Inhibition of the STAT3-EPHX2 axis promotes regression of ulcerative colitis by treatment with novel porphyrin derivative.

LD4, a novel porphyrin derivative, has attracted much attention for its excellent anti-inflammatory properties. It can promote the healing of colonic mucosa, reduce inflammatory response, regulate oxidative stress, and thus improve ulcerative colitis (UC) symptoms. However, the specific signaling pathways of LD4-PDT involved in UC have not been explored. The present study aimed to elucidate the effects of LD4 on UC and to investigate the underlying mechanisms both in vivo and in vitro. We classified and screened the LD4-PDT proteomic data to obtain key targets. Proteomic data revealed that EPHX2 and STAT3 are key targets of LD4-PDT for UC. Moreover, transcription factor STAT3 positively regulates the expression of EPHX2. Inhibiting EPHX2 can prevent the activation of NF-κB signaling pathway. Next, through pharmacological inhibition experiments, we confirmed that LD4-PDT can reduce intestinal inflammation by inhibiting STAT3-EPHX2 axis. However, by treating normal intestinal epithelial cells and colon cancer cells with TPPU and Stattic, our data confirmed that the STAT3-EPHX2 axis does not exist in colon cancer. In this study, we demonstrated that the transcription factor STAT3 can positively regulate the expression of EPHX2 in normal colon. LD4 can alleviate UC by inhibiting the STAT3-EPHX2 axis, but this axis does not exist in colon cancer. LD4-PDT may become a new and effective method for treating UC.

[Regulation of intracellular level of ATP and NADH in Escherichia coli to promote succinic acid production].

Succinic acid is an important C4 platform chemical that is widely used in food, chemical, medicine sectors. The bottleneck of fermentative production of succinic acid by engineered Escherichia coli is the imbalance of intracellular cofactors, which often leads to accumulation of by-products, lower yield and low productivity. Stoichiometric analysis indicated that an efficient production of succinic acid by E. coli FMME-N-26 under micro-aeration conditions might be achieved when the TCA cycle provides enough ATP and NADH for the r-TCA pathway. In order to promote succinic acid production, a serial of metabolic engineering strategies include reducing ATP consumption, strengthening ATP synthesis, blocking NADH competitive pathway and constructing NADH complementary pathway were developed. As result, an engineered E. coli FW-17 capable of producing 139.52 g/L succinic acid and 1.40 g/L acetic acid in 5 L fermenter, which were 17.81% higher and 67.59% lower than that of the control strain, was developed. Further scale-up experiments were carried out in a 1 000 L fermenter, and the titer of succinic acid and acetic acid were 140.2 g/L and 1.38 g/L, respectively.

Perioperative safety assessment of patients undergoing unilateral or bilateral hip replacements.

Introduction: Due to the aging of the world population and the increase of obesity rate, it is expected that the number of joint replacement surgery will continue to increase in the next few years. This study evaluated the safety differences between unilateral and bilateral hip replacement surgeries. Methods: The data for patients who underwent hip arthroplasty in 2021 and 2022 were examined. The data set included 68 patients who were grouped according to the type of hip replacement needed, sex, age, and body mass index. Total blood loss and operative time were the safety-related indicators used to compare the groups. Results: Regardless of whether the unilateral replacement group was compared with the overall bilateral replacement group or separately with the staged and simultaneous bilateral replacement groups, simultaneous bilateral replacement surgeries were equally safe as the other types of hip replacements. The total blood loss and operative time for the simultaneous bilateral replacement group were not significantly different from those in the unilateral and staged bilateral replacement groups. For overweight patients, the operative time for simultaneous bilateral replacements was significantly shorter than that for unilateral replacements. Conclusions: These findings suggest that for patients requiring bilateral hip replacements, the blood loss risk for patients undergoing simultaneous bilateral hip replacements was similar to that for patients undergoing either unilateral or staged bilateral hip replacements. Thus, simultaneous bilateral total hip replacement (THR) are safe and should be considered for candidate patients.

Effects of 3-Methyladenine on Microglia Autophagy and Neuronal Apoptosis After Radiation-Induced Brain Injury.

