Increase in Autoantibodies-Abzymes with Peroxidase and Oxidoreductase Activities in Experimental Autoimmune Encephalomyelitis Mice during the Development of EAE Pathology

The exact mechanisms of multiple sclerosis (MS) development are still unknown, but the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice is associated with the violation of bone marrow hematopoietic stem cells (HSCs) differentiation profiles associated with the production of harmful for human’s autoantibodies hydrolyzing myelin basic protein, myelin oligodendrocyte glycoprotein (MOG_35–55), and DNA. It was shown that IgGs from the sera of healthy humans and autoimmune patients oxidize many different compounds due to their H₂O₂-dependent peroxidase and oxidoreductase activity in the absence of H₂O₂. Here we first analyzed the change in the relative redox activities of IgGs antibodies from the blood of C57BL/6 mice over time at different stages of the EAE development. It was shown that the peroxidase activity of mice IgGs in the oxidation of ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) is on average 6.9-fold higher than the oxidoreductase activity. The peroxidase activity of IgGs increased during the spontaneous development of EAE during 40 days, 1.4-fold. After EAE development acceleration due to mice immunization with MOG_35–55 (5.3-fold), complexes of bovine DNA with methylated bovine serum albumin (DNA-metBSA; 3.5-fold), or with histones (2.6-fold), the activity was increased much faster. The increase in peroxidase activity after mice immunization with MOG_35–55 and DNA-metBSA up to 40 days of experiments was relatively gradual, while for DNA-histones complex was observed its sharp increase at the acute phase of EAE (14–20 days). All data show that IgGs’ redox activities can play an important role in the protection of mice from toxic compounds and oxidative stress.     

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Liposomal honokiol, a potent anti-angiogenesis agent, in combination with radiotherapy produces a synergistic antitumor efficacy without increasing toxicity

Honokiol is an active compound purified from magnolia that has been shown to induce cell differentiation, apoptosis, and anti-angiogenesis effects, as well as an enhancement in tumor growth delay in combination with chemotherapeutic agents in several mouse xenograft models. Our goal was to investigate the radiosensitization effect of honokiol on lung carcinoma. The radiosensitization effect of liposomal honokiol in Lewis lung carcinoma cells (LL/2) was analyzed using an in vitro clonogenic survival assay. For an in vivo study, Lewis lung carcinoma-bearing C57BL/6 mice were treated with either liposomal honokiol at 25 mg/kg or 5 Gy of single tumor radiation, or a combination of both over 12 days of treatment. The tumor growth delay and the survival time were evaluated. In addition, histological analysis of tumor sections was performed to examine changes by detecting the microvessel density and apoptosis in tumor tissues. In the clonogenic survival assay, LL/2 cells treated with IC₅₀ Lipo-HNK for 24 h showed a radiation enhancement ratio of 1.9. After 12 days of combination treatment, the tumor volume decreased 78% and produced an anti-tumor activity 1.3-fold greater than a predicted additive effect of honokiol and radiation alone. This combination treatment also caused an 8.7 day delay in tumor growth. The cell cycle distribution and histological analysis demonstrated that liposomal honokiol has an anti-tumor effect via inducing apoptosis and inhibiting angiogenesis. Liposomal honokiol can enhance tumor cell radiosensitivity in vitro and in vivo, indicating that radiotherapy combined with liposomal honokiol can lead to greater anti-tumor efficacy.     

空间记忆相关蛋白的蛋白质组学研究

C57BL/6J小鼠在评价空间记忆的多T迷宫(MTM)和Barnes迷宫(BM)中表现不同,本研究拟寻找导致这种行为差异的海马蛋白.应用双向凝胶电泳结合质谱鉴定和数据库检索,分析比较经两种迷宫训练测试后小鼠海马蛋白水平的不同,发现经过BM和MTM训练的小鼠有29种蛋白表达存在明显差异.其中,在BM训练组中5种蛋白表达上调,而在MTM组中24种蛋白表达上调.与空间记忆相关的蛋白按功能可分为如下6类:(1)能量代谢相关蛋白;(2)细胞骨架相关蛋白;(3)分子伴侣;(4)神经发育相关蛋白;(5)转录因子和蛋白合成相关蛋白;(6)信号转导蛋白.本研究结果丰富了空间记忆的机制,对于神经科学的进一步发展具有启发意义.     

