PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

Boiling histotripsy exhibits anti-fibrotic effects in animal models of liver fibrosis.

Liver fibrosis is a hallmark of chronic liver disease which could lead to liver cirrhosis or liver cancer. However, there is currently lack of a direct treatment for liver fibrosis. Boiling histotripsy (BH) is an emerging non-invasive high-intensity focused ultrasound technique that can be employed to mechanically destruct solid tumour at the focus via acoustic cavitation without significant adverse effect on surrounding tissue. Here, we investigated whether BH can mechanically fractionate liver fibrotic tissue thereby exhibiting an anti-fibrotic effect in an animal model of liver fibrosis. BH-treated penumbra and its identical lobe showed reduced liver fibrosis, accompanied by increased hepatocyte specific marker expression, compared to the BH-untreated lobe. Furthermore, BH treatment improved serological liver function markers without notable adverse effects. The ability of BH to reduce fibrosis and promote liver regeneration in liver fibrotic tissue suggests that BH could potentially be an effective and reliable therapeutic approach against liver fibrosis.

Noninvasive mechanical destruction of liver tissue and tissue decellularisation by pressure-modulated shockwave histotripsy.

Introduction: Boiling histotripsy (BH) is a promising High Intensity Focused Ultrasound (HIFU) technique that can be used to mechanically fractionate solid tumours at the HIFU focus noninvasively, promoting tumour immunity. Because of the occurrence of shock scattering phenomenon during BH process, the treatment accuracy of BH is, however, somewhat limited. To induce more localised and selective tissue destruction, the concept of pressure modulation has recently been proposed in our previous in vitro tissue phantom study. The aim of the present study was therefore to investigate whether this newly developed histotripsy approach termed pressure-modulated shockwave histotripsy (PSH) can be used to induce localised mechanical tissue fractionation in in vivo animal model. Methods: In the present study, 8 Sprague Dawley rats underwent the PSH treatment and were sacrificed immediately after the exposure for morphological and histological analyses (paraffin embedded liver tissue sections were stained with H&E and MT). Partially exteriorised rat's left lateral liver lobe in vivo was exposed to a 2.0 MHz HIFU transducer with peak positive (P +) and negative (P -) pressures of 89.1 MPa and -14.6 MPa, a pulse length of 5 to 34 ms, a pressure modulation time at 4 ms where P + and P - decreased to 29.9 MPa and - 9.6 MPa, a pulse repetition frequency of 1 Hz, a duty cycle of 1% and number of pulses of 1 to 20. Three lesions were produced on each animal. For comparison, the same exposure condition but no pressure modulation was also employed to create a number of lesions in the liver. Results and Discussion: Experimental results showed that a partial mechanical destruction of liver tissue in the form of an oval in the absence of thermal damage was clearly observed at the HIFU focus after the PSH exposure. With a single pulse length of 7 ms, a PSH lesion created in the liver was measured to be a length of 1.04 ± 0.04 mm and a width of 0.87 ± 0.21 mm which was 2.37 times in length (p = 0.027) and 1.35 times in width (p = 0.1295) smaller than a lesion produced by no pressure modulation approach (e.g., BH). It was also observed that the length of a PSH lesion gradually grew towards the opposite direction to the HIFU source along the axial direction with the PSH pulse length, eventually leading to the generation of an elongated lesion in the liver. In addition, our experimental results demonstrated the feasibility of inducing partial decellularisation effect where liver tissue was partially destructed with intact extracellular matrix (i.e., intact fibrillar collagen) with the shortest PSH pulse length. Taken together, these results suggest that PSH could be used to induce a highly localised tissue fractionation with a desired degree of mechanical damage from complete tissue fractionation to tissue decellularisation through controlling the dynamics of boiling bubbles without inducing the shock scattering effect.

Metabolic activity of visceral adipose tissue is associated with age-related macular degeneration: a pilot 18F-FDG PET/CT study.