Objective: To determine the effect of the autophagy inhibitor, 3-methyladenine (3-MA), on cognitive function changes, microglia activity, neuronal apoptosis, and inflammation in rats following radiation-induced brain injury. Methods: The following groups were established: control, model, and 3-MA. A rat model of radiation-induced brain injury was generated with a medium dose of X-rays. A Morris water maze was used to observe the cognitive function of the rats. H&E staining was used to observe the pathological changes in the hippocampus. The morphological and quantitative changes of neuronal nuclear (NeuN)-positive neurons and Iba-1-positive microglia in the ipsilateral hippocampus were analyzed by immunohistochemistry. Western blot analysis was done to measure the changes of NeuN ionized calcium binding adapter molecule 1(Iba-1) and apoptosis-related proteins. Immunofluorescence staining of Iba-1 and Microtuble-associated protein light chain 3 (LC3) was done to evaluate the changes in microglia autophagy. TUNEL staining was used to detect apoptosis in the hippocampus. Enzyme-Linked Immunosorbent Assay was used to detect the levels of TNF-α and IL-6 as a measure of the inflammatory response in the hippocampus. Results: After irradiation, the nucleus of the neurons in the hippocampus was constricted, the pyramidal tract structure was disordered, neuronal apoptosis was increased (P < .001), the expression of microglia increased (P < .01), autophagy was increased (P < .05), and conversion of microglia to the M2 type increased (P < .05). After 3-MA administration, the level of autophagy decreased (P < .05), the damage to the hippocampal region was reduced, neuronal apoptosis decreased (P < .01), and the activity of the microglia decreased (P < .01). Conclusion: Radiation can active the Microglia. 3-MA inhibits autophagy and excessive activity in microglia, and promotes the conversion of microglia from the M1 to the M2 type, thereby promoting the recovery of brain tissue following radiation exposure.

Activating transcription factor 3 (ATF3) regulates cell growth, apoptosis, invasion and collagen synthesis in keloid fibroblast through transforming growth factor beta (TGF-beta)/SMAD signaling pathway.

The successful treatment of keloids is a great challenge in the plastic surgery field. Activating transcription factor 3 (ATF3) is discovered as an adaptive responsive gene, which plays a critical role in fibroblast activation. This study aimed to investigate the expression and biological role of ATF3 in the pathogenesis of keloids. ATF3 expression in normal skins and keloids was evaluated by real-time PCR, western blot and immunohistochemistry. Effects of ATF3 on cell growth, apoptosis, invasion and collagen production were evaluated in keloid fibroblast cells overexpressing or downregulating ATF3. ATF3 expression was significantly elevated in keloid tissues when compared with that of normal skins and parakeloidal skin tissues. Moreover, ATF3 promoted cell proliferation and collagen production in keloid fibroblast cells. Conversely, transfection with siRNA targeting ATF3 led to decreased cell viability and collagen synthesis via inhibiting transforming growth factor-ß1 (TGF-ß1) and fibroblast growth factor 2/8 (FGF2/8) production in keloid fibroblasts. ATF3 could reduce the apoptosis rate of keloid fibroblast cells. Molecularly, we found that ATF3 promoted BCL2 level and inhibit the expression of BCL2 associated agonist of cell death (Bad), Caspase3 and Caspase9 in keloid fibroblast cells. ATF3 also enhanced the invasive potential via upregulating the expression of Matrix Metalloproteinases (MMP) family members (MMP1, MMP2, MMP9 and MMP13). ATF3 could induce activation of TGF-ß/Smad signaling pathway in fibroblasts. Collectively, ATF3 could promote growth and invasion, and inhibit apoptosis via TGF-ß/Smad pathway in keloid fibroblast cells, suggesting that ATF3 might be considered as a novel therapeutic target for the management of keloid.

Overexpression of miR-133a-3p inhibits fibrosis and proliferation of keloid fibroblasts by regulating IRF5 to inhibit the TGF-ß/Smad2 pathway.

