Clinical Correlates of the PET-based Braak Staging Framework in Alzheimer's Disease.

In vivo Alzheimer's disease diagnosis and staging is traditionally based on clinical features. However, the agreement between clinical and pathological Alzheimer's disease diagnosis, whose diagnosis assessment includes amyloid and Braak histopathological tau staging, is not completely convergent. The development of positron emission tomography (PET) tracers targeting neurofibrillary tangles offers prospects for advancing the staging of Alzheimer's disease from both biological and clinical perspectives. Recent advances in radiochemistry made it possible to apply the postmortem Braak staging framework to tau-PET images obtained in vivo. Here, our aim is to provide a narrative review of the current literature on the relationship between Alzheimer's disease clinical features and the PET-based Braak staging framework. Overall, the available studies support the stepwise increase in disease severity following the advance of PET-based Braak stages, with later stages being associated with worse cognitive and clinical symptoms. In line with this, there is a trend for unimpaired cognition, mild cognitive impairment, and Alzheimer's disease dementia to be compatible with early, intermediate, and late patterns of tau deposition based on PET-based Braak stages. Moreover, neuropsychiatric symptom severity seems to be linked to the extent of tau-PET signal across Braak areas. In sum, this framework seems to correspond well with the clinical progression of Alzheimer's disease, which is an indication of its potential utility in research and clinical practice, especially for detecting preclinical tau levels in individuals without symptoms. However, further research is needed to improve the generalizability of these findings and to better understand the applications of this staging framework.

Eigenpulses of Dispersive Time-Varying Media.

We develop a compact theory that can be applied to a variety of time-varying dispersive materials. The continuous-wave reflection and transmission coefficients are replaced with equivalent operator expressions. In addition to comparing this approach to existing numerical and analytical techniques, we find that the eigenfunctions of these operators represent pulses that do not change their spectra after interaction with the time-varying, dispersive material. In addition, the poles of these operators represent the nontime harmonic bound states of the system.

Correlation between HRCT signs and levels of CA125, SCCA, and NSE for different pathological types of lung cancer.

OBJECTIVE: The aim of this study was to investigate the correlation between high-resolution CT (HRCT) signs and serum tumor markers, to improve the diagnostic level and identify different pathological types of lung cancer. PATIENTS AND METHODS: 102 patients with pathologically confirmed lung cancer were selected as the observation group. HRCT scan and serum tumor markers [cancer antigen 125 (CA125), squamous cell carcinoma antigen (SCCA), and neuron-specific enolase (NSE)] were performed to analyze the correlation. RESULTS: Among the 102 cases of lung cancer, 88 cases were of lobulation sign, 78 cases of speculation sign, 45 cases of pleural indentation sign, 35 cases of vessel tracking sign, and 34 cases of vacuole sign. CA125 had the highest concentration in lung adenocarcinoma (55.74±14.18) ng/ml, and SCCA had the highest concentration in lung squamous cell carcinoma (18.98±6.37) ng/ml. The concentration of NSE in small cell lung cancer was the highest (48.12±16.19) ng/ml. CONCLUSIONS: Pleural indentation sign and vacuole sign were more likely to happen in lung adenocarcinoma and lung squamous cell carcinoma, respectively. The significant increase of CA125, SCCA, and NSE concentrations suggested that lung cancer patients were more likely to suffer from lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer, respectively.

Effects of ciprofol for the induction of general anesthesia in patients scheduled for elective surgery compared to propofol: a phase 3, multicenter, randomized, double-blind, comparative study.

