A taste alteration-related scale assesses megestrol to improve chemotherapy-induced anorexia.

PURPOSE: We evaluated the efficacy of megestrol in improving chemotherapy-related anorexia by analyzing the related scales of taste alteration. METHODS: We conducted the current study on a group of advanced patients with cancer with two or more chemotherapy cycles. The chemotherapy-induced taste alteration scale (CiTAs) scale helped assess the megestrol effects on basic taste perception, aversive taste changes, unpleasant symptoms, and associated concerns. Furthermore, the Short Nutritional Assessment Questionnaire scale (SNAQ) helped measure the impact of megestrol on malnutrition likelihood in patients experiencing chemotherapy-induced anorexia. The World Health Organization Quality of Life (WHOQOL)-BREF Scale was used to evaluate the quality of life of participants, producing scores related to physical health, psychological well-being, environmental factors, and social relationships. RESULTS: The CiTAs scale assessment indicated that administering megestrol significantly enhanced taste perception among advanced patients with cancer undergoing chemotherapy. Notably, the megestrol group patients showed significantly higher Short Nutritional Assessment Questionnaire (SNAQ) scores than the control group. The megestrol group patients also exhibited higher physiological (PHYS) scores than their control group counterparts. However, this distinction was not statistically significant. The study findings indicate that patients who received megestrol demonstrated significantly higher scores in psychological (PSYCH) and environmental(ENVIR) domains than the control group. Furthermore, megestrol administration was associated with significantly elevated SOCIL and ENVIR levels in patients. CONCLUSION: The proficient efficacy evaluation of megestrol in enhancing appetite, mitigating malnutrition likelihood, and improving the quality of life of chemotherapy-induced anorexic patients can be achieved through taste-related scales.

Summary of drug therapy to treat cognitive impairment-induced obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a severe sleep disorder associated with intermittent hypoxia and sleep fragmentation. Cognitive impairment is a signifi- cant and common OSA complication often described in such patients. The most commonly utilized methods in clinical OSA treatment are oral appliances and continuous positive airway pressure (CPAP). However, the current therapeutic methods for improving cognitive function could not achieve the expected efficacy in same patients. Therefore, further understanding the molecular mechanism behind cognitive dysfunction in OSA disease will provide new treatment methods and targets. This review briefly summarized the clinical manifestations of cognitive impairment in OSA disease. Moreover, the pathophysiological molecular mechanism of OSA was outlined. Our study concluded that both SF and IH could induce cognitive impairment by multiple signaling pathways, such as oxidative stress activation, inflammation, and apoptosis. However, there is a lack of effective drug therapy for cognitive impairment in OSA. Finally, the therapeutic potential of some novel compounds and herbal medicine was evaluated on attenuating cognitive impairment based on certain preclinical studies.

Case report: Application of morphology in the diagnosis of siderosis in a patient with tuberculosis infection.

A 49-year-old male who had been working in welding for more than 30 years was admitted to the hospital for a medical checkup that revealed a lung shadow without specific symptoms such as coughing and sputum. Imaging studies showed diffuse ground-glass changes in both lungs, wall cavities with wall nodules, multiple peripheral nodules, and some nodules with calcification. The patient has been engaged in welding work for more than 30 years and exposed to iron dust. Lung tissue biopsy, routine morphological and pathological fluid basis examination of alveolar lavage fluid, can be considered as pulmonary iron particles, which can be regarded as iron dust lung. Acid-fast bacilli were detected in both fibrobronchoscopic brush extract and alveolar lavage fluid acid-fast staining. As the pathological examination revealed granulomatous inflammation showed caseation necrosis, the patient was judged to have concomitant pulmonary TB. After the diagnosis was made, the patient was no longer exposed to dust and was treated with appropriate anti- tuberculosis (TB) therapy. Lung lesions caused by welding have been reported, but the simultaneous finding of siderosis with pulmonary TB is specific to the case presented here. By describing the imaging features, combining different staining methods of alveolar lavage fluid and pathological examination of lung tissue, we showed various morphological manifestations of this case, aiming at improving the morphological diagnosis level of laboratory physicians and enabling patients to be diagnosed and treated early.