AIM: Keloid is a benign dermal tumor with excessive hyperplasia and deposition of collagen. As a common tumor suppressor gene, miR-133a-3p has not been studied in keloid. This study will delve into the specific mechanism of miR-133a-3p in keloid. METHODS: Normal skin fibroblasts and keloid fibroblasts (KFs) were first isolated from patients' normal skin and keloid, and cells were identified by morphological observation and immunofluorescence. The expressions of miR-133a-3p and extracellular matrix (ECM)-associated markers (Collagen I, III and α smooth muscle activin) were detected by Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Cell viability and apoptosis of KFs were examined by Cell Counting Kit-8 assay, flow cytometry, and Caspase-3 colorimetry. TargetScan predicted target gene for miR-133a-3p was verified by luciferase assay, qRT-PCR and Western Blot (WB). WB was used to study protein expression of TGFBR1, phosphorylated -Smad2 (p-Smad2) and Smad2. Finally, a series of rescue experiments were performed to verify the intervention of target genes on miR-133a-3p. RESULTS: MiR-133a-3p was lowly expressed in keloid tissue and KFs. Overexpression of miR-133a-3p inhibited the expression of ECM-associated markers, reduced KFs viability, and promoted apoptosis. It was verified that interference regulator 5 (IRF5) is miR-133a-3p target gene. The rescue experiments showed that IRF5 reversed the effect of miR-133a-3p mimic on inhibiting fibrosis, and reversed the effects on promoting apoptosis and reducing cell proliferation. CONCLUSION: Overexpressed miR-133a-3p inhibits fibrosis by down-regulating IRF5 and thus inhibiting the TGF-ß/Smad2 pathway. And it also promotes KFs apoptosis and reduces proliferation.

miR-27b promotes angiogenesis and skin repair in scalded rats through regulating VEGF-C expression.

In this study, the effects of miR-27b on angiogenesis in skin repair procedure in rats with deep II degree scald were explored. The rat model of deep II scald was established. miR-27b mimics and inhibitor were injected daily at the wound site for 3 weeks. The healing of scald was observed at 0, 3, 7, 14, and 21 days after the model was established, and the pathological changes of skin were observed by HE and Masson's trichrome stains. Skin tissues were taken 14 days after the operation; CD31 and Ki-67 immunohistochemistry was exerted to evaluate neovascularization and proliferation. Human microvascular endothelial cells (HMEC-1) cells were cultured in vitro. miR-27b mimics or inhibitor was transfected to construct over-expression or inhibition cell lines. MTT assay, scratch test, and angiogenesis test were used to evaluate cell proliferation, migration, and vascular regeneration. Finally, RT-PCR and Western blot were exerted to determine the expression of vascular endothelial growth factor C (VEGF-C), epidermal growth factor (EGF) mRNAs, and protein, respectively. Control, inhibitor, mi-NC, VEGF-C, inhibitor + si-NC, and inhibitor + VEGF-C siRNA groups were used to further analyze the mechanism of miR-27b on VEGF-C; the above experiments were repeated. In contrast to model group, miR-27b inhibitor could significantly promote the healing of scalded skin, alleviate the pathological status of scalded, and promote the angiogenesis and proliferation (p < 0.05). In vitro, miR-27b inhibitor evidently promoted cell proliferation, migration, and angiogenesis and increased the expression of VEGF-C, EGF genes, and protein, while miR-27b mimics significantly reversed the above trends. Further studies shown that downregulation of miR-27b expression can promote the proliferation, migration, and angiogenesis of HMEC-1 cells by promoting the expression of VEGF-C. miR-27b promotes angiogenesis and skin repair in scalded rats through regulating VEGF-C expression.

Down-regulation of mir-27b promotes angiogenesis and fibroblast activation through activating PI3K/AKT signaling pathway.

To study the effects of mir-27b on angiogenesis and fibroblast activation and to explore its further mechanism. Humanmicrovascular endothelial cell (HMEC)-1 and humannormal skin fibroblast (BJ) cells were treated with mir-27b inhibitor negative control reagent, mir-27b inhibitor, LY294002, and mir-27b inhibitor + LY294002, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to detect the T-cell proliferation. The migration ability was detected by Scratch assays. The angiogenesis of HMEC-1 cells was observed by in vitro tube formation assay. The mRNA and protein expression of vascular endothelial growth factor (VEGF) in HMEC-1 cells and the mRNA and protein expression of collagen I, collagen III, α-SMA, and MMP1 in BJ cells were detected by quantitativereal-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. Meanwhile, the PI3K/protein kinase B (AKT) pathway-related proteins were also detected by Western blot. The proliferation, migration, angiogenesis, the mRNA and protein expression of VEGF and the protein expression of p-PI3K and p-AKT in HMEC-1 cells were increased after treated with mir-27b inhibitor. Meanwhile, the proliferation, migration, and the protein expression of collagen I, collagen III, α-SMA, MMP1, p-PI3K, and p-AKT in BJ cells were increased after treated with mir-27b inhibitor. However, the angiogenesis and fibroblast activation of mir-27b inhibitor was reversed by LY294002, and the activate effect to PI3K/AKT pathway was also inhibited. Down-regulation of mir-27b could promote angiogenesis and fibroblast activation, and its mechanism is related to activate PI3K/AKT signaling pathway.