Background: Obesity is known to increase the risk and severity of age-related macular degeneration (AMD). Increased inflamed metabolic activity of visceral adipose tissue (VAT) is considered as a crucial underlying mechanism for the harmful effects of obesity. In this study, we aimed to investigate the inflamed metabolic activity of VAT with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and their association with AMD. Materials and methods: A total of 57 elderly participants (aged ≥ 50 years) who underwent 18F-FDG PET/CT for health screening and subsequent fundoscopic exam for complaint of recently impaired vision were enrolled. The metabolic activity of VAT was measured from the maximum standardized uptake value (SUVmax) of VAT. The early AMD participant was defined as the participant with either eye satisfying AMD and without any sign of advanced AMD (neovascular AMD or geographic atrophy). The late AMD participant was defined as the participant with either eye satisfying advanced AMD. Results: VAT SUVmax was highest in participants with late AMD, intermediate in early AMD, and lowest in non-AMD participants. The levels of systemic inflammation surrogate markers were also highest in late AMD group. Furthermore, VAT SUVmax was positively correlated with systemic inflammation surrogate markers and independently associated with the late AMD. Conclusions: The metabolic activity of VAT evaluated by 18F-FDG PET/CT was associated with the severity of AMD and synchronized with the level of systemic inflammation. Thus, VAT SUVmax could be potentially employed as a surrogate marker of obesity-driven VAT inflammation associated with AMD.

Investigation of the long-term healing response of the liver to boiling histotripsy treatment in vivo.

Boiling histotripsy (BH) is a promising High-Intensity Focused Ultrasound technique that can be employed to mechanically fractionate solid tumours. Whilst studies have shown the feasibility of BH to destroy liver cancer, no study has reported on the healing process of BH-treated liver tissue. We therefore extensively investigated the evolution of the healing response of liver to BH in order to provide an insight into the healing mechanisms. In the present study, 14 Sprague Dawley rats underwent the BH treatment and were sacrificed on days 0, 3, 7, 14, and 28 for morphological, histological, serological and qPCR analyses. The area of the treated region was 1.44 cm2 (1.2 cm × 1.2 cm). A well-defined BH lesion filled with coagulated blood formed on day 0. A week after the treatment, fibroblast activation was induced at the treatment site, leading to the formation of extracellular matrix structure (ECM). The ECM was then disrupted for 7 to 28 days. Regenerated normal hepatocytes and newly formed blood vessels were found within the BH region with the absence of hepatic fibrosis. No significant morphological, histological and genetic changes around the BH lesion occurred. These results suggest that BH could be a safe and promising therapeutic tool for treating solid tumours without inducing any significant adverse effect such as the formation of liver fibrosis.

The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia.

Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbates ischemic brain damage by causing intracerebral hemorrhage and increasing neurotoxicity. In the present study, we investigated whether the neuroprotant otaplimastat reduced delayed rtPA treatment-evoked neurotoxicity in male Sprague Dawley rats subjected to embolic middle cerebral artery occlusion (eMCAO). Otaplimastat reduced cerebral infarct size and edema and improved neurobehavioral deficits. In particular, otaplimastat markedly reduced intracerebral hemorrhagic transformation and mortality triggered by delayed rtPA treatment, consequently extending the therapeutic time window of rtPA. We further found that ischemia-evoked extracellular matrix metalloproteases (MMPs) expression was closely correlated with cerebral hemorrhagic transformation and brain damage. In ischemic conditions, delayed rtPA treatment further increased brain injury via synergistic expression of MMPs in vascular endothelial cells. In oxygen-glucose-deprived endothelial cells, otaplimastat suppressed the activity rather than protein expression of MMPs by restoring the level of tissue inhibitor of metalloproteinase (TIMP) suppressed in ischemia, and consequently reduced vascular permeation. This paper shows that otaplimastat under clinical trials is a new drug which can inhibit stroke on its own and extend the therapeutic time window of rtPA, especially when administered in combination with rtPA.

SP-1154, a novel synthetic TGF-ß inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice.

OBJECTIVE: Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-ß /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-ß/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. METHODS: NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. KEY FINDINGS: SP-1154 inhibited TGF-ß/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD. CONCLUSION: Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.

Chronic physical exercise alleviates stress-associated amygdala metabolic activity in obese women: A prospective serial 18F-FDG PET/CT study.