OBJECTIVE: Ciprofol is a newly developed intravenous sedative-hypnotic drug. The objective of the study was to prove whether ciprofol was non-inferior to propofol for the successful induction of general anesthesia. The ideal post-induction sedation level was assessed by comparing patients' clinical symptoms and their hemodynamic effects in responding to noxious stimuli, mostly tracheal intubation and bispectral index (BIS) alterations following ciprofol/propofol administration. PATIENTS AND METHODS: In this multi-center, randomized, double-blind phase 3 trial, selective surgery patients were randomly assigned in a 1:1 ratio to either ciprofol 0.4 mg/kg (n = 88) or propofol 2.0 mg/kg (n = 88) groups. The primary endpoint was the percentage of patients with successful anesthesia inductions. Secondary endpoints included the times to successful induction of general anesthesia and loss of the eyelash reflex, changes in BIS, as well as safety indicators. RESULTS: The anesthesia induction success rates for both ciprofol 0.4 mg/kg and propofol 2 mg/kg groups were 100.0%, with a 95% CI lower success limit of -4.18% difference between the two groups, indicating that ciprofol was non-inferior to propofol. For secondary outcomes, the average time to successful anesthesia and loss of the eyelash reflex were 0.91 min and 0.80 min for ciprofol and 0.80 min and 0.71 min for propofol, respectively. The pattern of BIS changes with ciprofol was similar to propofol and stable during the anesthesia maintenance period. Safety was comparable with 88.6% TEAEs in the ciprofol group compared to 95.5% in the propofol group. The incidence of injection pain was significantly lower in the ciprofol group compared to the propofol group (6.8% vs. 20.5%, p < 0.05). In addition, the patients treated with ciprofol had a lesser increase in blood pressure and heart rate, and fewer cases with BIS > 60 within 15 min of intravenous administration, which indicated that ciprofol may provide a better ideal sedation level during the post-induction period under an equivalent dosing regimen to propofol. CONCLUSIONS: Ciprofol for patients undergoing selective surgery is a new option for the induction of general anesthesia.

Effect of coccidial challenge and vaccination on the performance, veterinary postmortem scores, and blood biochemistry of broiler chickens.

A total of 960 male Cobb 500 broilers were used in a growth performance study to explore the effect of coccidial vaccination and/or coccidial challenge on blood biochemistry and veterinary postmortem metrics. Day-old chicks were randomly divided into one of the 4 experimental treatments. Treatments were arranged in a 2 × 2 factorial arrangement, with the factors being without or with vaccination (administered on day 1) or coccidial challenge (oral gavage on day 7). Growth performance was monitored on a weekly basis. Blood sample collection, as well as full veterinary necropsies, were carried out on days 6, 8, 13, 20, 27, and 34. Birds that did not receive the vaccination but were challenged with coccidiosis had higher feed conversion ratio, lower body weights, and higher mortality than the other experimental groups, and this effect was particularly evident from day 13 to day 20. Birds challenged with coccidiosis had lower plasma sodium and total carotenoid concentrations and higher potassium and globulin concentrations than nonchallenged birds. Significant interactions between age and experimental treatment for these blood parameters were observed, particularly on day 13. The necropsy results confirmed the effectiveness of the challenge and vaccination treatments, wherein birds that were challenged had higher coccidiosis scores on day 13 and day 27 than birds that were not challenged. These results demonstrate the potential for plasma sodium, potassium, total protein, total carbon dioxide, globulin, and carotenoid analysis for early diagnosis of coccidiosis in growing broiler chickens. Further work is necessary to establish whether the changes in blood biochemistry observed in the present study are transferable to alternative flocks of chicken and whether early diagnosis and intervention may mitigate performance losses associated with this disease.

Experimental study on synergistic effect of HIFU treatment of tumors using Bifidobacterium bound with cationic phase-change nanoparticles.

OBJECTIVE: Anaerobic bacteria can enter the solid tumor in the hypoxic region to colonize and proliferate. Aggregation of nanoparticles in the tumor area can enhance molecular imaging and therapy. It is hypothesized that the combination of the two could possibly achieve better imaging and tumor treatment. This study presents a biocompatible bacteria-based system that can deliver cationic phase-change nanoparticles (CPNs) into solid tumor to achieve enhanced imaging and treatment integration. MATERIALS AND METHODS: Cationic phase-change nanoparticles (CPNs) and Bifidobacterium longum (BF) were mixed to determine the best binding rate and were placed in an agar phantom for ultrasonography. BF-CPNs complex adhesion to breast cancer cells was observed by laser confocal microscopy. In vivo, BF-CPNs and control groups were injected into tumors in breast cancer nude mouse models. Nanoparticles distribution was observed by ultrasound and in vivo fluorescence imaging. HIFU ablation was performed after injection. Gross and histological changes were compared and synergy was evaluated. RESULTS: Bifidobacterium longum (BF) and CPNs were combined by electrostatic adsorption. The BF-CPNs particles could increase the deposition of energy after liquid-gas phase-change during High Intensity Focused Ultrasound (HIFU) irradiation of tumor. CONCLUSIONS: This study shows a valid method in diagnosis and therapy integration for providing stronger imaging, longer retention time, and more effective tumor treatment.

