A Comparative Study of the Effects of Electronic Cigarette and Traditional Cigarette on the Pulmonary Functions of C57BL/6 Male Mice.

INTRODUCTION: Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms. METHODS: A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells. RESULTS: Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS: The findings of the present study indicate that the safety of E-cig should be further evaluated. IMPLICATIONS: Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.

DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis.

Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.

Mechanism of Ferulic Acid in PI3K/AKT Pathway and Research in Glioblastoma.

Phenolic acids and their analogues in nature exist in many diseases of oxidative stress with beneficial effects on human health (such as cancer). Phenolic acids possess a variety of pharmacological activities, with anti-inflammatory, anticancer and cytotoxic, antioxidant, immunomodulatory, antimicrobial, insecticidal and other biological activities. Numerous in vitro and in vivo studies have shown that because phenolic acids have antioxidant capacity, they can reflect their strong anticancer potential by regulating cell growth and metastasis and promoting cancer cell death. Studies have shown that the consumption of natural polyphenols can significantly reduce the risk of cancer metastasis. A combination of phenolic acids with traditional chemoradiation or other polyphenols may be effective in reducing cancer spread.Ferulic acid is ubiquitous, and widely found in plants, such as angelica, chuanxiong, cohote, three, edge, reed root, tomato, sweet corn, and rice are produced by the metabolism of phenylalanine and tyrosine. It is the most abundant hydroxyl cassia bark-acid acid in the plant kingdom, with anti-inflammatory, antidiabetic, anticancer and antioxidant activity, and polyphenols composed of hydroxyl cassia bark-acid derivatives, flavone-3-alcohol and flavonol retain non-cancer-cells-and-significantly-inhibit glioblastoma viability in a dose-dependent manner, which deserves further investigation as potential anticancer drugs. This paper summarizes the role of ferulic acid in the PI3K / AKT pathway and its mechanism in glioblastoma resistance.

4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling.

BACKGROUND: Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI. METHODS: We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state. RESULTS: We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1ß and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro. CONCLUSION: These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI.

DsbA-L alleviates tubular injury in diabetic nephropathy by activating mitophagy through maintenance of MAM integrity.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate ATG14- and Beclin1-mediated mitophagy and play key roles in the development of diabetic nephropathy (DN). DsbA-L is mainly located in MAMs and plays a role in renoprotection, but whether it activates mitophagy by maintaining MAM integrity remains unclear. In the present study, we found that renal tubular damage was further aggravated in diabetic DsbA-L-/- mice compared with diabetic mice and that this damage was accompanied by disrupted MAM integrity and decreased mitophagy. Furthermore, notably decreased expression of ATG14 and Beclin1 in MAMs extracted from the kidneys of diabetic DsbA-L-/- mice was observed. In vitro, overexpression of DsbA-L reversed the disruption of MAM integrity and enhanced mitophagy in HK-2 cells, a human proximal tubular cell line, after exposure to high-glucose (HG) conditions. Additionally, compared with control mice, DsbA-L-/- mice were exhibited down-regulated expression of helicase with zinc finger 2 (HELZ2) in their kidneys according to transcriptome analysis; HELZ2 serves as a cotranscription factor that synergistically functions with PPARα to promote the expression of mitofusin 2 (MFN-2). Treatment of HK-2 cells with MFN-2 siRNA resulted in MAM uncoupling and decreased mitophagy. Moreover, HG notably reduced the expression of HELZ2 and MFN-2 and inhibited mitophagy, and these effects were partially blocked by overexpression of DsbA-L and altered upon cotreatment with HELZ2 siRNA, HELZ2 overexpression or MK886 (PPARα inhibitor) treatment. These data indicate that DsbA-L alleviates diabetic tubular damage by activating mitophagy through maintenance of MAM integrity via the HELZ2/MFN-2 pathway.

PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease.

BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2-/- mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2-/- mice. RESULTS: Diabetic PT-Pacs-2-/- mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2-/- mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.

Effects of HIF-1α on renal fibrosis in cisplatin-induced chronic kidney disease.

Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.

Aristolochic acid induces renal fibrosis by arresting proximal tubular cells in G2/M phase mediated by HIF-1α.

Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.

PACS-2: A key regulator of mitochondria-associated membranes (MAMs).