MicroRNA-138 Suppresses Adipogenic Differentiation in Human Adipose Tissue-Derived Mesenchymal Stem Cells by Targeting Lipoprotein Lipase.

PURPOSE: Adipogenic differentiation of adipose tissue-derived mesenchymal stem cells (AMSCs) is critical to many disease-related disorders, such as obesity and diabetes. Studies have demonstrated that miRNA-138 (miR-138) is closely involved in adipogenesis. However, the mechanisms affected by miR-138 remain unclear. This work aimed to investigate interactions between miR-138 and lipoprotein lipase (LPL), a key lipogenic enzyme, in AMSCs. MATERIALS AND METHODS: Human AMSCs (hAMSCs) isolated from human abdomen tissue were subjected to adipogenic differentiation medium. Quantitative real-time polymerase chain reaction and Western blot assay were applied to measure the expressions of miR-138, LPL, and the two adipogenic transcription factors cytidine-cytidine-adenosine-adenosine-thymidine enhancer binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). The relationship between miR-138 and LPL was predicted utilizing the miRTarBase database and validated by dual luciferase reporter assay. RESULTS: Showing increases in C/EBPα and PPARγ expression levels, hAMSCs were induced into adipogenic differentiation. During adipogenesis of hAMSCs, miR-138 expression was significantly downregulated. Overexpression of miR-138 by transfection inhibited hAMSCs adipogenic differentiation in vitro. Mechanically, LPL was a target of miR-138. LPL expression was upregulated during adipogenesis of hAMSCs, and this upregulation was reversed by miR-138 overexpression. Functionally, silencing of LPL by transfection exerted similar inhibition of the expressions of C/EBPα and PPARγ. Meanwhile, LPL ectopic expression was able to partly abolish the suppressive effect of miR-138 overexpression on adipogenic differentiation of hAMSCs. CONCLUSION: Upregulation of miR-138 inhibits adipogenic differentiation of hAMSCs by directly downregulating LPL.

Penoscrotal Strangulation Caused by a Steel Ring: A Case Report.

INTRODUCTION: Strangulation of the penis and scrotum by a constricting object has been rarely reported. AIM: To describe a man with penoscrotal strangulation caused by a steel ring and its successful removal. METHODS: A 28-year-old man presented to the emergency department with a 7-hour history of a steel ring lodged at the base of his penis and scrotum. Removal was accomplished with the assistance of fire brigade personnel who used their hydraulic cable cutter to shear the ring. During the removal, there were no complications. RESULTS: The hydraulic cable cutter avoided thermal injury and shortened removal time compared with procedures described in the literature. The patient's recovery was uneventful, with erectile function restored after 1 week. CONCLUSION: Genital incarceration is an urgent clinical situation requiring prompt treatment. However, suitable tools for removing the foreign object are not readily available in emergency and urology departments. Cooperation with other disciplines, even non-medical disciplines, can result in creative and timely measures for removal of the object. Zhang J, Wang X, Zhang J, et al. Penoscrotal Strangulation Caused by a Steel Ring: A Case Report. Sex Med 2017;5:e131-e133.

Effect of mesenchymal stem cell transplantation on brain-derived neurotrophic factor expression in rats with Tourette syndrome.

The aim of the present study was to investigate the effect of bone marrow mesenchymal stem cell (MSC) transplantation on brain-derived neurotrophic factor (BDNF) expression in the striatum of Tourette syndrome (TS) rats. In addition, the possible mechanism of MSC transplantation in the treatment of TS was investigated. A total of 72 Wistar rats were randomly allocated into the control (sham surgery) group and the two experimental groups, including the TS+vehicle and TS+MSC. MSCs were co-cultured with 5-bromodeoxyuridine for 24 h for labeling prior to grafting. An autoimmune TS rat model was successfully established in the present study. Rat MSCs were cultured and expanded using density gradient centrifugation in vitro, identified by flow cytometry and then transplanted into the striata of the TS+MSC group rats. The mRNA and protein expression levels of BDNF were detected by RT-qPCR and ELISA, respectively. The results indicated that the stereotypic behavior of TS rats was reduced 7 days after MSC transplantation, while the mRNA and protein BDNF levels in the striatum increased, compared with the sham surgery group (P<0.05). In addition, the BDNF mRNA and protein expression level was lower in the striatum of TS+MSC transplantation, compared with that in TS+vehicle rats. In conclusion, intrastriatal transplantation of MSCs may provide relief from stereotypic TS behavior, since the BDNF level was reduced in TS rats after MSC transplantation.

