This case highlights the benefits of using postoperative computed tomography combined with the automated fat measurement technique to determine whether reoperation is necessary or to predict patient prognosis by identifying potential residual lipoma post-surgery.

Non-electrocardiography- and electrocardiography-gated computed tomography angiography for the evaluation of feline coronary arteries.

Objectives: Few studies have directly compared the clinical feasibility of electrocardiography-gated and non-electrocardiography-gated multidetector computed tomography for evaluating coronary arteries in veterinary medicine. We aimed to characterize and visualize feline coronary arteries using these two imaging modalities. We hypothesed that ECG-gated MDCT is superior to or advantageous to the non-ECG gated. Methods: This prospective, controlled, comparative pilot study examined six client-owned cats (five clinically normal and one with hypertrophic cardiomyopathy) using non-electrocardiography-gated and retrospective electrocardiography-gated scans. Optimal non-electrocardiography scan timing or electrocardiography-gated R-R reconstruction interval for coronary artery visualization was determined. The degree of opacification and sharpness of proximal coronary branches was subjectively graded; coronary dominance, left coronary artery branching types, and the diameter and length of coronary artery branches were also assessed. Results: Non-electrocardiography-gated images provided the least information on the bilateral coronary artery ostium and proximal segments, while electrocardiography-gated images clarified the detailed course of the main coronary branches at diastole in all cats. The degree of opacification and sharpness of the coronary arteries was subjectively evaluated as good/excellent in all cats. Coronary dominance (left: four; right: two) and left coronary artery branching types (three different patterns, two additional tortuous branches) varied. Body weight and sex were not significantly associated with coronary artery length or diameter. Vertebral heart score positively correlated with the right coronary artery and negatively correlated with the left main coronary artery. Clinical significance: Electrocardiography-gated multidetector computed tomography provides images with adequate resolution to identify the anatomy of feline coronary arteries. Detailed morphological knowledge of feline coronary vessels will enable novel diagnostic and therapeutic methods in veterinary medicine.

Evaluation of the pulmonary vein ostia during the cardiac cycle using electrocardiography-gated cardiac computed tomography in cats.

Several studies in humans have provided detailed descriptions of the anatomy of the pulmonary veins (PVs) and their ostia for the implementation of thoracic interventions, such as radiofrequency ablation, for patients with atrial fibrillation. These studies have shown that electrocardiography (ECG)-gated multidetector computed tomography (MDCT) can evaluate the dimensional variations in the PVs or ostium according to the cardiac cycle. However, few studies have examined the PVs or ostia using MDCT in veterinary medicine. Therefore, this study investigated the variation in the diameter of the PV ostium in cats during the cardiac cycle using ECG-gated MDCT and determined the correlation between the size of the heart or left atrium (LA) and diameter of the PV ostium. This study included six cats, including five normal animals and one cat with hypertrophic cardiomyopathy. The PVs were found to drain into the LA via three ostia, i.e., the right cranial ostium, left cranial ostium, and caudodorsal ostium. Moreover, a diametric variation was observed in all PV ostia according to the cardiac cycle phase on ECG-gated MDCT: the maximal diameter was observed at the end of ventricular systole, and the minimal diameter was observed at the end of ventricular diastole for each PV ostium. There were no significant correlations between the heart or LA size and maximal or minimal diameter of each of the three PV ostia (p > 0.05); however, the enlargement of each PV ostium at the end of ventricular systole differed significantly from that at the end of ventricular diastole. This study suggested the clinical feasibility of ECG-gated MDCT in providing more detailed anatomical information about the PVs, including the dimensional changes during the cardiac cycle in cats. Based on this study, knowledge of the variations in the PV ostium offers interesting avenues for research into the effect of PV function. Furthermore, ECG-gated MDCT could allow for greater clinical application of interventional procedures in animals with various cardiac diseases.

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.

Metabolic Functions of G Protein-Coupled Receptors and ß-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity.

Seven transmembrane receptors (7TMRs), often termed G protein-coupled receptors (GPCRs), are the most common target of therapeutic drugs used today. Many studies suggest that distinct members of the GPCR superfamily represent potential targets for the treatment of various metabolic disorders including obesity and type 2 diabetes (T2D). GPCRs typically activate different classes of heterotrimeric G proteins, which can be subgrouped into four major functional types: Gαs, Gαi, Gαq/11, and G12/13, in response to agonist binding. Accumulating evidence suggests that GPCRs can also initiate ß-arrestin-dependent, G protein-independent signaling. Thus, the physiological outcome of activating a certain GPCR in a particular tissue may also be modulated by ß-arrestin-dependent, but G protein-independent signaling pathways. In this review, we will focus on the role of G protein- and ß-arrestin-dependent signaling pathways in the development of obesity and T2D-related metabolic disorders.

Functional Analysis of Human and Feline Coronavirus Cross-Reactive Antibodies Directed Against the SARS-CoV-2 Fusion Peptide.

To face the continuous emergence of SARS-CoV-2 variants, broadly protective therapeutic antibodies are highly needed. We here focused on the fusion peptide (FP) region of the viral spike antigen since it is highly conserved among alpha- and betacoronaviruses. First, we found that coronavirus cross-reactive antibodies are commonly formed during infection, being omnipresent in sera from COVID-19 patients, in ~50% of pre-pandemic human sera (rich in antibodies against endemic human coronaviruses), and even in feline coronavirus-infected cats. Pepscan analyses demonstrated that a confined N-terminal region of the FP is strongly immunogenic across diverse coronaviruses. Peptide-purified human antibodies targeting this conserved FP epitope exhibited broad binding of alpha- and betacoronaviruses, besides weak and transient SARS-CoV-2 neutralizing activity. Being frequently elicited by coronavirus infection, these FP-binding antibodies might potentially exhibit Fc-mediated effector functions and influence the kinetics or severity of coronavirus infection and disease.