Mitochondria-associated membranes (MAMs) are the organellar contact sites between mitochondria and the endoplasmic reticulum (ER), and recent studies demonstrated that MAMs, which serve as multiple scaffolds of proteins, are involved in Ca2+ signaling, lipid metabolism, mitochondrial morphology and functions, and autophagy. Importantly, several pathological conditions, such as obesity, diabetes mellitus and neurodegenerative diseases, indicate the significant role of MAMs in cellular homeostasis. Phosphofurin acidic cluster sorting protein 2(PACS-2), a multifunctional sorting protein at MAMs, plays a critical role in mitochondria, ER and lysosome homeostasis. In this review, we summarize the current understanding of the role of PACS-2 as a key regulator of MAMs and present the structure and other functions of PACS-2. Moreover, we describe the relationship between PACS-2 and diseases to reveal its potential as a novel therapeutic target that can be applied for the treatment of diseases.

Quercetin prevents bone loss in hindlimb suspension mice via stanniocalcin 1-mediated inhibition of osteoclastogenesis.

Recent studies demonstrate that diet quercetin (Quer) has obvious bone protective effects on ovariectomized rodents but thus far there is no direct evidence to support the inhibitory effect of Quer on bone loss caused by long-term unloading. In the present study, we investigated whether Quer could prevent bone loss induced by unloading in mice. Mice were subjected to hindlimb suspension (HLS) and received Quer (25, 50, 100 mg· kg-1 ·day-1, ig) for 4 weeks. Before euthanasia blood sample was collected; the femurs were harvested and subjected to MicroCT analysis. We showed that Quer administration markedly improved bone microstructure evidenced by dose-dependently reversing the reduction in bone volume per tissue volume, trabecular number, and bone mineral density, and the increase of trabecular spacing in mice with HLS. Analysis of serum markers and bone histometric parameters confirmed that Quer at both middle and high doses significantly decreased bone resorption-related markers collagen type I and tartrate-resistant acid phosphatase 5b, and increased bone formation-related marker procollagen 1 N-terminal propeptide as compared with HLS group. Treatment with Quer (1, 2, 5 µM) dose-dependently inhibited RANKL-induced osteoclastogenesis through promoting the expression of antioxidant hormone stanniocalcin 1 (STC1) and decreasing ROS generation; knockdown of STC1 blocked the inhibitory effect of Quer on ROS generation. Knockdown of STC1 also significantly promoted osteoclastogenesis in primary osteoclasts. In conclusion, Quer protects bones and prevents unloading-caused bone loss in mice through STC1-mediated inhibition of osteoclastogenesis. The findings suggest that Quer has the potential to prevent and treat off-load bone loss as an alternative supplement.

Health information and health-seeking behaviour in Yemen: perspectives of health leaders, midwives and mothers in two rural areas of Yemen.

BACKGROUND: Humanitarian crises can lead to the rapid change in the health needs of women and newborns, which may give rise to a complex situation that would require various interventions as solutions. This study aimed to examine the health education and promotion patterns, health-seeking behaviour of mothers, and barriers to the use of maternal health services from public health facilities in two rural areas of Yemen. METHODS: We used a qualitative approach. We conducted in-depth interviews and focus group discussions with frontline health professionals and mothers respectively. Nine in-depth interviews were conducted with the health professionals, including 4 health leaders and 5 midwives, and 2 focus group discussions with mothers aged 18-45 years in Abyan and Lahj. Thematic analysis approach was used to analyze the data in Atlas.ti (version 8) Software. RESULTS: Our data showed that health education and promotion activities on maternal health were ad hoc and coverage was poor. Maternal health services were underutilized by women. According to the data from the focus group discussions, the poor quality of services, as indicated by inadequate numbers of female doctors, lack of medical equipment and medicines, and costs of services were barriers to use maternal health services. Moreover, the use of prenatal and postnatal care services was associated with women's' perceived need. However, according to the health professionals, the inadequate human resource, workload, and inadequate funding from government have contributed significantly to the perceived quality of maternal health services provided by public health facilities. Despite the identified barriers, we found that a safe motherhood voucher scheme was instituted in Lahj which facilitated the use of maternal health services by disadvantaged women by removing financial barriers associated with the use of maternal health services. CONCLUSION: This study identified several obstacles, which worked independently or jointly to minimize the delivery and use of health services by rural women. These included, inadequate funding, inadequate human resources, poor quality of health services, and high cost of services. These barriers need to be addressed to improve the use of reproductive health services in Yemen.

Efficient brain uptake of piperine and its pharmacokinetics characterization after oral administration.