Diabetes and body mass index in relation to risk of active tuberculosis: a prospective population-based cohort.

SETTING: Although diabetes (DM) and low body mass index (BMI) are established risk factors for active tuberculosis (TB), the joint effect of type 2 diabetes (T2D) and BMI is unclear.DESIGN: A prospective cohort of 63,257 adults aged 45-74 years were recruited from 1993 to 1998 in Singapore. Active TB cases were identified via linkage with the National TB Registry up to December 2014. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relations of T2D and BMI, independently and jointly, with TB risk.RESULTS: T2D was associated with increased TB risk (HR 2.31, 95% CI 1.93-2.78). Conversely, BMI was inversely associated with TB risk: HR for underweight (BMI < 18.5 kg/m²) was 2.87 (95% CI 2.15-3.82) compared to obese (BMI ≥ 27.5 kg/m²) individuals. Compared to obese individuals without T2D, HR for active TB among underweight individuals with T2D was 8.30 (95% CI 4.43-15.54). There was no statistically significant interaction between BMI and T2D on TB risk (Pinteraction = 0.85).CONCLUSION: Underweight and T2D are independent determinants for active TB. This has important public health implications in Asia where prevalence of tuberculous infection is high, and T2D occurs at lower levels of BMI.

The embryonic and evolutionary boundaries between notochord and cartilage: a new look at nucleus pulposus-specific markers.

The adult nucleus pulposus (NP) and articular cartilage are similar in terms of their histocytological components and biomechanical functionalities, requiring a deep understanding of NP-specific markers to better evaluate stem-cell-based NP regeneration. Here, we seek to distinguish NP cells from articular chondrocytes (ACs), focusing on differences in their embryonic formation and evolutionary origin. Embryonically, NP cells are conservatively derived from the axial notochord, whereas ACs originate in a diversified manner from paraxial mesoderm and neural crest cells. Evolutionarily, although the origins of vertebrate NP and AC cells can be traced to similar structures within protostomia-like bilaterian ancestors, the distant phylogenetic relationship between the two groups of animals and the differences in the bodily origins of the tissues suggest that the tissues may in fact have undergone parallel evolution within the protostomia and deuterostomia. The numbers of supposedly NP-specific markers are increasing gradually as microarray studies proceed, but no final consensus has been attained on the specificity and physiology of "exclusive" NP markers because of innate variations among species; intrinsic expression of genes that destabilize the circadian clock; and cooperation by, and crosstalk among, different genes in terms of physiology-related phenotypes. We highlight the embryonic and evolutionary boundaries between NP and AC cells, to aid in recognition of the challenges associated with evaluation of the role played by nucleopulpogenic differentiation during stem-cell-based intervertebral disc regeneration.

Effect of IFN-λ2 on combined allergic rhinitis with nasal polyps.

OBJECTIVE: This study sought to investigate the expression of interferon-λ2 (IFN-λ2) in patients with combined allergic rhinitis and nasal polyps (AR+NP), analyze the correlation between IFN-λ2 and tryptase, interleukin 10 (IL-10), and interleukin 12 (IL-12), and identify its peripheral blood cell origins. PATIENTS AND METHODS: ELISA kits were used to investigate plasma levels of IFN-λ2, tryptase, IL-10, and IL-12 in AR+NP patients and healthy controls (HC). Flow cytometry analysis was carried out to detect IFN-λ2 expression in peripheral blood leukocytes. Immunocytochemical staining was performed to detect nasal polyp IFN-λ2 expression in AR+NP patients. RESULTS: Elevated plasma IFN-λ2 levels and positive correlations between plasma IFN-λ2 and tryptase levels in AR+NP patients indicated that IFN-λ2 likely contributes to AR+NP pathogenesis. IFN-λ2 expression was upregulated in cytotoxic T cells and eosinophils in AR+NP patients. Nasal polyp mast cells and macrophages in AR+NP patients expressed IFN-λ2. CONCLUSIONS: The close correlation between IFN-λ2 expression and AR+NP may provide experimental evidence for a possible effect of IFN-λ2 against the allergic inflammatory reaction. Therefore, IFN-λ2 actions may have a potential utility for the treatment and prevention of AR+AP.

