Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVß5/AMPK signaling pathway after intracerebral hemorrhage in mice.

BACKGROUND: Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVß5/AMPK pathway after ICH. METHODS: Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVß5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function. RESULTS: Endogenous irisin and its receptor, integrin αVß5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVß5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVß5, p-AMPK and Bcl-2, and decreased the expression of IL-1ß, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVß5 inhibitor cilengitide and AMPK inhibitor dorsomorphin. CONCLUSIONS: This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVß5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.

Subcutaneous, but not visceral, adipose tissue as a marker for prognosis in gastric cancer patients with cachexia.

BACKGROUND & AIMS: Adipose tissue loss is one of the features in patients with cancer cachexia. However, whether subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) contribute differently to the progress of cancer cachexia in gastric cancer patients with cachexia remains unclear. This study aim to investigate the effect of SAT and VAT in gastric cancer patients with cachexia. METHODS: Gastric cancer patients who underwent surgery were divided into cancer cachexia group and non-cachexia group. A new deep learning system was developed to segment SAT and VAT from the computed tomography images at the third lumbar vertebra. Indexes of SAT (SATI) and VAT (VATI) were compared between cachexia and non-cachexia groups. The prognostic values of SATI and VATI for patients with gastric cancer cachexia were analyzed by Kaplan-Meier method and Cox regression. RESULTS: A total of 1627 gastric cancer patients (411 cachexia and 1216 non-cachexia) were included in this study. A new V-Net-Based segmentation deep learning system was developed to quickly (0.02 s/image) and accurately segment SAT (dice scores = 0.96) and VAT (dice scores = 0.98). The SATI of gastric cancer patients with cachexia were significantly lower than non-cachexia patients (44.91 ± 0.90 vs. 50.92 ± 0.71 cm2/m2, P < 0.001), whereas no significant difference was detected in VATI (35.98 ± 0.84 VS. 37.90 ± 0.45 cm2/m2, P = 0.076). Cachexia patients with low SATI showed poor survival than those with high SATI (HR = 1.35; 95% CI = 1.06-1.74). In contrast, VATI did not show close correlation with survival in patients with cachexia (HR = 1.18; 95% CI = 0.92-1.51). CONCLUSION: SAT and VAT showed different effects on gastric cancer patients with cachexia. More attention should be paid to the loss of SAT during the progress of cancer cachexia.

Mitochondrial Quality Control: A Pathophysiological Mechanism and Therapeutic Target for Stroke.

Stroke is a devastating disease with high mortality and disability rates. Previous research has established that mitochondria, as major regulators, are both influenced by stroke, and further regulated the development of poststroke injury. Mitochondria are involved in several biological processes such as energy generation, calcium homeostasis, immune response, apoptosis regulation, and reactive oxygen species (ROS) generation. Meanwhile, mitochondria can evolve into various quality control systems, including mitochondrial dynamics (fission and fusion) and mitophagy, to maintain the homeostasis of the mitochondrial network. Various activities of mitochondrial fission and fusion are associated with mitochondrial integrity and neurological injury after stroke. Additionally, proper mitophagy seems to be neuroprotective for its effect on eliminating the damaged mitochondria, while excessive mitophagy disturbs energy generation and mitochondria-associated signal pathways. The balance between mitochondrial dynamics and mitophagy is more crucial than the absolute level of each process. A neurovascular unit (NVU) is a multidimensional system by which cells release multiple mediators and regulate diverse signaling pathways across the whole neurovascular network in a way with a high dynamic interaction. The turbulence of mitochondrial quality control (MQC) could lead to NVU dysfunctions, including neuron death, neuroglial activation, blood-brain barrier (BBB) disruption, and neuroinflammation. However, the exact changes and effects of MQC on the NVU after stroke have yet to be fully illustrated. In this review, we will discuss the updated mechanisms of MQC and the pathophysiology of mitochondrial dynamics and mitophagy after stroke. We highlight the regulation of MQC as a potential therapeutic target for both ischemic and hemorrhagic stroke.

Plasma concentration of interleukin-6 was upregulated in cancer cachexia patients and was positively correlated with plasma free fatty acid in female patients.

BACKGROUND: Cancer cachexia is a clinical manifestation in various advanced cancers that characterized by muscle atrophy and fat loss as its main features; it is frequently associated with systemic inflammatory response. However, the differences in inflammatory response and lipid metabolism of different genders remain unclear. This study explores the difference between cachexic and non-cachexic patients in different genders and cancer types and focus on the plasma inflammation factors levels and lipid metabolism parameters in different genders. METHODS: We first analyzed the general characteristics in 311 cancer patients between cachexic and non-cachexic patients, with an emphasis on expression levels related to inflammatory factors and lipid metabolism parameters. We then further analyzed these characteristics in different genders and cancer types. Lastly, the correlations between plasma interleukin-6 (IL-6) and lipid metabolism parameters in cachexia patients of different genders were analyzed. RESULTS: Among 311 patients, there were 74 cancer cachexia patients (50 males and 24 females) and 237non-cachexia patients (150 males and 87 females). Body mass index (BMI), TNM stage, plasma concentration of hemoglobin, platelet, lymphocyte count, total protein, albumin, prealbumin, total cholesterol, apolipoprotein E (ApoE), free fatty acid (FFA) and IL-6 were significantly different between cachexic and non-cachexic patients (all p < 0.05). In addition, these characteristics were different in different cancer types. When compared to male non-cachexic patients, male cachexic patients showed a significant increase in plasma levels of IL-6 and platelet, later TNM stage, with marked decrease in their plasma total protein, albumin, prealbumin, ApoE as well as their lymphocyte counts and hemoglobin levels (all p < 0.05). In comparison with female non-cachexic patients, female cachexic patients' IL-6 levels and FFA were significantly elevated with noticeable decrease in their BMI, total cholesterol, ApoE and prealbumin, as well as later TNM stage (all p < 0.05). Correlation analysis revealed that IL-6 levels in female cachexic patients had a significant positive correlation with FFA expression, but this correlation not reflected in male patients. CONCLUSION: This study demonstrates the different metabolic characteristics of male and female cancer cachexia patients. Future study about cancer cachexia should pay attention to different genders and cancer types.

The hydroxypropyl-ß-cyclodextrin complexation of toltrazuril for enhancing bioavailability.

INTRODUCTION: Toltrazuril (Tol) is used to prevent and combat coccidiosis. However, its low aqueous solubility and poor oral bioavailability limit clinical application. METHODS: To overcome the shortcomings, toltrazuril-hydroxypropyl-ß-cyclodextrin inclusion complex (Tol-HP-ß-CD) was prepared and characterized. The comparative plasma disposition kinetics of Tol was analyzed after a single orally administered dose of 10 mg/kg Tol or Tol-HP-ß-CD in rabbits. Solution-stirring method was selected to prepare the inclusion complex. Complex formation was characterized by thin-layer chromatography, Fourier transform infrared spectrophotometry, and 1H nuclear magnetic resonance spectroscopy. In plasma profile, plasma samples were collected between 1 and 10 days following administration. Plasma Tol concentrations were determined by high-performance liquid chromatography. RESULTS: In rabbit plasma, the time to peak concentration (Tmax) of Tol-HP-ß-CD was shorter than that of Tol (12 h vs 24 h). Cmax (19.92±1.02 µg/mL) and area under the concentration-time curve (AUC0-∞, 1,176.86±70.26 mg/L h) of the Tol-HP-ß-CD group significantly increased (p,0.01) than those of the Tol group (Cmax, 8.02±1.04 µg/mL; AUC0-∞, 514.03±66.65 mg/L h). CONCLUSION: It can be concluded that the Tol-HP-ß-CD increased the aqueous solubility and enhanced the oral bioavailability in rabbits. Complexation with HP-ß-CD is a feasible way to prepare a rapidly absorbed and more bioavailable Tol oral product.

Novel thermosensitive in situ gel based on poloxamer for uterus delivery.

Side effects and drug residues are major concerns affecting hormone therapy of bovine reproductive diseases. Fertility-promoting intrauterine infusion liquid (FPL), an effective alternative to hormone therapy, is associated with short retention time and low therapeutic efficacy. To address these problems, we developed a thermosensitive in situ gel based on poloxamer 407 for local uterine administration. To achieve the desired gelling temperature and enhance local retention property, we added poloxamer 188 and HPMC to the formulation containing poloxamer 407 and FPL. After screening was performed, the optimized formulation showed good temperature sensitivity in vitro and in vivo. Gelation temperature was approximately 27°C. In vitro release tests showed that icariin (the major active compound in FPL) was slow released from in situ forming gel. After the gel was locally administered, uterine and ovarian indexes were significantly increased in the gel group compared with the control group (P<0.05). The serum estradiol level of the gel group was significantly higher than that of the control group (P<0.01). Histological evaluation did not show mucosa irritation in the gel group. Therefore, the proposed in situ forming gel system based on poloxamer 407 is a promising local drug delivery system to treat bovine uterine diseases.