Tanshinone IIA inhibits cardiomyocyte apoptosis and rescues cardiac function during doxorubicin-induced cardiotoxicity by activating the DAXX/MEK/ERK1/2 pathway.

BACKGROUND: Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood. PURPOSE: We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF. METHODS: In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day. RESULT: The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3. CONCLUSION: Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.

Metformin Reduces Blood Glucose in Treatment-Naive Type 2 Diabetes by Altering the Gut Microbiome.

BACKGROUND: Our aim in this study was to better understand the causality of metformin and gut microbiome in the treatment of type 2 diabetes (T2D). METHODS: This study was conducted on individuals with newly diagnosed and treatment-naive T2D. We used 16S rRNA sequencing to assess the effect of metformin on composition and diversity of the gut microbiota. We also compared the differences in relative abundance of gut microbiome at the genus level in patients with treatment-naive T2D before and after 2 months of metformin treatment. Spearman's rank correlation coefficient analysis was used to identify genus abundance in relation to blood glucose and related factors. RESULTS: Metformin significantly reduced blood glucose and levels of the related factors in treatment-naive individuals with T2D after 2 months of treatment. The 16S rRNA sequencing showed that metformin treatment altered composition and diversity of gut microbiome. Megamonas and Klebsiella in the T2D groups were significantly higher compared with the control group. Metformin treatment caused a significant reduction in Megamonas and Klebsiella. Spearman's rank correlation coefficient analysis showed a significant positive correlation between Megamonas and blood glucose, glycated hemoglobin (A1C), serum fructosamine and alanine aminotranferase (ALT). Klebsiella showed a significant positive correlation between A1C and ALT. CONCLUSION: Metformin reduces blood glucose in T2D by interacting with different gut bacteria, possibly Megamonas and Klebsiella pneumoniae.

Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis.

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

Response to PD-1-Based Immunotherapy for Non-Small Cell Lung Cancer Altered by Gut Microbiota.

INTRODUCTION: This study was designed to identify a group of bacteria in the human gut microbiota with specific effects on PD-1-based immunotherapy for patients with non-small cell lung cancer (NSCLC). METHODS: The study was performed in patients with advanced NSCLC, who received PD-1 monoclonal antibody (mAb) treatment for 6 months after one or several prior therapies. The combination of blood immune-related factors of the participants and their 16S rRNA gene sequencing from fecal samples at baseline was used to investigate the diversity and composition of the gut microbiota. The differences in relative abundance of gut microbiota at the genus level were compared, and the relation to blood immune-related factors was assessed using Spearman's rank correlation coefficient analysis. RESULTS: The 16S rRNA gene sequencing showed a clear difference in the diversity and composition of the gut microbiota between groups with stable disease (SD) and progressive disease (PD). A comparison of differences in relative abundance at the genus level showed that the relative abundance of Escherichia-Shigella, Akkermansia and Olsenella in the SD group was significantly higher than that in the PD group. The SD group had significantly higher interleukin-12 (IL-12) and interferon γ (IFN-γ) levels than the PD group. Interestingly, the numbers of white blood cells and sorted cells in the SD group were higher than those in the PD group. Spearman's rank correlation coefficient analysis showed that Escherichia-Shigella was positively correlated with IL-12, IFN-γ and basophils. Akkermansia was positively correlated with monocytes. CONCLUSION: The response to PD-1-based immunotherapy in patients with NSCLC is affected by the diversity and composition of the gut microbiota. Escherichia-Shigella and Akkermansia may have specific effects on PD-1 inhibitory immunotherapy for NSCLC.

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation.

Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, has a favorable safety profile in patients with B cell-related malignancies. A primary adverse effect of ibrutinib is thrombocytopenia in the early stages of treatment, but platelet counts increase or recover as treatment continues. Currently, the effects of ibrutinib on megakaryopoiesis remain unclear. In this study, we investigated the mechanism by which ibrutinib induces thrombocytopenia using cord blood CD34+ hematopoietic stem cells (HSCs), a human megakaryoblastic cell line (SET-2), and C57BL/6 mice. We show that treatment with ibrutinib can suppress CD34+ HSC differentiation into megakaryocytes (MKs) and decrease the number of colony-forming unit-MKs (CFU-MKs). The ibrutinib-dependent inhibition of early megakaryopoiesis seems to mainly involve impaired proliferation of progenitor cells without induction of apoptosis. The effects of ibrutinib on late-stage megakaryopoiesis, in contrast to early-stage megakaryopoiesis, include enhanced MK differentiation, ploidy, and proplatelet formation in CD34+ HSC-derived MKs and SET-2 cells. We also demonstrated that MK adhesion and spreading, but not migration, were inhibited by ibrutinib. Furthermore, we revealed that integrin αIIbß3 outside-in signaling in MKs was inhibited by ibrutinib. Consistent with previous clinical observations, in C57BL/6 mice treated with ibrutinib, platelet counts decreased by days 2 to 7 and recovered to normal levels by day 15. Together, these results reveal the pathogenesis of ibrutinib-induced transient thrombocytopenia. In conclusion, ibrutinib suppresses early megakaryopoiesis, as evidenced by inhibition of MK progenitor cell proliferation and CFU-MK formation. Ibrutinib enhances MK differentiation, ploidy, and proplatelet formation, while it impairs integrin αIIbß3 outside-in signaling.

Transcription factor Isl1 is dispensable for the development of the mouse prosensory region.

In order to identify genes involved in the development of inner ear hair cells, we investigated the role of the transcription factor Islet-class LIM-homeodomain (LIM-HD) 1 (Isl1) in the development of the mouse prosensory region. Isl1 was deleted using the Pax2-Cre system, and deletion of both alleles was verified using cochlea sections. Changes in the number of prosensory region cells were measured to determine the effect of Isl1 on the development of the mouse prosensory region. In order to test whether Isl1 formed a protein complex with Ldb1 and Gata3, co-immunoprecipitation experiments were performed in HEK293 cells using the Flag-tagged LIM-domain of Isl1, HA-tagged LID of Ldb1 and Myc-tagged C-terminal domain of Gata3. The expression of Gata3, Sox2, Jag1 and P27 proteins in the prosensory region were not affected in Isl1-/- prosensory cells. Thus, Isl1 did not form a protein complex with Gata3 through Ldb1 in the Isl1-/- cells. Our results suggest that Isl1 may be dispensable for the development of the mouse prosensory region.

Rapid quantification of tenofovir in umbilical cord plasma and amniotic fluid in hepatitis B mono-infected pregnant women during labor by ultra-performance liquid chromatography/tandem mass spectrometry.

RATIONALE: Tenofovir (TFV) is a first-line antiviral agent against hepatitis B virus (HBV) and is recommended for the prevention of mother-to-infant transmission of HBV. To study the distribution of TFV in umbilical cord plasma and amniotic fluid of HBV-infected pregnant women, a rapid and sensitive method for TFV determination was developed and validated. METHODS: The quantification method was developed using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The analytes were separated on an Acquity UPLC HSS T3 column under gradient elution with methanol and 0.01% ammonia solution in 10 mM ammonium acetate/water. This is the first reported method for the determination of TFV using alkaline rather than acidic mobile phases. Linearity, accuracy, precision, limit of quantification, specificity and stability were assessed. RESULTS: Detection of TFV was achieved within 4 min. The calibration curves for TFV quantification showed excellent linearity in the range of 1-500 ng/mL. The intra- and interbatch precision and accuracy ranged from -4.35% to 6.92%. This method was successfully applied to determination of samples from 50 HBV mono-infected women undergoing tenofovir disoproxil fumarate therapy. The mean concentrations of TFV in the umbilical cord and amniotic fluid samples were 29.2 (4.6-86) and 470.9 (156-902) ng/mL, respectively, which showed a moderate positive correlation (r = 0.5299, P<0.001). CONCLUSIONS: A simple, rapid but sensitive bioanalytical method to determine TFV concentration in both umbilical cord plasma and amniotic fluid using LC/MS/MS was developed and applied to HBV-infected women during labor who were undergoing TDF therapy, which will help us understand the efficacy and safety of tenofovir during pregnancy.

Expression of Lhx6 in the adult and developing mouse retina.

PURPOSE: To investigate the expression patterns of LIM Homeobox 6 (Lhx6) in the adult and developing mouse retina. METHODS: The Lhx6-GFP knock-in allele was used to activate constitutive expression of a GFP reporter in Lhx6 expressing cells. Double labeling with GFP and retinal markers in the mouse retina at postnatal day 56 (P56) was performed to identify the cell types expressing Lhx6. To determine the neuronal cell types that express Lhx6, double labeling with GFP and various retinal markers was employed in the differentiating retina at P7 and P15. RESULTS: GFP + Lhx6 lineage cells were determined in Brn3a + retinal ganglion cells (RGCs), ChAT + amacrine cells (ACs), and Islet-class LIM-homeodomain 1 (Isl1+) ACs in the mouse retina at P56. In the ganglion cell layer (GCL), Lhx6 was expressed in Brn3a + RGCs but not Brn3b + RGCs at P15. Moreover, in the inner nuclear layer (INL), Lhx6 was not expressed in Bhlhb5+ ACs at P15. However, Lhx6 was weakly expressed in Glyt1+ ACs and Pax6+ ACs, and strongly expressed in Isl1+ and ChAT + ACs at P15. CONCLUSION: Lhx6 was expressed in RGCs and ACs in both the adult and developing mouse retina.

Associations of DNMT3B -149C>T and -2437T>A polymorphisms and lung cancer risk in Chinese population.

BACKGROUND: DNMT3B polymorphisms are associated with the susceptibility of lung cancer. DNMT3B -2437T>A is a novel polymorphism, and its influence on the risk of lung cancer in Chinese was investigated in this study. In addition, effect of DNMT3B -149C>T polymorphism on lung cancer was also explored. METHODS: Genotyping in subjects were performed by PCR-RFLP. Haplotype frequencies were estimated by estimating haplotype software. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by unconditional logistic regression analysis. RESULTS: Neither of the two polymorphisms was correlated with lung cancer (-149C>T: CT+TT vs CC: OR = 0.78, 95%CI, 0.57 to 1.05, P = 0.361; -2437T>A: AT+AA vs TT: OR = 0.99, 95%CI, 0.74 to 1.33, P = 0.168). In stratification analysis, T-allele carrier genotype of -149C>T polymorphism resulted in a reduced lung cancer risk at stage II, compared with CC (OR = 0.46, 95%CI, 0.28 to 0.77, P = 0.023). In haplotype analysis, when -149C/-2437T was used as reference, the other combined genotypes of the two polymorphisms had no significant effect on lung cancer risk (P > 0.05). CONCLUSIONS: The two DNMT3B polymorphisms are not correlated with lung cancer risk among Chinese population nor the haplotype of them.

Pou4f2-GFP knock-in mouse line: A model for studying retinal ganglion cell development.

Pou4f2 acts as a key node in the comprehensive and step-wise gene regulatory network (GRN) and regulates the development of retinal ganglion cells (RGCs). Accordingly, deletion of Pou4f2 results in RGC axon defects and apoptosis. To investigate the GRN involved in RGC regeneration, we generated a mouse line with a POU4F2-green fluorescent protein (GFP) fusion protein expressed in RGCs. Co-localization of POU4F2 and GFP in the retina and brain of Pou4f2-GFP/+ heterozygote mice was confirmed using immunofluorescence analysis. Compared with those in wild-type mice, the expression patterns of POU4F2 and POU4F1 and the co-expression patterns of ISL1 and POU4F2 were unaffected in Pou4f2-GFP/GFP homozygote mice. Moreover, the quantification of RGCs showed no significant difference between Pou4f2-GFP/GFP homozygote and wild-type mice. These results demonstrated that the development of RGCs in Pou4f2-GFP/GFP homozygote mice was the same as in wild-type mice. Thus, the present Pou4f2-GFP knock-in mouse line is a useful tool for further studies on the differentiation and regeneration of RGCs.

Endoplasmic reticulum stress-mediated hippocampal neuron apoptosis involved in diabetic cognitive impairment.

Poor management of DM causes cognitive impairment while the mechanism is still unconfirmed. The aim of the present study was to investigate the activation of C/EBP Homology Protein (CHOP), the prominent mediator of the endoplasmic reticulum (ER) stress-induced apoptosis under hyperglycemia. We employed streptozotocin- (STZ-) induced diabetic rats to explore the ability of learning and memory by the Morris water maze test. The ultrastructure of hippocampus in diabetic rats and cultured neurons in high glucose medium were observed by transmission electron microscopy and scanning electron microscopy. TUNEL staining was also performed to assess apoptotic cells while the expression of CHOP was assayed by immunohistochemistry and Western blot assay in these hippocampal neurons. Six weeks after diabetes induction, the escape latency increased and the average frequency in finding the platform decreased in diabetic rats (P < 0.05). The morphology of neuron and synaptic structure was impaired; the number of TUNEL-positive cells and the expression of CHOP in hippocampus of diabetic rats and high glucose medium cultured neurons were markedly altered (P < 0.05). The present results suggested that the CHOP-dependent endoplasmic reticulum (ER) stress-mediated apoptosis may be involved in hyperglycemia-induced hippocampal synapses and neurons impairment and promote the diabetic cognitive impairment.

Antineuroinflammatory and neurotrophic effects of CNTF and C16 peptide in an acute experimental autoimmune encephalomyelitis rat model.

Experimentalallergic encephalomyelitis (EAE) is an animal model for inflammatory demyelinating autoimmune disease, i.e., multiple sclerosis (MS). In the present study, we investigated the antineuroinflammatory/neuroprotective effects of C16, an ανß3 integrin-binding peptide, and recombinant rat ciliary neurotrophic factor (CNTF), a cytokine that was originally identified as a survival factor for neurons, in an acute rodent EAE model. In this model, C16 peptide was injected intravenously every day for 2 weeks, and CNTF was delivered into the cerebral ventricles with Alzet miniosmotic pumps. Disease severity was assessed weekly using a scale ranging from 0 to 5. Multiple histological and molecular biological assays were employed to assess inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and gliosis in the brain and spinal cord of different groups. Our results showed that the EAE induced rats revealed a significant increase in inflammatory cells infiltration, while C16 treatment could inhibit the infiltration of leukocytes and macrophages down to 2/3-1/3 of vehicle treated EAE control (P < 0.05). The delayed onset of disease, reduced clinical score (P < 0.01) in peak stage and more rapid recovery also were achieved in C16 treated group. Besides impairing inflammation, CNTF treatment also exerted direct neuroprotective effects, decreasing demyelination and axon loss score (P < 0.05 versus vehicle treated EAE control), and reducing the neuronal death from 40 to 50% to 10 to 20% (P < 0.05). Both treatments suppressed the expression of cytokine tumor necrosis factor-α and interferon-γ when compared with the vehicle control (P < 0.05). Combined treatment with C16 and CNTF produced more obvious functional recovery and neuroprotective effects than individually treatment (P < 0.05). These results suggested that combination treatment with C16 and CNTF, which target different neuroprotection pathways, may be an effective therapeutic alternative to traditional therapy.

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia.

Diabetes mellitus is known to cause kidney impairment; however, the mechanism remains elusive. The aim of this study was to investigate the role of C/EBP homologous protein (CHOP), an important protein in endoplasmic reticulum stress­mediated mesangial cell apoptosis in hyperglycemia. Mesangial cells were cultured in normal (control group) and high glucose medium (high glucose group). TUNEL staining was performed to assess apoptotic cells in the groups. The expression of CHOP and caspase­3 was also assayed by immunohistochemistry and western blot analysis. Following 24 h culture in high glucose medium, TUNEL­positive cells were observed to be significantly increased (P<0.01). The expression of CHOP and caspase­3 in mesangial cells was also found to be significantly enhanced under high glucose conditions compared with the normal group (P<0.01). The results indicate that CHOP mediates apoptosis in mesangial cells under hyperglycemia and may play a role in the development of diabetic nephropathy.

Protective effect of tanshinone IIA on rat kidneys during hypothermic preservation.

Renal preservation is a universal problem since ischemia/reperfusion (I/R) injury remains an unresolved issue during the procedure of renal transplantation. Tanshinone IIA, one of the effective components of the traditional Chinese medicine Danshen, was reported to exhibit a variety of biochemical activities, including protection against I/R injury. Therefore, identifying the specific molecular pathway mediating tanshinone IIA protection of renal preservation would be of great value to the patients concerned. In this study, rats were divided into two groups and the kidneys were isolated and preserved in two solutions separately, one with Celsior solution and the other with tanshinone IIA additionally added to the Celsior solution. The superoxide dismutase (SOD) activity and the quantity of malonaldehyde (MDA) were measured, the expression of CHOP and caspase-12 were assessed by immunohistochemistry staining, and real-time quantitative reverse transcription-polymerase chain reaction analysis was performed after 0, 24 and 48 h of preservation. A significant increase in the activities of SOD and a decrease in the quantity of MDA were observed in the kidneys preserved with tanshinone IIA at 24 and 48 h (P<0.01). The expression of CHOP and caspase-12 was lower in the kidneys preserved with tanshinone IIA at 24 and 48 h than that in the kidneys preserved with Celsior solution alone (P<0.05). The results suggest that the supplementation of tanshinone IIA in standard Celsior solution may significantly improve long-term kidney preservation. Attenuating oxidative stress injury and decreasing endoplasmic reticulum (ER) stress­mediated apoptosis may play a role in the protection of kidney hypothermic preservation.

Effects of gestational isoflurane exposure on postnatal memory and learning in rats.

A maternal fetal rat model was developed to study the effects of gestational isoflurane exposure on postnatal memory and learning and investigate the potential mechanisms. Pregnant rats at gestational day 14 were exposed to 1.3% isoflurane for 4h. Spatial learning and memory of the offspring were examined using the Morris Water Maze. The expression levels of C/EBP homologous transcription factor protein (CHOP) and caspase-12 in the hippocampus of the pups were determined by immunohistochemistry and western blot analysis. Simultaneously, the ultrastructure changes of synapse in the hippocampal CA1 and dentate gyrus region were also observed by transmission electron microscopy (TEM). Prenatal exposure to isoflurane impaired postnatal spatial memory and learning in the offspring rats as shown by the longer escape latency and the fewer times of original platform crossing in the Morris Water Maze test. The number of CHOP and caspase-12 positive neurons significantly increased by 138% and 147% respectively in the hippocampus of isoflurane-exposed pups, as well as the levels of CHOP and caspase-12 protein. Furthermore, TEM studies showed changes of synaptic ultrastructure in isoflurane-exposed hippocampus characterized by the decreased synapse number, the widened synaptic cleft and the thinned postsynaptic densities. These results demonstrate that gestational exposure to a clinically relevant concentration of isoflurane could cause neuron apoptosis, changes of synaptic structure, and postnatal spatial memory and learning impairments in offspring. Our study further showed that the up-regulation of CHOP and caspase-12 may contribute to isoflurane-induced neuron apoptosis.