Aloe vera and Vitis vinifera improve wound healing in an in vivo rat burn wound model.

Aloe vera and Vitis vinifera have been traditionally used as wound healing agents. The present study aimed to investigate the effects of aloe emodin and resveratrol in the burn wound healing procedure. Burn wounds are common in developed and developing countries, however, in developing countries, the incidence of severe complications is higher and financial resources are limited. The results of the present study demonstrated that neither aloe emodin or resveratrol were cytotoxic to THP-1 macrophages at concentrations of 1, 100 and 500 ng/ml. A significant increase in wound-healing activity was observed in mice treated with the aloe emodin and resveratrol, compared with those which received control treatments. The levels of IL-1ß in the exudates of the burn wound area of the treated mice increased in a time-dependent manner over 7 days following burn wound injury. At 10 days post-injury, steady and progressive wound healing was observed in the control animals. The present study confirmed that increased wound healing occurs following treatment with aloe emodin,, compared with resveratrol, providing support for the use of Aloe vera plants to improve burn wound healing.

A New Infracture Technique for Reduction Malarplasty with an L-Shaped Osteotomy Line.

BACKGROUND: Reduction malarplasty is one of the most common surgical procedures performed in the Asian population for aesthetic purposes. Although multiple methods have been developed for reduction malarplasty, including a variety of infracture techniques, most of the current procedures have limitations. In the current study we created a new infracture method to circumvent these shortcomings. MATERIAL AND METHODS: Between January 2004 and October 2013, we applied this novel infracture technique in 700 patients. The highest area of the zygomatic body was marked pre-operatively and ground intra-operatively through an intraoral incision. An L-shaped incomplete osteotomy of the zygomatic body was performed with a reciprocating saw, and then a complete perpendicular osteotomy (1 cm anterior to the articular tubercle of the zygomatic arch) was made through a pre-auricular incision. Light pressure on the posterior part of the arch produced a greenstick fracture of the anterior osteotomy site, resulting in posterior-inward repositioning of the malar complex. Internal fixation was not required. RESULTS: Satisfactory aesthetic results and good post-operative stability were achieved. Three months post-operatively, the bone around the zygomatic arc osteotomy line was remodeled. The bone posterior to the articular tubercle of the zygomatic arch was partially absorbed, leading to a depression of the root of the arc and a natural transition on both sides of the osteotomy line, making the midface more slender. Instead, the anterior bone presented with new bones, making the malar complex more stable. CONCLUSIONS: This new method has multiple advantages, including simple manipulation, no need for internal fixation, short operative and recovery times, and few complications. X-ray images showing the bony changes demonstrated that the infracture technique is an effective and ideal method for reduction malarplasty.

EGCG regulates the cross-talk between JWA and topoisomerase IIα in non-small-cell lung cancer (NSCLC) cells.

(-)-epigallocatechin-3-gallate (EGCG) is a well-known cancer chemopreventive agent. The potential mechanisms include regulation of multiple molecules. Carcinogenesis in lung cancer is related to the imbalance of tumor suppressor and oncogene. JWA is a structurally novel microtubule-binding protein and is a potential tumor suppressor. DNA topoisomerase IIα is a nuclear enzyme that governs DNA topology and is usually highly expressed in many types of cancer. It serves as a target of anticancer drugs. In the current study, the regulation of JWA and topoisomerase IIα by EGCG, and thereafter the mutual interaction between them was investigated. The results revealed that EGCG up-regulated JWA while decreased topoisomerase IIα expression in both human non-small cell lung cancer (NSCLC) cells and an NSCLC xenograft mice model. There was a negative correlation between JWA and topoisomerase IIα in NSCLC as well as in human NSCLC tissue specimens. Topoisomerase IIα overexpression reduced JWA at the translational level. Meanwhile, JWA-induced topoisomerase IIα degradation was regulated both in the transcriptional and post-translational level. Interestingly, JWA and topoisomerase IIα regulated each other in the cells arrested in G2/M. Furthermore, JWA and topoisomerase IIα synergistically affected NCI-H460 cells invasion. These results may serve a novel mechanism for cancer prevention.

Efficacy of prevascularization for segmental bone defect repair using ß-tricalcium phosphate scaffold in rhesus monkey.

