Geniposide attenuates spermatogenic dysfunction via inhibiting endoplasmic reticulum stress in male mice.

BACKGROUND: Spermatogenesis dysfunction is common in clinically infertile patients. Geniposide (GP) is one of the important active ingredients extracted from Eucommia ulmoides. However, the protective effect and mechanism of GP in the treatment of spermatogenic dysfunction is not known yet. METHODS: After cyclophosphamide-induced spermatogenic dysfunction was established in male mice, we gavaged GP for 4 weeks to evaluate spermatogenic function and anti-apoptotic effects by fertility, testicular weight, sperm quality, endoplasmic reticulum stress (ER stress), comet assay and serum testosterone level. RESULTS: GP can improve the damage of fertility and reproductive organs induced by cyclophosphamide and increase the number and activity of sperm. In comet assay, it was found that GP administration could alleviate sperm DNA damage induced by cyclophosphamide. In addition, GP treatment can significantly reduce ThT fluorescence intensity and improve endoplasmic reticulum stress induced by cyclophosphamide. Besides, TUNEL staining and WB showed that GP could inhibit the excessive apoptosis of cells and protect testis. (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: The protective effect of Geniposide on cyclophosphamide-induced spermatogenic dysfunction in mice is related to the inhibition of endoplasmic reticulum stress.

Fluorofoldamer-Based Salt- and Proton-Rejecting Artificial Water Channels for Ultrafast Water Transport.

Here, we report on a novel class of fluorofoldamer-based artificial water channels (AWCs) that combines excellent water transport rate and selectivity with structural simplicity and robustness. Produced by a facile one-pot copolymerization reaction under mild conditions, the best-performing channel (AWC 1) is an n-C8H17-decorated foldamer nanotube with an average channel length of 2.8 nm and a pore diameter of 5.2 Å. AWC 1 demonstrates an ultrafast water conduction rate of 1.4 × 1010 H2O/s per channel, outperforming the archetypal biological water channel, aquaporin 1, while excluding salts (i.e., NaCl and KCl) and protons. Unique to this class of channels, the inwardly facing C(sp2)-F atoms being the most electronegative in the periodic table are proposed as being critical to enabling the ultrafast and superselective water transport properties by decreasing the channel's cavity and enhancing the channel wall smoothness via reducing intermolecular forces with water molecules or hydrated ions.

Hybrid Pyridine-Pyridone Foldamer Channels as M2-Like Artificial Proton Channels.

Currently, completely abiotic channel systems that concurrently reproduce the high selectivity and high permeation rate of natural protein channels are rare. Here, we provide one such biomimetic channel system, i.e., a novel family of helically folded hybrid amide foldamers that can serve as powerful artificial proton channels to mimic key transport features of the exceptionally selective Matrix-2 (M2) proton channels. Possessing an angstrom-scale tubular pore 3 Šin diameter, these low water permeability artificial channels transport protons at a rate 1.22 and 11 times as fast as gramicidin A and M2 channels, respectively, with exceptionally high selectivity factors of 167.6, 122.7, and 81.5 over Cl- , Na+ , and K+ ions. Based on the experimental and computational findings, we propose a novel proton transport mechanism where a proton may create a channel-spanning water chain from two or more short water chains to facilitate its own transmembrane flux via the Grotthuss mechanism.

Protective Effects of Sesamin on Cytoxan-Induced Spermatogenesis Dysfunction by Regulating RNF8-ubH2A/ubH2B Pathways in Male Mice.

Most of the clinically infertile patients show spermatogenesis dysfunction. Cyclophosphamide, as an anticancer drug, can induce spermatogenesis dysfunction. Sesamin is the main bioactive component of natural lignans in sesame. It is abundant in sesame oil and has strong biological activities such as antioxidant, antibacterial, and hypoglycemic properties. By establishing the model of spermatogenic dysfunction induced by cyclophosphamide in male mice and then feeding sesamin (50, 100, and 200 mg/kg) for 2 weeks, we proved that sesamin can improve the reproductive organ damage induced by cyclophosphamide and increase the number and activity of sperms. Sesamin can resist cyclophosphamide-induced sperm nuclear maturity and DNA damage by increasing the expression levels of histones H2A and H2B in the testis. In addition, sesamin can improve the ubiquitination of histones regulated by RNF8 to protect the testis. In conclusion, these results suggest that sesamin can improve spermatogenic dysfunction induced by cyclophosphamide, which may be mediated by ubiquitination of histones.

Foldamer-based ultrapermeable and highly selective artificial water channels that exclude protons.

The outstanding capacity of aquaporins (AQPs) for mediating highly selective superfast water transport1-7 has inspired recent development of supramolecular monovalent ion-excluding artificial water channels (AWCs). AWC-based bioinspired membranes are proposed for desalination, water purification and other separation applications8-18. While some recent progress has been made in synthesizing AWCs that approach the water permeability and ion selectivity of AQPs, a hallmark feature of AQPs-high water transport while excluding protons-has not been reproduced. We report a class of biomimetic, helically folded pore-forming polymeric foldamers that can serve as long-sought-after highly selective ultrafast water-conducting channels with performance exceeding those of AQPs (1.1 × 1010 water molecules per second for AQP1), with high water-over-monovalent-ion transport selectivity (~108 water molecules over Cl- ion) conferred by the modularly tunable hydrophobicity of the interior pore surface. The best-performing AWC reported here delivers water transport at an exceptionally high rate, namely, 2.5 times that of AQP1, while concurrently rejecting salts (NaCl and KCl) and even protons.

Crystal Packing-Guided Construction of Hetero-Oligomeric Peptidic Ensembles as Synthetic 3-in-1 Transporters.

Strategies to generate heteromeric peptidic ensembles via a social self-sorting process are limited. Herein, we report a crystal packing-inspired social self-sorting strategy broadly applicable to diverse types of H-bonded peptidic frameworks. Specifically, a crystal structure of H-bonded alkyl chain-appended monopeptides reveals an inter-chain separation distance of 4.8 Šdictated by the H-bonded amide groups, which is larger than 4.1 Šseparation distance desired by the tightly packed straight alkyl chains. This incompatibility results in loosely packed alkyl chains, prompting us to investigate and validate the feasibility of applying bulky tert-butyl groups, modified with an anion-binding group, to alternatively interpenetrate the straight alkyl chains, modified with a crown ether group. Structurally, this social self-sorting approach generates highly stable hetero-oligomeric ensembles, having alternated anion- and cation-binding units vertically aligned to the same side. Functionally, these hetero-oligomeric ensembles promote transmembrane transport of cations, anions and more interestingly zwitterionic species such as amino acids.

Small Molecule-Based Highly Active and Selective K+ Transporters with Potent Anticancer Activities.

We report here a novel class of cation transporters with extreme simplicity, opening a whole new dimension of scientific research for finding small molecule-based cation transporters for therapeutic applications. Comprising three modular components (a headgroup, a flexible alkyl chain-derived body, and a crown ether-derived foot for ion binding), these transporters efficiently (EC50 = 0.18-0.41 mol % relative to lipid) and selectively (K+/Na+ selectivity = 7.0-9.5) move K+ ions across the membrane. Importantly, the most active (EC50 = 0.18-0.22 mol %) and highly selective series of transporters A12, B12, and C12 concurrently possess potent anticancer activities with IC50 values as low as 4.35 ± 0.91 and 6.00 ± 0.13 µM toward HeLa and PC3 cells, respectively. Notably, a mere replacement of the 18-crown-6 unit in the structure with 12-crown-4 or 15-crown-5 units completely annihilates the cation-transporting ability.

Buckyball-Based Spherical Display of Crown Ethers for De Novo Custom Design of Ion Transport Selectivity.

Searching for membrane-active synthetic analogues that are structurally simple yet functionally comparable to natural channel proteins has been of central research interest in the past four decades, yet custom design of the ion transport selectivity still remains a grand challenge. Here we report on a suite of buckyball-based molecular balls (MBs), enabling transmembrane ion transport selectivity to be custom designable. The modularly tunable MBm-Cn (m = 4-7; n = 6-12) structures consist of a C60-fullerene core, flexible alkyl linkers Cn (i.e., C6 for n-C6H12 group), and peripherally aligned benzo-3m-crown-m ethers (i.e., m = 4 for benzo-12-crown-4) as ion-transporting units. Screening a matrix of 16 such MBs, combinatorially derived from four different crown units and four different Cn linkers, intriguingly revealed that their transport selectivity well resembles the intrinsic ion binding affinity of the respective benzo-crown units present, making custom design of the transport selectivity possible. Specifically, MB4s, containing benzo-12-crown-4 units, all are Li+-selective in transmembrane ion transport, with the most active MB4-C10 exhibiting an EC50(Li+) value of 0.13 µM (corresponding to 0.13 mol % of the lipid present) while excluding all other monovalent alkali-metal ions. Likewise, the most Na+ selective MB5-C8 and K+ selective MB6-C8 demonstrate high Na+/K+ and K+/Na+ selectivity values of 13.7 and 7.8, respectively. For selectivity to Rb+ and Cs+ ions, the most active MB7-C8 displays exceptionally high transport efficiencies, with an EC50(Rb+) value of 105 nM (0.11 mol %) and an EC50(Cs+) value of 77 nM (0.079 mol %).

Macrocyclic Pyridone Pentamers for Highly Selective High-Capacity Removal of Caesium Ions from Radioactive High-Salinity Waste.

We report here that macrocyclic H-bonded pyridone pentamers, containing five properly and convergently spaced electron-rich O-atoms that decorate a rigid cavity of 2.85 Šacross, exhibit an extraordinarily high yet pH-independent capacity and selectivity in Cs+ removal. In particular, with [host]=240 µM and [Cs+ ]=15 µM, a single extraction efficiently removes more than 91% of Cs+ ions from artificial sea water, containing various competitive metal ions at a total concentration of 0.68 M ([total Mn+ ]/[Cs+ ]=4.5×104 ]). To our best knowledge, these pyridone pentamers represent the best small organic molecule-based extractants that target Cs+ ions.

Interplay between male reproductive system dysfunction and the therapeutic effect of flavonoids.

Male infertility has affected many families around the world. However, due to the mechanism underlying male reproductive system dysfunction are not completely elucidated, the use of drugs for male reproductive system dysfunction treatment only insignificant higher pregnancy outcomes, low-quality evidence suggests that clinical pregnancy rates may increase. Therefore, the focus in the future will be on developing more viable treatment options to prevent or treatment of male reproductive system dysfunction and achieve the purpose of improving fertility. Interestingly, natural products, as the potential inhibitors for the treatment of male reproductive system dysfunction, have shown a good therapeutic effect. Among many natural products, flavonoids have been extensively investigated for the treatment of male reproductive system dysfunction, such as testicular structural disruption, spermatogenesis disturbance and sperm quality decline. Flavonoids have been reported to have antioxidant, anti-inflammatory, immune stimulating, anti-apoptotic, anticarcinogenic, anti-allergic and antiviral activities, investigating for the treatment of male reproductive system dysfunction. In this review, we evaluate the therapeutic effects of flavonoids on male reproductive system dysfunction under different cellular scenarios and summarize the therapeutic strategies of flavonoids based on the aforementioned retrospective analysis. In the end, we describe some perspective research areas relevant to the application of flavonoids in the treatment of male reproductive system dysfunction.

Aquafoldmer-Based Aquaporin-like Synthetic Water Channel.

Synthetic water channels were developed with an aim to replace aquaporins for possible uses in water purification, while concurrently retaining aquaporins' ability to conduct highly selective superfast water transport. Among the currently available synthetic water channel systems, none possesses water transport properties that parallel those of aquaporins. In this report, we present the first synthetic water channel system with intriguing aquaproin-like features. Employing a "sticky end"-mediated molecular strategy for constructing abiotic water channels, we demonstrate that a 20% enlargement in angstrom-scale pore volume could effect a remarkable enhancement in macroscopic water transport profile by 15 folds. This gives rise to a powerful synthetic water channel able to transport water at a speed of ∼3 × 109 H2O s-1 channel-1 with a high rejection of NaCl and KCl. This high water permeability, which is about 50% of aquaporin Z's capacity, makes channel 1 the fastest among the existing synthetic water channels with high selectivity.

Polypyridine-Based Helical Amide Foldamer Channels: Rapid Transport of Water and Protons with High Ion Rejection.

Synthetic strategies that enable rapid construction of covalent organic nanotubes with an angstrom-scale tubular pore remain scarcely reported. Reported here is a remarkably simple and mild one-pot polymerization protocol, employing POCl3 as the polymerization agent. This protocol efficiently generates polypyridine amide foldamer-based covalent organic nanotubes with a 2.8 nm length at a yield of 50 %. Trapping single-file water chains in the 2.8 Štubular cavity, rich in hydrogen-bond donors and acceptors, these tubular polypyridine ensembles rapidly and selectively transport water at a rate of 1.6×109  H2 O⋅S-1 ⋅channel-1 and protons at a speed as fast as gramicidin A, with a high rejection of ions.

Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels.

Reported herein is a series of pore-containing polymeric nanotubes based on a hydrogen-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of about a 6.5 Šdiameter, mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membranes. The reported polymer channel, having an average molecular weight of 18.2 kDa and 3.6 nm in helical height, exhibits the highest anion-transport activities for iodide (EC50 =0.042 µm or 0.028 mol % relative to lipid), whcih is transported 10 times more efficiently than chlorides (EC50 =0.47 µm). Notably, even in cholesterol-rich environment, iodide transport activity remains high with an EC50 of 0.37 µm. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.

Pyridine/Oxadiazole-Based Helical Foldamer Ion Channels with Exceptionally High K+ /Na+ Selectivity.

Protein channels are characterized by high transport selectivity, which is essential for maintaining cellular function. Efforts to reproduce such high selectivity over the past four decades have not been very successful. We report a novel series of aromatic foldamer-based polymeric channels where the backbone is stabilized by differential electrostatic repulsions among heteroatoms helically arrayed along the helical backbone. Nanotubes averaging 2.3 and 2.7 nm in length mediate highly efficient transport of K+ ions as a consequence of hydrophilic electron-rich hollow cavities that are 3 Šin diameter. Exceptionally high K+ and Na+ selectivity values of 16.3 and 12.6, respectively, are achieved.

Protective effects of Salidroside on spermatogenesis in streptozotocin induced type-1 diabetic male mice by inhibiting oxidative stress mediated blood-testis barrier damage.

Spermatogenic dysfunction is one of the major secondary complications of male diabetes. Salidroside (SAL) is the important active ingredients isolated from Herba Cistanche, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. The present study was designed to determine whether SAL contributes to the recovery from spermatogenic dysfunction in streptozotocin (STZ) induced type-1 diabetic mice. SAL (25, 50, or 100 mg/kg) and Clomiphene citrate (CC, 5 mg/kg) were orally administered to male type-1 diabetic mice for 10 weeks. Testis tissues were collected for histopathological and biochemical analysis. Moreover, reproductive organ weight, sperm parameters, and testicular cell DNA damage were estimated. The results revealed that SAL significantly improved the weight of the reproductive organs, sperm parameters and testicular morphology to different degrees in type-1 diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked downregulation the fluorescence expressions of p38 MAPK phosphorylation and upregulation the protein expressions of ZO-1, Occludin, Claudin-11 and N-cadherin after SAL administration (100 mg/kg) compared with the type-1 diabetic group. In conclusion, these results demonstrated that SAL exerts protective effects on type-1 diabetes-induced male spermatogenic dysfunction, which is likely mediated by inhibiting oxidative stress-mediated blood testis barrier damage.

Protective effects of betaine on diabetic induced disruption of the male mice blood-testis barrier by regulating oxidative stress-mediated p38 MAPK pathways.

BACKGROUND: Blood-testis barrier (BTB) impairments is one of the major secondary complications of diabetes. Betaine (BET) is the important active ingredients isolated from Lycium barbarum, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. This study aimed to establish whether BET contributes to the recovery from BTB dysfunction in streptozotocin (STZ) induced diabetic mice. METHODS: BET (200, 400, 800 mg/kg) was orally administered to diabetic mice for 8 weeks. Testis tissues were collected for histopathological and biochemical analysis, the reproductive organ weight was estimated. Antioxidant enzyme activity and BTB associated protein expressions were determined with their corresponding assay kits and western blot analysis. The results revealed that BET significantly improved the weight of the reproductive organs and testicular morphology in diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked down-regulated the expressions of p38 MAPK phosphorylation and up-regulation the protein expressions of ZO-1, Occludin, Claudin-11, N-cadherin, and Connexin-43 after BET administration compared with the diabetic group. In conclusion, these results demonstrated that BET exerts protective effects on diabetes-induced BTB dysfunction, which may be through regulating oxidative stress-mediated p38 MAPK pathways.

Molecular Ion Fishers as Highly Active and Exceptionally Selective K+ Transporters.

We report here a unique ion-fishing mechanism as an alternative to conventional carrier or channel mechanisms for mediating highly efficient and exceptionally selective transmembrane K+ flux. The molecular framework, underlying the fishing mechanism and comprising a fishing rod, a fishing line and a fishing bait/hook, is simple yet modularly modifiable. This feature enables rapid construction of a series of molecular ion fishers with distinctively different ion transport patterns. While more efficient ion transports are generally achieved by using 18-crown-6 as the fishing bait/hook, ion transport selectivity (K+/Na+) critically depends on the length of the fishing line, with the most selective MF6-C14 exhibiting exceptionally high selectivity (K+/Na+ = 18) and high activity ( EC50 = 1.1 mol % relative to lipid).

Molecular Swings as Highly Active Ion Transporters.

Ions are transported across membrane mostly via carrier or channel mechanisms. Herein, a unique class of molecular-machine-inspired membrane transporters, termed molecular swings is reported that utilize a previously unexplored swing mechanism for promoting ion transport in a highly efficient manner. In particular, the molecular swing, which carries a 15-crown-5 unit as the ion-binding and transporting unit, exhibits extremely high ion-transport activities with EC50 values of 46 nm (a channel:lipid molar ratio of 1:4800 or 0.021 mol % relative to lipid) and 110 nm for K+ and Na+ ions, respectively. Remarkably, such ion transport activities remain high in a cholesterol-rich environment, with EC50 values of 130 (0.045 mol % relative to lipid/cholesterol) and 326 nm for K+ and Na+ ions, respectively.

Structurally simple trimesic amides as highly selective anion channels.

Trimesic amide molecules, which contain simple alkyl chains in their periphery, exhibit interesting anion-transport functions. The most active and highly selective channel TA12 efficiently transports ClO4- anions across membranes, with other anions conducted in the order of I- > NO3- > Br- > Cl-.

Versatile Types of DNA-Based Nanobiosensors for Specific Detection of Cancer Biomarker FEN1 in Living Cells and Cell-Free Systems.

Flap structure-specific endonuclease 1 (FEN1) is overexpressed in various types of human cancer cells and has been recognized as a promising biomarker for cancer diagnosis in the recent years. In order to specifically detect the abundance and activity of this cancer-overexpressed enzyme, different types of DNA-based nanodevices were created during our investigations. It is shown in our studies that these newly designed biosensors are highly sensitive and specific for FEN1 in living cells as well as in cell-free systems. It is expected that these nanoprobes could be useful for monitoring FEN1 activity in human cancer cells, and also for cell-based screening of FEN1 inhibitors as new anticancer drugs.