The role of chronic viral hepatitis on tuberculosis treatment interruption.

BACKGROUND: Tuberculosis (TB) drug-induced liver injury (TB-DILI) usually occurs within 8 weeks of anti-tuberculosis drug initiation. In Singapore, we suspected that the onset of TB drug-induced transaminitis may be confounded with hepatitis C virus (HCV) and hepatitis B (HBV) virus co-infection. OBJECTIVE: To determine the impact of HCV/HBV co-infection on the course of treatment in patients with TB treatment interrupted due to transaminitis. DESIGN: TB patients with treatment interruption during 2013-2014 were identified through the Singapore national TB registry. Case notes of those with transaminitis were perused. RESULTS: Of 3860 TB patients notified, 140 had suspected TB-DILI. Of these, respectively 20/140 (14.3%) and 16/140 (11.4%) were HCV- or HBV-positive. The median time to treatment interruption/transaminitis was 5 weeks vs. 9.9 weeks and 9.6 weeks for transaminitis patients without chronic liver disease and with HCV/HBV co-infection (P < 0.01). Multivariate logistic regression analysis revealed that having HCV/HBV co-infection was associated with treatment interruption occurring beyond 8 weeks (adjusted OR [aOR] 4.06, 95%CI 1.28-12.85); HCV transaminitis patients were more likely to take 10 months to complete anti-tuberculosis treatment (aOR 5.11, 95%CI 1.21-21.67) than those without chronic liver disease. CONCLUSION: TB treatment interruption due to transaminitis in HCV/HBV co-infected patients occurred later than in those without liver disease. Most had completed 2 months of pyrazinamide-containing intensive phase treatment before the onset of transaminitis.

Effects of NGX6 expression on proliferation and invasion of nasopharyngeal carcinoma cells and survival of patients.

OBJECTIVE: To detect the expressions of nasopharyngeal carcinoma-associated gene 6 (NGX6) in nasopharyngeal carcinoma cells and tissues, and to investigate the effects of NGX6 on the proliferation and invasion of nasopharyngeal carcinoma cells and the survival of patients. PATIENTS AND METHODS: The human nasopharyngeal carcinoma cells (HONE1) and immortalized human nasopharyngeal epithelial cells (NP69) were selected and cultured. The mRNA and protein expression levels of NGX6 were detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The expression of NGX6 in HONE1 was up-regulated using the gene transfection technique. Moreover, the effects of NGX6 on the proliferation and invasion capacities of HONE1 were observed via methyl thiazolyl tetrazolium (MTT) assay and Transwell assay. 50 biopsy tissue specimens of nasopharyngeal carcinoma and 20 non-neoplastic nasopharyngeal biopsy tissue specimens were collected, and the immunohistochemical method was used to detect the protein expression of NGX6 in tumor tissues of patients with esophageal carcinoma. Finally, the follow-up data of patients were recorded, Kaplan-Meier method was used for survival analysis, and the difference in survival rates was detected using the Log-rank test. RESULTS: The results of qRT-PCR and Western blot showed that the mRNA and protein expressions of NGX6 in HONE1 were significantly lower than those in nasopharyngeal carcinoma cells (NP69). After the overexpression of NGX6, the protein expression of NGX6 in HONE1 was significantly increased, but the proliferation and invasion capacities of HONE1 were significantly decreased. Besides, the immunohistochemical results revealed that the expression of NGX6 in tumor tissues of patients with nasopharyngeal carcinoma was significantly lower than that in normal tissues; the survival analysis showed that the level of NGX6 was positively correlated with the survival and prognosis of patients with nasopharyngeal carcinoma. CONCLUSIONS: NGX6 is lowly expressed in nasopharyngeal carcinoma, and it can inhibit the proliferation and invasion of nasopharyngeal carcinoma cells, whose expression is positively correlated with the survival and prognosis of patients with nasopharyngeal carcinoma.

GSK3ß controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.

This corrects the article DOI: 10.1038/onc.2013.279.

Effects of hTERT antisense oligodeoxynucleotide on cell apoptosis and expression of hTERT and bcl-2 mRNA in keloid fibroblasts.