1. Piperine, the major biological active component in black pepper has been associated with miscellaneous pharmacological effects, especially on central nervous system. To correlate with its neurological activity, a comprehensive pharmacokinetic profile of piperine in brain, plasma and cerebrospinal fluid after oral administration in rats was investigated in this study. 2. It was noted that piperine could efficiently penetrate and homogeneously distribute into brain with similar pharmacokinetics profiles in each region. In addition, piperine concentrations in brain and plasma were found to be comparable with brain to plasma area under curve extrapolated to infinity (AUC0→∞) ratios of 0.95 and 1.10 for total concentration and unbound concentrations, respectively. Piperine also demonstrated high affinity toward brain tissue (98.4-98.5%) and plasma protein (96.2-97.8%) leading to a brain distribution volume of 36.32 ± 1.40 ml/g brain. Moreover, its efficient membrane permeability (P app values of 5.41 ± 0.40 × 10- 5 cm/s and 4.78 ± 0.16 × 10- 5 cm/s for basolateral to apical and apical to basolateral transport in Caco-2 monolayer model) and limited hepatic metabolism (Clint of 8.15 µl/min/mg) could also contribute to its quick and high extent brain exposure. 3. In summary, this study for the first time demonstrated high brain penetration potency of piperine could be resulted from its high brain tissue affinity and membrane permeability together with its limited liver metabolism.

Brain Uptake of Bioactive Flavones in Scutellariae Radix and Its Relationship to Anxiolytic Effect in Mice.

Scutellariae Radix (SR) and its bioactive flavones elicit a variety of effects in the brain. However, the brain uptake of individual SR flavones and its relationship to the elicited effects after SR administration remain unknown. Moreover, previous studies seldom measured pharmacokinetic and pharmacodynamic outcomes simultaneously. In the current study, the brain uptake of six major SR flavones and the anxiolytic behavior following oral administration of a SR extract at two clinically relevant doses (600 and 1200 mg/kg twice daily) were simultaneously investigated in mice (n = 18 per group). Brain and plasma concentrations of the flavones were measured by LC-MS/MS, while the anxiolytic effect was evaluated using the elevated plus maze. To further investigate the mechanism behind the differential brain uptake of the six SR flavones, these flavones were separately administered to mice at an equivalent molar oral dose (n = 6). The brain tissue bindings of the SR flavones were also measured with the in vitro brain slice method. Our results indicated that all six SR flavones including three aglycons (baicalein, wogonin, and oroxylin A) and three glucuronides (baicalin, wogonoside, and oroxyloside) could pass through the blood-brain barrier, with brain concentrations ranging from 7.9 to 224.0 pmol/g. It provided novel evidence that oroxylin A had the highest brain uptake among the six SR flavones regardless of its limited content in SR extract, in which 3.6-3.9% of the administered oroxylin A dose was present in the brain 6 h postdosing and with a brain-to-plasma ratio of 0.42-0.46. Although SR extract contains flavones that are positive modulators of the benzodiazepine binding site of GABAA receptors (baicalein, wogonin, and baicalin), our behavioral study for the first time indicated that SR extract (a mixture of six flavones) did not elicit significant anxiolytic effect at the studied doses. Oroxylin A also demonstrated the highest brain uptake when the six flavones were separately administered to mice, and the highest affinity to brain tissues in the in vitro tissue binding assay. The high brain uptake of oroxylin A, a GABAA antagonist which had been reported to antagonize diazepam-induced anxiolytic effect, might have suppressed the anxiolytic effects of the other flavones and account for the lack of overall anxiolytic effect of SR extract. The current study illustrates the importance of monitoring pharmacokinetics in a behavioral study, particularly for herbal medicines which consist of multiple components that might have different or even opposite pharmacological effects on the same target.

Osteoprotective Effect of Radix Scutellariae in Female Hindlimb-Suspended Sprague-Dawley Rats and the Osteogenic Differentiation Effect of Its Major Constituent.

A number of medicinal herbs have demonstrated therapeutic effects for the prevention and treatment of disuse-induced osteoporosis. As a common ingredient in proprietary traditional Chinese medicines, the anti-osteoporosis effects of Radix Scutellariae extract (RSE, 50 mg/kg/day) were evaluated in a hindlimb suspended rat model. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and the micro-architecture observed by MicroCT assay with bone biomechanical properties evaluated by a three-point bending test. To elucidate potential mechanisms, the osteogenic differentiation effect of baicalin as the most abundant ingredient in RSE was investigated in rat bone marrow derived mesenchymal stem cells (rBMSC). After drug administration for 42 days, tibia-BMD was significantly increased to 0.176 ± 0.007 and 0.183 ± 0.011 g/cm² and f-BMD was enhanced to 0.200 ± 0.017 and 0.207 ± 0.021 g/cm² for RSE and ALE treatment, respectively, whereas tibia-BMD and femur-BMD of the HLS group were 0.157 ± 0.009 and 0.176 ± 0.008 g/cm². Deterioration of bone trabecula microstructure was improved by RSE and ALE with increased morphological parameters such as bone volume fraction, trabecular thickness, and trabecular number, as well as connectivity density compared to the HLS group (p < 0.01). A three-point bending test suggested that bone mechanical strength was also enhanced by RSE and ALE treatments with increased maximum stress, young's modulus, maximum load, and stiffness compared to those of the HLS group (p < 0.05). Besides, serum TRACP levels were significantly suppressed by RSE and ALE treatments. Furthermore, in vitro studies demonstrated that baicalin significantly increased ALP activities and the formation of mineralized nodules in rBMSC. Conclusively, supplementation of RSE could significantly prevent weightlessness induced osteoporosis, which might attribute to the osteogenic differentiation enhancement effect of baicalin.

[Value of quantitative iodine-based material decomposition images with gemstone spectral CT imaging in the follow-up of patients with hepatocellular carcinoma after TACE treatment].

OBJECTIVE: To investigate the value of quantitative iodine-based material decomposition images with gemstone spectral CT imaging in the follow-up of patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoebolization (TACE). METHODS: Consecutive 32 HCC patients with previous TACE treatment were included in this study. For the follow-up, arterial phase (AP) and venous phase (VP) dual-phase CT scans were performed with a single-source dual-energy CT scanner (Discovery CT 750HD, GE Healthcare). Iodine concentrations were derived from iodine-based material-decomposition images in the liver parenchyma, tumors and coagulation necrosis (CN) areas. The iodine concentration difference (ICD) between the arterial-phase (AP) and venal-phase (VP) were quantitatively evaluated in different tissues.The lesion-to-normal parenchyma iodine concentration ratio (LNR) was calculated. ROC analysis was performed for the qualitative evaluation, and the area under ROC (Az) was calculated to represent the diagnostic ability of ICD and LNR. RESULTS: In all the 32 HCC patients, the region of interesting (ROI) for iodine concentrations included liver parenchyma (n=42), tumors (n=28) and coagulation necrosis (n=24). During the AP the iodine concentration of CNs (median value 0.088 µg/mm(3)) appeared significantly higher than that of the tumors (0.064 µg/mm(3), P=0.022) and liver parenchyma (0.048 µg/mm(3), P=0.005). But it showed no significant difference between liver parenchyma and tumors (P=0.454). During the VP the iodine concentration in hepatic parenchyma (median value 0.181 µg/mm(3)) was significantly higher than that in CNs (0.140 µg/mm(3), P=0.042). There was no significant difference between liver parenchyma and tumors, CNs and tumors (both P>0.05). The median value of ICD in CNs was 0.006 µg/mm(3), significantly lower than that of the HCC (0.201 µg/mm(3), P<0.001) and hepatic parenchyma (0.117 µg/mm(3), P<0.001). The ICDs in tumors and hepatic parenchyma showed no significant difference (P=0.829). During the AP, the LNR had no significant difference between CNs and tumors (a median value 1.805 vs. 1.310, P=0.389), and during the VP, the difference was also non-significant (the median value 0.647 vs. 0.713, P=0.660). The mean Az value of ICDs for evaluation of surviving tumor tissues was 0.804, whiles LNR measured a disappointing result in both AV images and VP images. CONCLUSION: Quantitative iodine-based material decomposition images with gemstone spectral CT imaging can improve the diagnostic efficacy of CT imaging for HCC patients after TACE treatment.

Treatment of Radix Dipsaci extract prevents long bone loss induced by modeled microgravity in hindlimb unloading rats.

CONTEXT: Radix Dipsaci is a kidney tonifying herbal medicine with a long history of safe use for treatment of bone fractures and joint diseases in China. Previous studies have shown that Radix Dipsaci extract (RDE) could prevent bone loss in ovariectomized rats. OBJECTIVE: This study investigates the effect of RDE against bone loss induced by simulated microgravity. MATERIALS AND METHODS: A hindlimb unloading rat model was established to determine the effect of RDE on bone mineral density and bone microarchitecture. Twenty-four male Sprague-Dawley rats were divided into four groups (n = 6 per group): control (CON), hindlimb unloading with vehicle (HLU), hindlimb unloading treated with alendronate (HLU-ALN, 2.0 mg/kg/d), and hindlimb unloading treated with RDE (HLU-RDE, 500 mg/kg/d). RDE or ALN was administrated orally for 4 weeks. RESULTS: Treatment with RDE had a positive effect on mechanical strength, BMD, BMC, bone turnover markers, and the changes in urinary calcium and phosphorus excretion. MicroCT analysis showed that RDE significantly prevented the reduction of the bone volume fraction, connectivity density, trabecular number, thickness, tissue mineral density, and tissue mineral content as well as improved the trabecular separation and structure model index. DISCUSSION AND CONCLUSION: RDE was demonstrated to prevent the loss of bone mass induced by HLU treatment, which suggests the potential application of RDE in the treatment of microgravity-induced bone loss.

Synthesis, spectroscopic properties, and biological applications of eight novel chlorinated fluorescent proteins-labeling probes.

Eight novel chlorinated fluorescent proteins-labeling probes with a linker and reactive group were prepared in 7 steps by the reaction of chlorinated resorcinols with 3, 6-dichloro-4-carboxyphthalic anhydride in the presence of methanesulfonic acid. Structures of target compounds and intermediates were determined via IR, MS, (1)H NMR and element analysis. The spectral properties of the chlorinated fluoresceins were studied. These fluorescent probes showed absorbance peaks at 508-536 nm and fluorescence peaks at 524-550 nm. It was found that they have absorption and emission maxima at long wavelengths and high fluorescence quantum yields. Emission spectra of chlorinated fluoresceins shifted towards long wavelength with increase in chlorine. The probes were used for fluorescence imaging of cells in order to investigate whether they can conjugate to cells. The fluorescence imaging of living cells showed that they were localized in cell nucleus. However, they were localized in cytosol of chemically fixed cells. These probes will be useful reagents for the preparation of stable fluorescent conjugates.

1-(1,3-Benzodioxol-5-yl-carbo-nyl) piperidine, a modulator of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, ameliorates exercise-induced fatigue in mice.

The current study was designed to investigate the effects of 1-(1,3-benzodioxol-5-yl-carbonyl) piperidine (1-BCP) on swimming endurance capacity which as one indicator of fatigue in the weight-loaded forced swimming mice. Mice were given either vehicle or 1-BCP (0.1, or 0.2 mmol/kg body weight daily) by intraperitoneal injection once daily for 2 weeks. The 1-BCP groups showed a significant increase in swimming time to exhaustion compared with the control group. 1-BCP increased the liver glycogen (LG) and muscle glycogen (MG) contents significantly, while decreased the lactic acid (LA) and blood urea nitrogen (BUN) levels notably compared with control group. Besides, 1-BCP treatment also significantly improved the endogenous cellular antioxidant enzymes in mice by increasing the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Therefore, this study demonstrated for the first time that the supplementation of 1-BCP, as a positive allosteric modulator of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, could enhance the endurance capacity of mice and facilitated them recovery from fatigue. Thus, we provide a new effective therapeutic strategy for fatigue.

Synthesis, crystal structure and anti-fatigue effects of some benzamide derivatives.

A series of benzamide derivatives such as 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine (1-BCP) were synthesized by the reaction of substituted benzoic acids with piperidine, morpholine or pyrrolidine using a novel method. The crystals of these benzamide derivatives were obtained by recrystallization. Structures of target and intermediate compounds were determined via FT-IR, 1H-NMR and elemental analysis and X-ray crystallography of select examples. The crystal structures of these compounds have potential applications to identify the binding site for allosteric modulators of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. The anti-fatigue effects of the benzamide derivatives in weight-loaded forced swimming mice were investigated in a swimming endurance capacity test used as an indicator of fatigue. The swimming times to exhaustion were longer in the b3, d3, and e3 groups than in the caffeine group (p<0.05). In conclusion, b3, d3 and e3 enhanced the forced swimming capacity of mice. The mechanism of the anti-fatigue effects will be studied in the future.

[Synthesis and antifatigue activities of new benzamide derivatives].

To explore novel antifatigue agents targeting with AMPA receptor, 10 compounds were synthesized and their structures were confirmed by 1H NMR, ESI-MS and elemental analysis. 1-BCP was treated as the leading compound. The antifatigue activities were evaluated by weight-loaded forced swimming test, and the AMPA receptor binding affinities were tested with radioligand receptor binding assays. The results unveiled that 5b appeared to possess potent antifatigue activities and high affinity with AMPA receptor, which deserved further studies.