Chemical synthesis and immunological evaluation of entirely carbohydrate conjugate Globo H-PS A1

An anticancer, entirely carbohydrate conjugate, Globo H-polysaccharide A1 (Globo H-PS A1), was chemically prepared and immunologically evaluated in C57BL/6 mice. Tumor associated carbohydrate antigen Globo H hexasaccharide was synthesized in an overall 7.8% yield employing a convergent [3 + 3] strategy that revealed an anomeric aminooxy group used for conjugation to oxidized PS A1 via an oxime linkage. Globo H-PS A1, formulated with adjuvants monophosphoryl lipid A and TiterMax® Gold. After immunization an antigen specific immune response was observed in ELISA with anti-Globo H IgG/IgM antibodies. Specificity of the corresponding antibodies was determined by FACS showing cell surface binding to Globo H-positive cancer cell lines MCF-7 and OVCAR-5. The anti-Globo H antibodies also exhibited complement-dependent cellular cytotoxicity against MCF-7 and OVCAR-5 cells.

An anticancer, entirely carbohydrate conjugate, Globo H-polysaccharide A1 (Globo H-PS A1), was chemically prepared and immunologically evaluated in C57BL/6 mice.     

Design,Synthesis and Bioactivity Evaluation of Coumarin–BMT Hybrids as New Acetylcholinesterase Inhibitors

Coumarin possesses the aromatic group and showed plentiful activities, such as antioxidant, preventing asthma and antisepsis. In addition, coumarin derivatives usually possess good solubility, low cytotoxicity and excellent cell permeability. In our study, we synthesized the compound bridge methylene tacrine (BMT), which has the classical pharmacophore structure of Tacrine (THA). Based on the principle of active substructure splicing, BMT was used as a lead compound and synthesized coumarin–BMT hybrids by introducing coumarin to BMT. In this work, 21 novel hybrids of BMT and coumarin were synthesized and evaluated for their inhibitory activity on AChE. All obtained compounds present preferable inhibition. Compound 8b was the most active compound, with the value of K_i as 49.2 nM, which was higher than Galantamine (GAL) and lower than THA. The result of molecular docking showed that the highest binding free energy was −40.43 kcal/mol for compound 8b, which was an identical trend with the calculated K_i.     

嗅觉记忆相关蛋白的蛋白质组学研究

应用双向凝胶电泳结合质谱鉴定和数据库检索, 分析比较了C57BL/6J小鼠在嗅觉训练和记忆测试后嗅球蛋白表达的差异, 探讨了与嗅觉记忆相关的蛋白质. C57BL/6J小鼠经嗅觉训练后, 可对相应的气味保持记忆能力, 其嗅球蛋白表达存在明显差异, 5种蛋白与嗅觉记忆形成显著相关. 上述蛋白功能涉及神经发育, 信号转导及细胞骨架和核苷酸代谢, 其中神经发育和信号转导相关蛋白表达上调, 而细胞骨架和核苷酸代谢相关蛋白表达水平降低. 这些与嗅觉记忆形成相关的蛋白深化了对嗅觉记忆机制的认识, 为研究和治疗认知相关疾病提供了新靶标.     

Enhanced Inhibition of Drug-Resistant Escherichia coli by Tetracycline Hydrochloride-Loaded Multipore Mesoporous Silica Nanoparticles

Drug-resistant bacterial infections exhibit a major threat to public health. Thus, exploring a novel antibacterial with efficient inhibition is urgently needed. Herein, this paper describes three types of MSNs (MSNs-FC2-R1, MSNs-FC2-R0.75, MSNs-FC2-R0.5) with controllable pore size (4–6 nm) and particle size (30–90 nm) that were successfully prepared. The MSNs were loaded with tetracycline hydrochloride (TCH) for effective inhibition of Escherichia coli (ATCC25922) and TCH-resistant Escherichia coli (MQ776). Results showed that the loading capacity of TCH in three types of MSNs was as high as over 500 mg/g, and the cumulative release was less than 33% in 60 h. The inhibitory rate of MSNs-FC2-R0.5 loaded with TCH against E. coli and drug-resistant E. coli reached 99.9% and 92.9% at the concentration of MIC, respectively, compared with the other two types of MSNs or free TCH. Modified MSNs in our study showed a great application for long-term bacterial growth inhibition.     