Background: Psychological stress is considered as a major risk factor for cardiovascular disease (CVD). Chronic exercise is known to reduce CVD risk partly through attenuating psychological stress. Obesity has been linked with increased levels of psychological stress. We aimed to prospectively evaluate whether physical exercise could alleviate stress-associated amygdala metabolic activity, assessed by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in women with obesity. Material and methods: A total of 43 participants were enrolled in this study. Twenty-three obese women were participated in a physical exercise program 5 days per week for 3 months. The exercise program consisted of aerobic exercise and resistance training. Serial 18F-FDG PET/CT was taken before the start of physical exercise program (baseline) and after finishing the program (post-exercise). A total of 20 participants who underwent 18F-FDG PET/CT for general health check-up were enrolled as non-obese control group. Brain amygdala activity (AmygA) was calculated as maximum standardized uptake value (SUVmax) of amygdala normalized to mean SUV of temporal lobe. Results: Chronic physical exercise significantly reduced AmygA and improved body adiposity and systemic inflammation. AmygA was highest in baseline, intermediate in post-exercise, and lowest in non-obese control group (0.76 ± 0.17, 0.61 ± 0.1, 0.52 ± 0.09, p < 0.001). Furthermore, physical exercise also abrogated the association of AmygA with systemic inflammation. Conclusions: Chronic physical exercise reduced stress-associated amygdala metabolic activity and broke its association with systemic inflammation in obese women. This study could explain the putative mechanism underlying the health beneficial effect of exercise on CVD via attenuation of stress neurobiology.

Stress-Related Amygdala Metabolic Activity Is Associated With Low Bone Mineral Density in Postmenopausal Women: A Pilot 18F-FDG PET/CT Study.

Background: Psychological stress is associated with postmenopausal osteoporosis. However, the underlying mechanism of stress-related brain neural activity with osteoporosis is not fully elucidated. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is an established method to evaluate the metabolic activity of brain amygdala, a region involved in stress. We aimed to evaluate the relationship between metabolic activity of amygdala (AmygA) and osteoporosis in postmenopausal women. Materials and Methods: A total of 115 postmenopausal women who underwent 18F-FDG PET/CT and dual-energy X-ray absorptiometry for routine health screening were enrolled in this study. AmygA was defined as the maximum standardized uptake value (SUVmax) of amygdala divided by the mean SUV of temporal lobe. The levels of psychological stress were measured using the Psychosocial Well-being Index-Short Form (PWI-SF). Results: The participants with osteoporosis exhibited significantly higher AmygA than without osteoporosis (0.81 ± 0.16 vs. 0.61 ± 0.13, p < 0.001). The AmygA value of 0.69 was suggested as an optimal cut-off value to identify participant with osteoporosis (sensitivity; 79.1%, specificity; 83.3%, area under the curve; 0.841, p < 0.001). Furthermore, AmygA showed significant association with osteoporosis in postmenopausal woman by multivariate analysis. Psychological stress scale (PWI-SF) was well correlated with AmygA and AmygA was highest in high stress risk-, intermediate in moderate stress risk-, and lowest in healthy group. Conclusions: AmygA measured by 18F-FDG PET/CT is associated with osteoporosis in postmenopausal women. Our results provide the possibility that stress-related neurobiological activity involving amygdala is linked with postmenopausal osteoporosis.

Association of Inflammatory Metabolic Activity of Psoas Muscle and Acute Myocardial Infarction: A Preliminary Observational Study with 18F-FDG PET/CT.

Inflamed skeletal muscle promotes chronic inflammation in atherosclerotic plaques, thereby contributing to the increased risk of coronary artery disease (CAD). In this study, we evaluated the metabolic activity of psoas muscle, using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), and its association with carotid artery inflammation and acute myocardial infarction (AMI). In total, 90 participants (32 AMI, 33 chronic stable angina (CSA), and 25 control) were enrolled in this prospective study. Metabolic activity of skeletal muscle (SM) was measured by using maximum standardized uptake value (SUVmax) of psoas muscle, and corresponding psoas muscle area (SM area) was also measured. Carotid artery inflammation was evaluated by using the target-to background ratio (TBR) of carotid artery. SM SUVmax was highest in AMI, intermediate in CSA, and lowest in control group. SM SUVmax was significantly correlated with carotid artery TBR and systemic inflammatory surrogate markers. Furthermore, SM SUVmax was independently associated with carotid artery TBR and showed better predictability than SM area for the prediction of AMI. Metabolic activity of psoas muscle assessed by 18F-FDG PET/CT was associated with coronary plaque vulnerability and synchronized with the carotid artery inflammation in the participants with CAD. Furthermore, it may also be useful to predict AMI.

Effect of Exercise on Inflamed Psoas Muscle in Women with Obesity: A Pilot Prospective 18F-FDG PET/CT Study.

Obesity increases inflammation in skeletal muscle thereby promoting systemic inflammation which leads to increased risk of cardiometabolic disease. This prospective study aimed to evaluate whether the metabolic activity of psoas muscle (PM) was associated with systemic inflammation, and whether physical exercise could reduce the PM metabolic activity evaluated by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in women with obesity. A total of 23 women with obesity who participated in a 3-month physical exercise program were enrolled. 18F-FDG PET/CT was performed before the start of the program (baseline) and after completion of the program. The maximum standardized uptake value of psoas muscle (PM SUVmax) was used for the PM metabolic activity. The SUVmax of spleen and bone marrow, and the high-sensitivity C-reactive protein were used to evaluate the systemic inflammation. At baseline, PM SUVmax was strongly correlated with the systemic inflammation. The exercise program significantly reduced the PM SUVmax, in addition to adiposity and systemic inflammation. Furthermore, we found that the association between PM SUVmax and the systemic inflammation disappeared after completion of the exercise program. In women with obesity, PM SUVmax, assessed by 18F-FDG PET/CT, was associated with obesity-induced systemic inflammation and exercise reduced the PM SUVmax and eliminated its association with systemic inflammation.

Metabolic Activity of Visceral Adipose Tissue Is Associated with Metastatic Status of Lymph Nodes in Endometrial Cancer: A 18F-FDG PET/CT Study.

Obesity contributes to increased cancer incidence and aggressiveness in patients with endometrial cancer. Inflamed metabolic activity of visceral adipose tissue (VAT) is regarded as a key underlying mechanism of adverse consequences of obesity. The aim of this study was to investigate the association between inflammatory metabolic activity of VAT evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and metastatic status of lymph nodes (LN) in patients with endometrial cancer. In total, 161 women with newly diagnosed endometrial cancer, who received preoperative 18F-FDG PET/CT, were enrolled. VAT inflammatory metabolic activity was defined as V/S ratio and measured from the maximum standardized uptake value (SUVmax) of VAT normalized to the SUVmax of subcutaneous adipose tissue (SAT). The positive LN metastasis group exhibited a significantly higher V/S ratio than the negative LN metastasis group. Systemic inflammatory surrogate markers including high sensitivity C-reactive protein, spleen SUVmax, and bone marrow SUVmax were also higher in the LN metastasis group than in the negative LN metastasis group, showing significant correlations with V/S ratio. In multivariate logistic regression analysis, V/S ratio was independently associated with LN metastasis. V/S ratio is independently associated with the LN metastasis status in patients with endometrial cancer. This finding could be useful as a potential surrogate marker of obesity-induced VAT inflammation associated with tumor aggressiveness.

Association of glucose uptake of visceral fat and acute myocardial infarction: a pilot 18F-FDG PET/CT study.

BACKGROUND: Inflamed visceral adipose tissue (VAT) facilitates chronic inflammation in atherosclerotic lesions thereby leading to increased risk of coronary artery disease (CAD). In this study, we evaluated the glucose uptake of VAT and the carotid artery with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and their association with CAD, including acute myocardial infarction (AMI). METHODS: A total of 90 participants were enrolled (32 with AMI, 33 with chronic stable angina; CSA, and 25 control participants) and undertook 18F-FDG PET/CT. VAT glucose uptake was measured by using maximum standardized uptake value (SUVmax) of VAT region. The target-to-background ratio (TBR) of carotid artery was defined as the SUVmax of carotid artery divided by the SUVmax of jugular vein. The SUVmax of spleen, bone-marrow (BM), and high-sensitivity C-reactive protein (hsCRP) were used for the assessment of systemic inflammatory activity. RESULTS: VAT SUVmax was highest in participants with AMI, intermediate in participants with CSA, and lowest in control participants. Carotid artery TBR and systemic inflammatory surrogate markers including spleen SUVmax, BM SUVmax, and hsCRP were also higher in the AMI group than in the CSA or control group. Furthermore, VAT SUVmax showed significant positive correlation with carotid artery TBR, spleen SUVmax, BM SUVmax, and hsCRP. In multivariate linear regression and logistic regression analyses, VAT SUVmax was independently associated with carotid artery TBR and AMI. CONCLUSIONS: Glucose uptake of VAT assessed by 18F-FDG PET/CT was associated with the severity of CAD and synchronized with the carotid artery inflammation in participants with CAD.

Exercise training reduces inflammatory metabolic activity of visceral fat assessed by 18 F-FDG PET/CT in obese women.

OBJECTIVES: Obesity plays pivotal roles in the increased risk of cardiometabolic disease via induction of the inflammatory reaction from macrophages in visceral adipose tissue (VAT), which may elevate the inflammatory activity of VAT. This prospective study aimed to evaluate whether the inflammatory activity of VAT existed in association with systemic inflammation, and whether exercise could ameliorate the inflammatory activity of VAT assessed by 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in obese women. DESIGN AND PATIENTS: A total of 23 obese women who participated in an exercise program were included. Subjects underwent 18 F-FDG PET/CT before the start of the exercise program (baseline) and after the completion of the 3-month exercise program. For the assessment of VAT metabolic activity, the maximum standardized uptake value (SUVmax) and the mean standardized uptake value (SUVmean) were measured. The SUVmax of spleen, bone marrow (BM) and the high-sensitivity C-reactive protein (hsCRP) were used as a surrogate marker for systemic inflammation. RESULTS: Baseline SUVmax of VAT was positively correlated with the SUVmax of spleen, BM and hsCRP, whereas VAT SUVmean was not correlated. Exercise reduced SUVmax of VAT in addition to adiposity, the SUVmax of spleen, BM and hsCRP. However, VAT SUVmean was not significantly changed. Furthermore, the association of SUVmax of VAT, and the SUVmax of spleen, BM and hsCRP was no longer relevant after exercise. CONCLUSION: In obese women, the SUVmax of VAT assessed by 18 F-FDG PET/CT was associated with systemic inflammation and exercise reduced the SUVmax of VAT and abrogated its association with systemic inflammation.

A Novel CD147 Inhibitor, SP-8356, Attenuates Pathological Fibrosis in Alkali-Burned Rat Cornea.

The corneal fibrotic responses to corneal damage often lead to severe corneal opacification thereby resulting in severe visual impairment or even blindness. The persistence of corneal opacity depends heavily on the activity of corneal myofibroblast. Myofibroblasts are opaque and synthesize a disorganized extracellular matrix (ECM) and thus promoting opacification. Cluster of differentiation 147 (CD147), a member of the immunoglobulin superfamily, is known to play important roles in the differentiation process from fibroblast to myofibroblast in damaged cornea and may therefore be an effective target for treatment of corneal opacity. Here, we examined the therapeutic efficacy of novel CD147 inhibiting verbenone derivative SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) on corneal fibrosis. Topical SP-8356 significantly reduced corneal haze and fibrosis in the alkali-burned cornea. In detail, SP-8356 inhibited both alpha-smooth muscle actin (α-SMA) expressing myofibroblast and its ECM-related products, such as matrix-metalloproteinase-9 and collagen type III and IV. Similar to SP-8356, topical corticosteroid (prednisolone acetate, PA) also reduced the ECM-related products and opacification. However, prednisolone acetate failed to decrease the population of α-SMA-positive corneal myofibroblast. In conclusion, SP-8356 is capable enough to prevent corneal haze by preventing pathological fibrosis after severe corneal damage. Therefore, SP-8356 could be a potentially promising therapeutic drug for corneal fibrosis.

Visceral fat metabolic activity evaluated by preoperative 18F-FDG PET/CT significantly affects axillary lymph node metastasis in postmenopausal luminal breast cancer.

Obesity is known to increase breast cancer risk and aggressiveness in postmenopausal luminal breast cancer and obesity-driven dysfunctional metabolic activity in visceral adipose tissue (VAT) is considered as one of the principal underlying mechanism. We aimed to investigate the relationship between VAT metabolic activity evaluated by preoperative 18F-FDG PET/CT and axillary lymph node (ALN) metastasis in postmenopausal luminal breast cancer patients. In total, 173 patients were enrolled in study. They all underwent preoperative 18F-FDG PET/CT and surgery. VAT metabolic activity was defined as the maximum standardized uptake value (SUVmax) of VAT divided by the SUVmax of subcutaneous adipose tissue (V/S ratio). In luminal breast cancer, the patients with ALN metastasis showed significantly higher V/S ratio than the patients without ALN metastasis. Furthermore, V/S ratio was significantly associated with ALN metastasis in luminal breast cancer patients. Erythrocyte sedimentation rate, which reflect the systemic inflammation, was significantly higher in ALN metastasis group than the negative ALN metastasis group in luminal breast cancer patients and showed significant positive correlation with V/S ratio. V/S ratio significantly affects the ALN metastasis status in postmenopausal luminal breast cancer patients and it may be useful as a potential biomarker of obesity-driven systemic inflammation associated with tumor aggressiveness.

SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice.

Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.

A novel CD147 inhibitor, SP-8356, reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation.

BACKGROUND: Neointimal hyperplasia and its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis. Cluster of differentiation 147 (CD147), a member of the immunoglobulin super family that induces the expression of matrix metalloproteinase-9 (MMP-9) by dimerization, may play important roles in neointimal hyperplasia and may therefore be an effective target for the treatment of this condition. Here, we investigated whether a novel CD147 inhibitor SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation. METHODS: Neointimal hyperplasia was induced in Sprague-Dawley rats by partial ligation of the right carotid artery combined with a high fat diet and vitamin D injection. Rats were subdivided into vehicle, SP-8356 (50 mg/kg), and rosuvastatin (10 mg/kg) groups. The drugs were administrated via intraperitoneal injections for 4 weeks. The elasticity of blood vessels was assessed by measuring pulse wave velocity using Doppler ultrasonography before sacrifice. Histomolecular analysis was carried out on harvested carotid arteries. RESULTS: SP-8356 significantly reduced MMP activity by inhibiting CD147 dimerization. SP-8356 reduced neointimal hyperplasia and prevented the deterioration of vascular elasticity. SP-8356 had a greater inhibitory effect on neointimal hyperplasia than did rosuvastatin. Furthermore, rosuvastatin did not improve vascular elasticity. SP-8356 increased the expression of smooth muscle myosin heavy chain (SM-MHC), but decreased the expression of collagen type III and MMP-9 in the neointimal region. In contrast to SP-8356, rosuvastatin did not alter the expression of SM-MHC or MMP-9. CONCLUSIONS: The ability of SP-8356 to reduce neointimal hyperplasia and improve arterial stiffness in affected carotid artery suggests that SP-8356 could be a promising therapeutic drug for vascular remodeling disorders involving neointimal hyperplasia and arterial stiffness.

Visualization of Synthetic Vascular Smooth Muscle Cells in Atherosclerotic Carotid Rat Arteries by F-18 FDG PET.

Synthetic vascular smooth muscle cells (VSMCs) play important roles in atherosclerosis, in-stent restenosis, and transplant vasculopathy. We investigated the synthetic activity of VSMCs in the atherosclerotic carotid artery using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Atherosclerosis was induced in rats by partial ligation of the right carotid artery coupled with an atherogenic diet and vitamin D injections (2 consecutive days, 600,000 IU/day). One month later, rats were imaged by F-18 FDG PET. The atherosclerotic right carotid arteries showed prominent luminal narrowing with neointimal hyperplasia. The regions with neointimal hyperplasia were composed of α-smooth muscle actin-positive cells with decreased expression of smooth muscle myosin heavy chain. Surrogate markers of synthetic VSMCs such as collagen type III, cyclophilin A, and matrix metallopeptidase-9 were increased in neointima region. However, neither macrophages nor neutrophils were observed in regions with neointimal hyperplasia. F-18 FDG PET imaging and autoradiography showed elevated FDG uptake into the atherosclerotic carotid artery. The inner vessel layer showed higher tracer uptake than the outer layer. Consistently, the expression of glucose transporter 1 was highly increased in neointima. The present results indicate that F-18 FDG PET may be a useful tool for evaluating synthetic activities of VSMCs in vascular remodeling disorders.