OBJECTIVE: This study was purposed to investigate the effects of hTERT antisense oligodeoxynucleotide (ASODN) on cell apoptosis and expression of hTERT and bcl-2 mRNA in keloid fibroblasts and to explore its anti-keloid effect. MATERIALS AND METHODS: Primary cultures of dermal fibroblasts derived from 12 keloid samples were established, strains of fibroblasts at passages 3 to 4 were used in this study. After treated by hTERT ASODN the proliferation of the fibroblasts was measured by cell count and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay method, the apoptosis was analyzed by flow cytometry (FCM), and the expression of hTERT and bcl-2 mRNA were observed by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The data was analyzed by statistical software (SPSS11.5). RESULTS: The results showed that after sealing hTERT gene with ASODN for 72 h, the fibroblasts growth was repressed and the ability of proliferation decreased as the fibroblasts were treated with 1.0 mol/L ASODN for 72 h, the fibroblasts apoptosis was induced and the expression of hTERT and bcl-2 mRNA was lower than that of controlled group. The result was significantly different between control group and treatment group and was related to the treatment time of ASODN (p<0.01), but the difference was no significant when compared 1.0 µmol/L SODN group with untreated group (p>0.05). CONCLUSIONS: As a negative modutory factor, hTERT-ASODN can suppress growth and proliferation of keloid fibroblasts. Decreasing the telomerase activity of keloid fibroblasts may be one of the most important mechanisms. That hTERT-ASODN inhibited telomerase activity in keloid fibroblasts is an important pathway that may play a key role in the anti- keloid therapy.

The effect of three-dimensional conformal radiotherapy on locally recurrent nasopharyngeal carcinoma and on the expression of succinate dehydrogenase B.

OBJECTIVE: Investigate the effect of three-dimensional conformal radiotherapy (3DCRT) on locally recurrent nasopharyngeal carcinoma (NPC) on the expression of succinate dehydrogenase B (SDHB). PATIENTS AND METHODS: Eighty-six patients diagnosed with locally recurrent NPC in our hospital were selected and divided into the control group (43 cases) and observation group (43 cases). Conventional two-dimensional radiotherapy was applied in the control group, and 3DCRT was adopted in the observation group. The curative effect of both groups was compared. RESULTS: The effective rate and the degree of alleviation of the observation group were higher than those of the control group, and the differences were statistically significant (p<0.05). There were no differences in the occurrence rate of complications from radiotherapy between the two groups (p>0.05). The survival rate and median survival time of the observation group were significantly higher than those of the control group (p<0.05). The positive expression rate of SDHB in the observation group after radiotherapy was significantly higher than that of the control group (p<0.05), and the median survival time of patients with positive expression of SDHB was significantly higher than patients with negative expression (p<0.05). CONCLUSIONS: 3DCRT applied for treatment of locally recurrent NPC was safe and effective. It also improved the positive expression rate of SDHB, which was associated with increased survival time.

The guiding significance of NT-proBNP and PCT levels in mechanical ventilator of patients with chronic respiratory failure.

OBJECTIVE: To analyze the guiding significance of N-terminal pro-brain natriuretic peptide (NT-proBNP) and procalcitonin (PCT) level in mechanical ventilator used for patients with chronic respiratory failure. PATIENTS AND METHODS: Eighty-two patients with simple chronic respiratory failure who were treated by mechanical ventilator were selected for this study. They were treated offline after they reached the standards of spontaneous breathing trial, and were divided into two groups: 1- the successful offline group with 59 patients and 2- the failure group with 23 patients. Differences of NT-proBNP and PCT levels, oxygenation index, average heart rate and mean arterial pressure between two groups were compared. RESULTS: The NT-proBNP and PCT levels in the failure group were significantly higher than those in the success group, while oxygenation index was significantly lower in the success group. All differences were statistically significant (p<0.05). Comparison of average heart rate and mean arterial pressure between two groups showed no statistically significant difference (p>0.05). CONCLUSIONS: Through multi-factor regression analyses we observed that NT-proBNP and PCT levels were independent risk factors for guiding the success rate of offline (p<0.05). Spontaneous breathing trial in combination with NT-proBNP and PCT levels improved the success rate of offline.

Effects of hemodialysis and hemoperfusion on inflammatory factors and nuclear transcription factors in peripheral blood cell of multiple organ dysfunction syndrome.

OBJECTIVE: To investigate the effects of hemodialysis (HD) and hemoperfusion (HP) on inflammatory factors and nuclear transcription factors in peripheral blood cell of multiple organ dysfunction syndrome (MODS) patients. PATIENTS AND METHODS: 92 cases of MODS patients undergoing maintained hemodialysis in our hospital were randomly divided into the control group and observation group. The control group was treated with conventional hemodialysis (HD), the observation group was treated with hemoperfusion combined therapy (HD+HP) based on the control group. The levels of serum creatinine (SCR), serum total cholesterol (TC), blood urea nitrogen (BUN) and serum albumin (Alb) were compared and analyzed between two groups before and after treatment. The levels of NK-κB p65 in the white cell of peripheral blood were compared between two groups before and after treatment by Western blot. The levels of inflammatory factors TNF-α and IL-6 in peripheral blood were detected between two groups before and after treatment using ELISA method. RESULTS: Compared with the control group, the levels of Scr, BUN and TC were significantly decreased, while the level of Alb was significantly increased (p < 0.05). The level of cytoplasm NK-κB p65 protein in peripheral blood was significantly increased in the observation group, while the level of nuclear NK-κB p65 in peripheral blood was significantly decreased (p < 0.05). CONCLUSIONS: Hemodialysis combined with hemoperfusion in treating MODS patients could significantly improve the biochemical indicators, effectively remove the inflammatory mediums, and significantly inhibit the activation of NK-κB.

The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function.

Poor graft function (PGF), including early and late PGF, is a serious complication following allotransplant. We recently reported that bone marrow microenvironment abnormalities may occur in cases of late PGF. Whether these abnormalities occur in early PGF remains unknown. To answer this question, we performed a nested case-control study comparing cellular elements of the bone marrow microenvironment in 10 subjects with early PGF, 30 subjects with late PGF and 40 subjects without PGF. Bone marrow endosteal cells, perivascular cells and endothelial cells were analyzed by flow cytometry and by hematoxylin-eosin and immunohistochemical staining in situ. Subjects with early and late PGF had similar abnormalities in these cell types compared with transplant recipients without PGF. However, none of the aforementioned elements of the bone marrow microenvironment were significantly different between early and late PGF patients. Our data suggest that similar abnormalities in the bone marrow microenvironment may occur in early and late PGF post allotransplant. Cellular approaches, such as the administration of mesenchymal stem cells, promise to be beneficial therapeutic strategies in patients with early or late PGF.

Proapoptotic effects of heme oxygenase-1 inhibitor on Kasumi-1 cells via the ATF4/CHOP/Ire-1α pathway.

We evaluated the effects of down-regulated heme oxygenase (HO)-1 expression on the proliferation of the acute myelocytic leukemia Kasumi-1 cell line by using the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) in combination with daunorubicin (DNR), and evaluated the mechanism. The proliferation rates of cells treated with 10 mg/mL DNR and 10 mM ZnPPIX individually or in combination for different time periods were detected using the MTT assay. The apoptotic outcomes of the blank control, ZnPPIX, DNR, and ZnPPIX groups in combination with the DNR group were detected by flow cytometry. The expression of HO-1, activating transcription factor 4, CCAAT-enhancer-binding protein homologous protein, and inositol-requiring enzyme-α mRNA and proteins were detected by fluorescent quantitative real-time polymerase chain reaction and western blotting, respectively. Combined administration inhibited the cells most potently and time-dependently, decreased the expression of HO-1, and significantly increased the expression of activating transcription factor 4, CCAAT-enhancer-binding protein homologous protein, and inositol-requiring enzyme-α expression levels. The cell apoptotic rates in the blank control, DNR, ZnPPIX, and combined administration groups were 8.32 ± 0.53, 39.16 ± 1.46, 10.46 ± 0.88, and 56.26 ± 2.24%, respectively. Inhibiting HO-1 expression can enhance the damaging effects of DNR on Kasumi-1 cells, providing experimental evidence for the improvement of therapeutic effects on acute myelocytic leukemia in clinical practice.

A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis.

AIM: To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice. METHODS: The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined. RESULTS: Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in ß-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the ß2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice. CONCLUSION: BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.