Data enhanced Hammett-equation: reaction barriers in chemical space

It is intriguing how the Hammett equation enables control of chemical reactivity throughout chemical space by separating the effect of substituents from chemical process variables, such as reaction mechanism, solvent, or temperature. We generalize Hammett''s original approach to predict potential energies of activation in non aromatic molecular scaffolds with multiple substituents. We use global regression to optimize Hammett parameters ρ and σ in two experimental datasets (rate constants for benzylbromides reacting with thiols and ammonium salt decomposition), as well as in a synthetic dataset consisting of computational activation energies of ∼2400 S_N2 reactions, with various nucleophiles and leaving groups (–H, –F, –Cl, –Br) and functional groups (–H, –NO₂, –CN, –NH₃, –CH₃). Individual substituents contribute additively to molecular σ with a unique regression term, which quantifies the inductive effect. The position dependence of substituents can be modeled by a distance decaying factor for S_N2. Use of the Hammett equation as a base-line model for Δ-machine learning models of the activation energy in chemical space results in substantially improved learning curves reaching low prediction errors for small training sets.

We generalize Hammett''s original approach to predict potential energies of activation in non aromatic molecular scaffolds with multiple substituents.     

Steroidal Antimetabolites Protect Mice against Trypanosoma brucei

Trypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt Acanthamoeba sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target T. brucei. We found that CHT/ERGT inhibited cell growth in vitro, yielding EC₅₀ values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered T. brucei cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with T. brucei, doubling their survival time following daily treatment for 8–10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development.     

Asparagus racemosus mediated silver chloride nanoparticles induce apoptosis in glioblastoma stem cells in vitro and inhibit Ehrlich ascites carcinoma cells growth in vivo

Glioblastoma multiforme (GBM) is a type of brain tumor that is most aggressive, proliferates rapidly and intensive invasion is governed by cell migration and destruction of the extracellular matrix. In the present study, we evaluated the antiproliferative efficacy of the synthesized silver chloride nanoparticles (AgCl-NPs) from Asparagus racemosus root extract against human glioblastoma stem cells (GSCs) and Ehrlich ascites carcinoma (EAC) cells. Biosynthesis of A. racemosus-AgCl-NPs was confirmed by color change, UV–visible spectroscopy and characterized by transmitted electron microscope, energy dispersive spectroscopy, x-ray powder diffraction and Fourier-transform infrared spectroscopy. The A. racemosus-AgCl-NPs inhibited GSCs and EAC cells growth with the IC₅₀ values of 4.8 and 4.69 µg/ml, respectively. A. racemosus-AgCl-NPs induced apoptosis in GSCs which was confirmed by annexin V/PI assay, various genes expression, and caspase-3 protein expression as detected by the immunofluorometric assay. The expression level of the TLR9, NFκB, TNFα, p21 and IKK genes were increased consequently with the decrease of PARP, EGFR, NOTCH2, mTOR and STAT3 genes in GSCs as examined by real-time PCR. The cell cycle arrest at G₀/G₁ phase was detected by flow cytometry. In addition, A. racemosus-AgCl-NPs caused significant inhibition of EAC cells growth, reduced tumor burden, increased the survival of EAC-bearing mice and restored the hematological parameters when compared with the control mice. The synthesized AgCl-NPs inhibited the proliferation of GSCs in vitro with the induction of apoptosis and inhibited the growth of EAC cells in vivo in mice by reducing the tumor burden and increasing the survival periods.     

Effects of vitamin d treatment on skeletal muscle histology and ultrastructural changes in a rodent model

Vitamin D is well known for its role in maintaining calcium and phosphorus homeostasis and in promoting bone mineralization; however, more of its pleiotropic effects have been described recently. The aim of the present investigation was to study the effect of vitamin D treatment on skeletal muscles changes under different dietary conditions using an animal model. Four groups of C57BL/6J mice (n = 11 each) were maintained on either low fat diet (LFD) or high fat diet ??(HFD) with and without 1α,25-dihydroxyvitamin D3 (calcitriol) for 16 weeks. Animal weigh was recorded at baseline and then regular intervals, and at the end of the study, skeletal muscle tissues were harvested for the evaluation of the histopathological and ultrastructural changes. When control C57BL/6J mice were fed high-fat diet for 12 weeks, body weight gain was significantly increased compared with mice fed a LFD. (30.2% vs. 8.4%, p < 0.01). There was a significant gradual decrease in the weight of HFD fed mice that were treated with vitamin D as compared with a steady increase in the weights of controls (6.8% vs. 28.7%, p < 0.01). While the LFD group showed some ultrastructural changes, HDF fed on mice showed great muscle structural abnormalities. The whole sarcosome along with its membrane and cristae were severely damaged with scattered myocytes in HFD group. Furthermore, the mitochondria appeared weak and were on the verge of degenerations. The bands were diminished with loss of connections among myofibrils. These changes were attenuated in the HFD group treated with vitamin D with tissues have regained their normal structural appearance. The current findings indicate an important effect of vitamin D on skeletal muscle histology under HFD conditions.     

Nanogold-actuated biomimetic peroxidase for sensitized electrochemical immunoassay of carcinoembryonic antigen in human serum

We present a method for the simultaneous determination of guanidinosuccinic acid (GSA) and guanidinoacetic acid (GAA) from urine by protein precipitation and liquid chromatography/tandem mass spectrometry. The chromatographic separation was performed using a cation exchange column with an elution gradient of 0.1 mM and 20 mM ammonium acetate buffers. GSA was detected with the mass spectrometer in negative ion mode monitoring at m/z 174.1, and GAA, creatinine, arginine, and homoarginine were in positive ion mode monitoring at m/z 118.1, 114.1, 175.1, and 189.1, respectively. As an internal standard, l-arginine-¹³C₆ hydrochloride and creatinine-d₃ (methyl-d₃) were used. The calibration ranges were 0.50-25.0 μg mL⁻¹, and good linearities were obtained for all compounds (r > 0.999). The intra- and inter-assay accuracies (expressed as recoveries) and precisions at three concentration levels (1.00, 5.00 and 25.0 μg mL⁻¹) were better than 83.8% and 7.41%, respectively. The analytical performance of the method was evaluated by determination of the compounds in urine from male C57BL/J Iar db/db diabetes mellitus (DM) mice. The values of GSA and GAA corrected by the ratios of the individual compounds to creatinine were significantly increased in DM mice compared with control mice. These results indicated that the newly developed method was useful for determining urinary guanidino compounds and metabolites of arginine.     

Hair Growth Promoting Activity of Cedrol Nanoemulsion in C57BL/6 Mice and Its Bioavailability

As the main component of Platycladus orientalis, cedrol has known germinal activity. A range of cedrol formulations have been developed to prevent hair-loss, but compliance remains key issues. In this study, we prepared cedrol nanoemulsion (CE-NE) and determined the particle size and PDI (polydispersion coefficient), investigated the hair growth activity and studied the bioavailability in vitro and in vivo. Results showed that the average particle size of CE-NE is 14.26 ± 0.16 nm, and the PDI value is 0.086 ± 0.019. In vitro drug release investigation and drug release kinetics analysis showed release profile of CE from nanoparticles demonstrates the preferred partition of CE in buffer pH 4.0, the release profile of CE-NE showed a first-order kinetics reaching around 36.7% after 6 h at 37 °C. We artificially depilated the back hair of C57BL/6 mice and compared the efficacy of a designed cedrol nanoemulsion to an existing ointment group. The hair follicles were imaged and quantified using a digital photomicrograph. The results showed that compared with the ointment, CE-NE had positive effects on hair growth, improved drug solubility. Compared with the ointment and 2% minoxidil groups, 50 mg/mL CE-NE led to more robust hair growth. Pharmacokinetics analysis showed that the AUC_0–t of CE-NE was 4-fold higher than that of the ointment group, confirming that the bioavailability of the nanoemulsion was greater than that of the ointment. CE-NE also significantly reduced the hair growth time of model mice and significantly increased the growth rate of hair follicles. In conclusion, these data suggest that the nanoemulsion significantly improved the pharmacokinetic properties and hair growth effects cedrol, enhancing its efficacy in vitro and in vivo.     

Immune recognition of cytochrome c I. — Molecular requirements for antibody recognition and immune response stimulation studied in vitro with synthetic peptides

The epitope specificity of antibodies to horse cytochrome c (cyt.c) in the primary and secondary immune response of C57BL mice was studied by means of the ELISA technique with synthetic peptides of cyt.c. It was found that, in the early primary response, N- and C-end fragments of cyt.c (peptides 2–13, 14–22 and 92–104) were preferentially recognized. In the secondary response, more antibodies to the epitopes of the central part of the molecule (peptides 61–69 and 46–56) were found. This was presumed to be due to the mode of cyt.c processing and presentation in the course of immune response: at first, cyt.c was recognized in the native form and then in the processed one. The capacity of cyt.c peptides to stimulate the formation of cyt.c-specific antibody-secreting cells (ASC) was studied in splenocyte culture of C57BL mice. Peptides stimulated more ASC than cyt.c did, but larger molar doses of peptides were required. Comparison of the capacity of related peptides (1–13 and 2–13, 61–69, 61–77 and 57–77) to be recognized by antibodies produced to native cyt.cin vivo and to stimulate anti-cyt.c ASC in vitro suggested certain molecular requirements for cyt.c epitope and agretope formation. These were partially confirmed by computer analysis.     

恐惧记忆相关蛋白的蛋白质组学研究

应用双向凝胶电泳结合质谱鉴定和数据库检索, 分析比较了CD1和C57BL/6J小鼠经条件性恐惧实验后海马蛋白表达的差异, 探讨了与恐惧记忆相关的蛋白质. CD1和C57BL/6J小鼠经条件性恐惧实验后, 海马蛋白表达存在明显差异, 29种蛋白(31个蛋白点)与恐惧记忆的形成显著相关. 其中24个蛋白点表达显著上调, 7个蛋白点显著下调. 与恐惧记忆相关的蛋白按功能可分为如下6类: (1) 能量代谢或线粒体功能相关蛋白; (2) 神经发育相关蛋白; (3) 信号转导相关蛋白; (4) 细胞骨架相关蛋白; (5) 氨基酸代谢和蛋白分解相关蛋白; (6) 伴侣蛋白. 这些恐惧记忆形成的相关蛋白深化了对恐惧记忆脑机制的认识, 为研究和治疗认知相关疾病提供了新靶标.     

Neuroprotection of N-benzyl Eicosapentaenamide in Neonatal Mice Following Hypoxic–Ischemic Brain Injury

Maca (Lepidium meyenii) has emerged as a popular functional plant food because of its medicinal properties and nutritional value. Macamides, as the exclusively active ingredients found in maca, are a unique series of non-polar, long-chain fatty acid N-benzylamides with multiple bioactivities such as antifatigue characteristics and improving reproductive health. In this study, a new kind of macamide, N-benzyl eicosapentaenamide (NB-EPA), was identified from maca. We further explore its potential neuroprotective role in hypoxic–ischemic brain injury. Our findings indicated that treatment with biosynthesized NB-EPA significantly alleviates the size of cerebral infarction and improves neurobehavioral disorders after hypoxic–ischemic brain damage in neonatal mice. NB-EPA inhibited the apoptosis of neuronal cells after ischemic challenge. NB-EPA improved neuronal cell survival and proliferation through the activation of phosphorylated AKT signaling. Of note, the protective property of NB-EPA against ischemic neuronal damage was dependent on suppression of the p53–PUMA pathway. Taken together, these findings suggest that NB-EPA may represent a new neuroprotectant for newborns with hypoxic–ischemic encephalopathy.     

Potential antidiabetic molecule involving a new chromium(III) complex of dipicolinic and metformin as a counter ion: Synthesis,structure, spectroscopy,and bioactivity in mice

The chromium(III) complex, Cr(C₇H₃NO₄)₂·C₄H₁₂N₅ (1), was synthesised by chelating chromium with dipicolinic (H₂dipic) in methanol, and its structure was characterised using elemental analysis (EA), spectroscopy (infrared, UV–visible, and fluorescence) and single-crystal X-ray method. The density functional theoretical (DFT) computation was performed using the Gaussian 09 package. The stability of solution at different temperatures and pH values, the electrochemical, morphological and thermal properties of complex 1 were discussed. The preliminary bioactivities of complex 1 in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) mice were investigated using daily oral gavage for 12 weeks. The cytotoxicity was assessed using the methyl thiazolyl tetrazolium (MTT) assays, and the acute toxicity experiment test was carried out on healthy C57BL/6 mice with this complex. The complex 1 crystallised in the monoclinic system with the space group P2(1)/n, R₁ = 0.0642. The DFT-optimised structure of complex 1 was in excellent agreement with the X-ray crystal structure. The complex 1 exhibited good physical and chemical properties and beneficial function on blood glucose and lipid metabolism for T2DM. The antidiabetic activity of chromium(III) might be associated with chromium(VI). Furthermore, the cytotoxicity and the acute toxicity experiments showed that the complex 1 was hypotonic and secure to organism. The study of complex 1 showed that the prepared complex on the basis of H₂dipic and Met could inhibit hyperglycaemia and hyperlipidaemia in vivo and did not have potential toxicity. These results demonstrated that the complex 1 might provide an important reference for the development of functional hypoglycaemic foods or pharmaceuticals of T2DM.     

Solar-microbial hybrid device based on oxygen-deficient niobium pentoxide anodes for sustainable hydrogen production

Hydrogen gas is emerging as an attractive fuel with high energy density for the direction of energy resources in the future. Designing integrated devices based on a photoelectrochemical (PEC) cell and a microbial fuel cell (MFC) represents a promising strategy to produce hydrogen fuel at a low price. In this work, we demonstrate a new solar-microbial (PEC–MFC) hybrid device based on the oxygen-deficient Nb₂O₅ nanoporous (Nb₂O_5–x NPs) anodes for sustainable hydrogen generation without external bias for the first time. Owing to the improved conductivity and porous structure, the as-prepared Nb₂O_5–x NPs film yields a remarkable photocurrent density of 0.9 mA cm^–2 at 0.6 V (vs. SCE) in 1 M KOH aqueous solution under light irradiation, and can achieve a maximum power density of 1196 mW m^–2 when used as an anode in a MFC device. More importantly, a solar-microbial hybrid system by combining a PEC cell with a MFC is designed, in which the Nb₂O_5–x NPs electrodes function as both anodes. The as-fabricated PEC–MFC hybrid device can simultaneously realize electricity and hydrogen using organic matter and solar light at zero external bias. This novel design and attempt might provide guidance for other materials to convert and store energy.     

5-HT1A receptor pharmacophores to screen for off-target activity of α1-adrenoceptor antagonists

The α₁-adrenoceptors (α₁-ARs), in particular the α_1A-AR subtype, are current therapeutic targets of choice for the treatment of urogenital conditions, such as benign prostatic hyperplasia (BPH). Due to the similarity between the transmembrane domains of the α₁-AR subtypes, and the serotonin receptor subtype 1A (5-HT_1A-R), currently used α₁-AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT_1A-R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT_1A-R agonists and antagonists. Through the structural diversity of the training sets used in their development, these pharmacophores define the properties of a compound needed to bind to 5-HT_1A receptors. Using these and previously published pharmacophores in virtual screening and profiling, we have identified unique chemical compounds (hits) that fit the requirements to bind to our target, the α_1A-AR, selectively over the off-target, the 5-HT_1A-R. Selected hits have been obtained and their affinities for α_1A-AR, α_1B-AR and 5-HT_1A-R determined in radioligand binding assays, using membrane preparations which contain human receptors expressed individually. Three of the tested hits demonstrate statistically significant selectivity for α_1A-AR over 5-HT_1A-R. All seven tested hits bind to α_1A-AR, with two compounds displaying K _i values below 1 μM, and a further two K _i values of around 10 μM. The insights and knowledge gained through the development of the new 5-HT_1A-R pharmacophores will greatly aid in the design and synthesis of derivatives of our lead compound, and allow the generation of more efficacious and selective ligands.