Although small animal model (rabbit) showed successful bone defect repair using prevascularized tissue-engineered bone grafts (TEBG), large animal (rhesus monkey) studies are still needed to extrapolate the findings from animal data to humans. In current study, we investigated the efficacy of prevascularized TEBG for segmental bone defect repair in rhesus monkey. The segmental diaphyseal defects were created in both tibias. In group A, the defect was filled with prevascularized MSCs/scaffold prepared by inserting saphenous vascular bundle into the side groove and a fascia flap coverage; In group B, the defect was filled with MSCs/scaffold with a fascia flap coverage; In group C, the defect was filled with MSCs/scaffold; In group D, the defect was filled with only scaffold. The angiogenesis and new bone formation were compared among groups at 4, 8, and 12 weeks postoperatively. The results showed the prevascularized TEBG in group A could augment new bone formation and capillary vessel in-growth. It had significantly higher values of vascularization and radiographic grading score compared with other groups. In conclusion, the in vivo experiment data of prevascularized TEBG was further enriched from small to large animal model. It implies that prevascularized TEBG has great potentials in clinical applications.

Influence of mesenchymal stem cell transplantation on stereotypic behavior and dopamine levels in rats with Tourette syndrome.

CONTEXT: Tourette syndrome (TS) is a heterogeneous neuropsychiatric disorder. Chronic motor and phonic tics are central symptoms in TS patients. For some patients, tics are intractable to any traditional treatment and cause lifelong impairment and life-threatening symptoms. New therapies should be developed to address symptoms and overt manifestations of TS. Transplantation of neurogenic stem cells might be a viable approach in TS treatment. OBJECTIVE: We used mesenchymal stem cell (MSC) transplantation to treat TS. We discuss the mechanism of action, as well as the efficiency of this approach, in treating TS. SETTINGS AND DESIGN: An autoimmune TS animal model was adopted in the present study. Forty-eight Wistar rats were randomly allocated to the control group and the 2 experimental groups, namely, TS rats+vehicle and TS rats+MSC. MSCs were co-cultured with 5-bromodeoxyuridine (BrdU) for 24 h for labeling prior to grafting. METHODS: Stereotypic behaviors were recorded at 1, 7, 14, and 28 days after transplantation. Dopamine (DA) content in the striatum of rats in the 3 groups was measured using a high-performance liquid chromatography column equipped with an electrochemical detector (HPLC-ECD) on day 28 after transplantation. STATISTICAL ANALYSIS: Statistical analysis was performed by repeated measurements analysis of variance to evaluate stereotypic behavior counts at different time points. RESULTS: TS rats exhibited higher stereotypic behavioral counts compared with the control group. One week after transplantation, TS rats with MSC grafts exhibited significantly decreased stereotypic behavior. Rats with MSC grafts also showed reduced levels of DA in the striatum when compared with TS rats, which were exposed only to the vehicle. CONCLUSIONS: Intrastriatal transplantation of MSCs can provide relief from the stereotypic behavior of TS. Our results indicate that this approach may have potential for developing therapies against TS. The mechanism(s) of the observed effect may be related to the suppression of DA system by decreasing the content of DA in TS rats.

Interaction of manganese(II) complex with apotransferrin and the apotransferrin enhanced anticancer activities.

Apotransferrin could bind a number of metal ions besides Fe, which makes it an attractive delivery vehicle for metal-based medicines. In order to evaluate whether anticancer Mn(II) complex of [(Adpa)Mn(Cl)(H(2)O)] Adpa=bis(2-pyridylmethyl)amino-2-propionic acid) (AdpaMn) could be transported by apotransferrin, we investigated its interaction with human apotransferrin by fluorescence and circular dichroism spectroscopy (CD). The association dynamics show that AdpaMn could bind to apotransferrin spontaneously in Hepes buffer. Synchronous fluorescence spectroscopy and CD spectroscopy show that the conjugation of AdpaMn and apotransferrin by hydrophobic interactions induces the change of the microenvironment and conformation of apotransferrin. The reversible binding and release of AdpaMn was studied with fluorescence titration method. The AdpaMn complex can be released from the AdpaMn-apotransferrin entity in weak acid environments. MTT assay in vitro confirms that apotransferrin can enhance the inhibition rate of AdpaMn on the proliferation of HepG-2 cells, so we deduce that AdpaMn could be transported by apotransferrin in vivo.

ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation.

Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4(-/-) mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre;ErbB4(-/-) hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4(-/-) mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia.