A 3D radially aligned nanofiber scaffold co-loaded with LL37 mimetic peptide and PDGF-BB for the management of infected chronic wounds.

Diabetic foot ulcers, pressure ulcers, and bedsores can easily develop into chronic wounds with bacterial infections, complicating wound healing. This work reports a two-step strategy for treating infected chronic wounds. Firstly, LL37 mimetic peptide-W379 peptides were rapidly released to eliminate the bacterial biofilm on the wound. Then, 3D radially aligned nanofiber scaffolds loaded with W379 antimicrobial peptide and PDGF-BB were used to treat the wound to prevent bacterial infection recurrence and promote angiogenesis and granulation tissue regeneration, thereby accelerating wound healing. In the presented study, we found that the combined use of burst and controlled release of W379 antimicrobial peptide effectively clears the bacterial biofilm and prevents the recurrence of bacterial infection. Additionally, we found that the removal of the bacterial biofilm contributed to modulating the local inflammatory response from a pro-inflammatory type to a pro-regenerative type. Furthermore, the use of PDGF-BB significantly promotes neovascularization and granulation tissue regeneration in the wound bed, resulting in accelerating re-epithelialization and wound closure. Our study provides a promising treatment method for the repair of infected chronic wounds.

[Progress on the effects of cancer-related fibroblast induced by Helicobacter pylori infection on gastric epithelial-mesenchymal transition].

Helicobacter pylori (Hp) is a Gram-negative bacterium that colonizes in the gastric mucosa. Hp induces the production of cancer-associated fibroblasts (CAF) in the stomach. The virulence factors of Hp and CAF trigger epithelial-mesenchymal transition (EMT), leading to local inflammation, damage to the gastric mucosa, and the occurrence of chronic gastritis. Here, we summarize the molecular mechanisms of CAF mediated gastric EMT after Hp infection, providing new insights into potential molecular targets and strategies for the future treatment of Hp infection associated gastric cancer.

Innervate Commercial Fabrics with Spirally-Layered Iontronic Fibrous Sensors Toward Dual-Functional Smart Garments.

Electronic fabrics exhibit desirable breathability, wearing comfort, and easy integration with garments. However, surficial deposition of electronically functional materials/compounds onto fabric substrates would consequentially alter their intrinsic properties (e.g., softness, permeability, biocompatibility, etc.). To address this issue, here, a strategy to innervate arbitrary commercial fabrics with unique spirally-layered iontronic fibrous (SLIF) sensors is presented to realize both mechanical and thermal sensing functionalities without sacrificing the intrinsic fabric properties. The mechanical sensing function is realized via mechanically regulating the interfacial ionic supercapacitance between two perpendicular SLIF sensors, while the thermal sensing function is achieved based on thermally modulating the intrinsic ionic impedance in a single SLIF sensor. The resultant SLIF sensor-innervated electronic fabrics exhibit high mechanical sensitivity of 81 N-1, superior thermal sensitivity of 34,400 Ω °C-1, and more importantly, greatly minimized mutual interference between the two sensing functions. As demonstrations, various smart garments are developed for the precise monitoring of diverse human physiological signals. Moreover, artificial intelligence-assisted object recognition with high-accuracy (97.8%) is demonstrated with a SLIF sensor-innervated smart glove. This work opens up a new path toward the facile construction of versatile smart garments for wearable healthcare, human-machine interfaces, and the Internet of Things.

Dopamine in the regulation of glucose and lipid metabolism: a narrative review.

OBJECTIVE: Owing to the global obesity epidemic, understanding the regulatory mechanisms of glucose and lipid metabolism has become increasingly important. The dopaminergic system, including dopamine, dopamine receptors, dopamine transporters, and other components, is involved in numerous physiological and pathological processes. However, the mechanism of action of the dopaminergic system in glucose and lipid metabolism is poorly understood. In this review, we examine the role of the dopaminergic system in glucose and lipid metabolism. RESULTS: The dopaminergic system regulates glucose and lipid metabolism through several mechanisms. It regulates various activities at the central level, including appetite control and decision-making, which contribute to regulating body weight and energy metabolism. In the pituitary gland, dopamine inhibits prolactin production and promotes insulin secretion through dopamine receptor 2. Furthermore, it can influence various physiological components in the peripheral system, such as pancreatic ß cells, glucagon-like peptide-1, adipocytes, hepatocytes, and muscle, by regulating insulin and glucagon secretion, glucose uptake and use, and fatty acid metabolism. CONCLUSIONS: The role of dopamine in regulating glucose and lipid metabolism has significant implications for the physiology and pathogenesis of disease. The potential therapeutic value of dopamine lies in its effects on metabolic disorders.

Supramolecular DNA-based catalysis in organic solvents.

The distinct folding accompanied by its polymorphic character renders DNA G-quadruplexes promising biomolecular building blocks to construct novel DNA-based and supramolecular assemblies. However, the highly polar nature of DNA limits the use of G-quadruplexes to water as a solvent. In addition, the archetypical G-quadruplex fold needs to be stabilized by metal-cations, which is usually a potassium ion. Here, we show that a noncovalent PEGylation process enabled by electrostatic interactions allows the first metal-free G-quadruplexes in organic solvents. Strikingly, incorporation of an iron-containing porphyrin renders the self-assembled metal-free G-quadruplex catalytically active in organic solvents. Hence, these "supraG4zymes" enable DNA-based catalysis in organic media. The results will allow the broad utilization of DNA G-quadruplexes in nonaqueous environments.

Shape morphing of hydrogels by harnessing enzyme enabled mechanoresponse.

Hydrogels have been designed to react to many different stimuli which find broad applications in tissue engineering and soft robotics. However, polymer networks bearing mechano-responsiveness, especially those displaying on-demand self-stiffening and self-softening behavior, are rarely reported. Here, we design a mechano-controlled biocatalytic system at the molecular level that is incorporated into hydrogels to regulate their mechanical properties at the material scale. The biocatalytic system consists of the protease thrombin and its inhibitor, hirudin, which are genetically engineered and covalently coupled to the hydrogel networks. The catalytic activity of thrombin is reversibly switched on by stretching of the hydrogels, which disrupts the noncovalent inhibitory interaction between both entities. Under cyclic tensile-loading, hydrogels exhibit self-stiffening or self-softening properties when substrates are present that can self-assemble to form new networks after being activated by thrombin or when cleavable peptide crosslinkers are constitutional components of the original network, respectively. Additionally, we demonstrate the programming of bilayer hydrogels to exhibit tailored shape-morphing behavior under mechanical stimulation. Our developed system provides proof of concept for mechanically controlled reversible biocatalytic processes, showcasing their potential for regulating hydrogels and proposing a biomacromolecular strategy for mechano-regulated soft functional materials.

Polymer Mechanochemistry in Microbubbles.

Polymer mechanochemistry is a promising technology to convert mechanical energy into chemical functionality by breaking covalent and supramolecular bonds site-selectively. Yet, the mechanochemical reaction rates of covalent bonds in typically used ultrasonication setups lead to reasonable conversions only after comparably long sonication times. This can be accelerated by either increasing the reactivity of the mechanoresponsive moiety or by modifying the encompassing polymer topology. Here, a microbubble system with a tailored polymer shell consisting of an N2 gas core and a mechanoresponsive disulfide-containing polymer network is presented. It is found that the mechanochemical activation of the disulfides is greatly accelerated using these microbubbles compared to commensurate solid core particles or capsules filled with liquid. Aided by computational simulations, it is found that low shell thickness, low shell stiffness and crosslink density, and a size-dependent eigenfrequency close to the used ultrasound frequency maximize the mechanochemical yield over the course of the sonication process.

Recombinant supercharged polypeptides for safe and efficient heparin neutralization.

Heparin is a widely used anticoagulant agent in the clinic. After application, its anticoagulant effect must be reversed to prevent potential side effects. Protamine sulfate (PS) is the only clinically licensed antidote that has been used for this purpose in the last 80 years, which, however, provokes severe adverse effects, such as systemic hypotension and even death. Herein, we demonstrate the potential of supercharged polypeptides as a promising alternative for protamine sulfate. A series of supercharged polypeptides with multiple positive charges was recombinantly produced, and the heparin-neutralizing performance of the polypeptides was evaluated in comparison with PS. It was found that increasing the number of charges significantly enhanced the ability to neutralize heparin and resist the screening effect induced by salt. In particular, the polypeptide bearing 72 charges (K72) exhibited an excellent heparin-neutralizing behavior that was comparable to that of PS. Further in vivo studies revealed that the heparin-triggered bleeding was almost completely alleviated by K72 while a negligible toxic effect was observed. Therefore, such recombinant supercharged polypeptides might replace protamine sulfate as heparin-reversal agents.

Programming DNA Circuits for Controlled Immunostimulation through CpG Oligodeoxynucleotide Delivery.

Herein, we present a DNA circuit programmed for the delivery of CpG oligodeoxynucleotides (CpG ODNs) with the pharmacological immunostimulation function. The circuit employs a complementary DNA (cDNA) strand to deactivate the biological function of CpG ODNs via hybridization, while T7 exonuclease mediates the activation by hydrolyzing the cDNA and releasing the CpG ODN as an active moiety. We investigated the influence of several factors on the kinetic profile and temporal behavior of the circuit. These include the design of the cDNA strand, the concentration of the DNA duplex, and the concentration of T7 exonuclease. The DNA circuit's in vitro activation resulted in toll-like receptor 9 stimulation in the HEK-engineered cell line, as well as tumor necrosis factor-alpha release by J774A.1 macrophages. By programming the DNA circuit to control the release of the CpG ODN, we achieved an altered pharmacological profile with acute and potent immunostimulation, in comparison to a system without controlled CpG ODN release, which exhibited a slow and delayed response. Our findings demonstrate the potential of DNA circuits in controlling the pharmacological activity of DNA strands for controlled drug delivery.

Optically Controlled Construction of Three-Dimensional Protein Arrays.

Protein crystallization is an important tool for structural biology and nanostructure preparation. Here, we report on kinetic pathway-dependent protein crystals that are controlled by light. Photo-responsive crystallites are obtained by complexing the model proteins with cationic azobenzene dyes. The crystalline state is readily switched to a dispersed phase under ultraviolet light and restored by subsequent visible-light illumination. The switching can be reversibly repeated for multiple cycles without noticeable structure deterioration. Importantly, the photo-treatment not only significantly increases the crystallinity, but creates crystallites at conditions where no ordered lattices are observed upon directly mixing the components. Further control over the azobenzene isomerization kinetics produces protein single crystals of up to ≈50 µm. This approach offers an intriguing method to fabricate metamaterials and study optically controlled crystallization.

Fracture Detection in Bio-Glues with Fluorescent-Protein-Based Optical Force Probes.

Glues are being used to bond, seal, and repair in industry and biomedicine. The improvement of gluing performance is hence important for the development of new glues with better and balanced property spaces, which in turn necessitates a mechanistic understanding of their mechanical failure. Optical force probes (OFPs) allow the observation of mechanical material damage in polymers from the macro- down to the microscale, yet have never been employed in glues. Here, the development of a series of ratiometric OFPs based on fluorescent-protein-dye and protein-protein conjugates and their incorporation into genetically engineered bio-glues is reported. The OFPs are designed to efficiently modulate Förster resonance energy transfer upon force application thereby reporting on force-induced molecular alterations independent of concentration and fluorescence intensity both spectrally and through their fluorescence lifetime. By fluorescence spectroscopy in solution and in the solid state and by fluorescence lifetime imaging microscopy, stress concentrations are visualized and adhesive and cohesive failure in the fracture zone is differentiated.

Piezoelectric Metal-Organic Frameworks Mediated Mechanoredox Borylation and Arylation Reactions by Ball Milling.

Herein, metal-organic frameworks UiO-66 and UiO-66-NH2 were synthesized, and their piezoelectric properties were characterized by piezoresponse force microscopy. Under mechanical agitation, the highly polarized UiO-66 and UiO-66-NH2 can act as electron donors to reduce aryl diazonium salts, forming the aryl radical species, which further react with bis(pinacolato)diborane or heteroarenes to generate the desired products with broad substrate scope. For all substrates, it was found that the reactions mediated by UiO-66-NH2 , which exhibited better piezoelectric property, were more efficient than those promoted by UiO-66. Moreover, it was shown that the convenient regeneration of spent catalysts can be reused for promoting mechanoredox reactions without loss of activities by taking advantage of the unmatched repairability of metal-organic frameworks. Mechanistic studies revealed that a radical pathway was involved in these transformations.

[Dual regulation of Qizhiweitong particles on gastric motility in the model rats with gastroparesis].

This paper was aimed to study the effects of Qizhiweitong particles (QZWT) on gastric motility in gastroparesis model rats, and to provide a theoretical and experimental basis for its clinical treatment. Rat gastroparesis model was established by bilateral injection of 6-hydroxydopamine into the substantia nigra in male Sprague-Dawley (SD) rats. The model rats received single gastric feeding of 1, 10, 30, 100, 200, 450, or 675 mg/kg QZWT or continuous administration of 675 mg/kg QZWT per day for 7 days. The gastric motility was measured by gastric emptying study and in vivo digital X-ray imaging system. The in vivo and ex vivo gastric longitudinal muscle contraction was recorded by PowerLab biological signal acquisition system. Gastric myoelectric signals were recorded by wireless implantable telemetry system. Protein expression levels of proinflammatory proteases in the myometrium were determined by Western blot. The results showed that the single administration of QZWT dose-dependently inhibited the contractile activity of isolated gastric strips from normal rats. The single administration of QZWT inhibited the in vivo contraction of gastric smooth muscle and gastric myoelectric signal in the control and model rats. The gastric emptying rate, in vivo and ex vivo gastric motility and gastric myoelectric signal in the model rats were significantly decreased compared with those in the control rats; While the continuous administration of QZWT markedly improved all the above indices of gastric motility function. The single administration of QZWT inhibited isolated gastric muscle strip contraction, and neither atropine nor nitric oxide synthase inhibitor pretreatments affected QZWT's inhibitory effects. The continuous administration of QZWT down-regulated the increased protein expression levels of nitric oxide synthase and cyclooxygenase 2 in the model group. These results suggest that, in clinical treatment, the single administration of QZWT may induce an analgesic effect by rapidly inhibiting gastric motility, while this effect is not related to acetylcholine or nitric oxide pathways. Long-term treatment with QZWT may ameliorate gastric motility through enhancing myoelectric activities, gastric smooth muscle contraction and gastric emptying, and this effect may partly be related to its anti-inflammatory effect.

Mechanochemical Divergent Syntheses of Oxindoles and α-Arylacylamides via Controllable Construction of C-C and C-N Bonds by Copper and Piezoelectric Materials.

Herein, we present the divergent syntheses of α-arylacylamides and oxindoles via mechanoredox chemistry by using easily accessible α-bromo N-sulfonyl amides as starting materials. Our system consists of a catalytic amount of CuII precatalyst and piezoelectric materials. The highly polarized BaTiO3 or PbTiO3 under mechanical agitation can act as an electron donor to realize the recycling of CuII and CuI . Control experiments and density functional theory calculations have been performed to support the proposed mechanistic rationale for the cascade reactions.

Impaired nitrergic relaxation in pyloric sphincter of the 6-OHDA Parkinson's disease rat.

Patients with Parkinson's disease (PD) often suffer from delayed gastric emptying, but the underlying mechanism remains unclear. We have shown previously that a PD rat model comprising bilateral substantia nigra destruction by 6-hydroxydopamine (6-OHDA rats) exhibits gastroparesis with alteration of neural nitric oxide synthase (nNOS) and acetylcholine in gastric corpus. However, changes in pyloric motility in the 6-OHDA rats have not been characterized. Solid gastric emptying test, immunofluorescence, Western blot, and in vitro pyloric motility recordings were used to assess pyloric motor function in the 6-OHDA rats. The 6-OHDA-treated rats displayed delayed solid gastric emptying and a lower basal pyloric motility index. In the 6-OHDA rats, high K+-induced transient contractions were weaker in pyloric sphincters. Electric field stimulation (EFS)-induced pyloric sphincter relaxation was lower in the 6-OHDA rats. NG-nitro-l-arginine methyl ester (l-NAME), a nonselective inhibitor of NOS, markedly inhibited the EFS-induced relaxation in both control and 6-OHDA rats. Pretreatment of tetrodotoxin abolished the effect of EFS on the pyloric motility. In addition, nNOS-positive neurons were extensively distributed in the pyloric myenteric plexus, whereas the number of nNOS-immunoreactive neurons and the protein expression of nNOS were significantly decreased in the pyloric muscularis of 6-OHDA rats. However, sodium nitroprusside-induced pyloric relaxations were similar between the control and 6-OHDA rats. These results indicate that the pyloric sphincters of 6-OHDA rats exhibit both weakened contraction and relaxation. The latter may be due to reduced nNOS in the pyloric myenteric plexus. The dysfunction of the pyloric sphincter might be involved in the delayed gastric emptying.NEW & NOTEWORTHY Reduced nitrergic neurons in pyloric myenteric plexus potently contributed to the attenuated relaxation in 6-hydroxydopamine (6-OHDA) rats, subsequently affecting gastric emptying. SNP could well improve the relaxation of pylori in 6-OHDA rats. The present study provides new insight into the diagnosis and treatment of delayed gastric emptying in patients with PD.

Activation of dopamine D2 receptor promotes pepsinogen secretion by suppressing somatostatin release from the mouse gastric mucosa.

In vivo administration of dopamine (DA) receptor (DR)-related drugs modulate gastric pepsinogen secretion. However, DRs on gastric pepsinogen-secreting chief cells and DA D2 receptor (D2R) on somatostatin-secreting D cells were subsequently acquired. In this study, we aimed to further investigate the local effect of DA on gastric pepsinogen secretion through DRs expressed on chief cells or potential D2Rs expressed on D cells. To elucidate the modulation of DRs in gastric pepsinogen secretion, immunofluorescence staining, ex vivo incubation of gastric mucosa isolated from normal and D2R-/- mice were conducted, accompanied by measurements of pepsinogen or somatostatin levels using biochemical assays or enzyme-linked immunosorbent assays. D1R, D2R, and D5R-immunoreactivity (IR) were observed on chief cells in mouse gastric mucosa. D2R-IR was widely distributed on D cells from the corpus to the antrum. Ex vivo incubation results showed that DA and the D1-like receptor agonist SKF38393 increased pepsinogen secretion, which was blocked by the D1-like receptor antagonist SCH23390. However, D2-like receptor agonist quinpirole also significantly increased pepsinogen secretion, and D2-like receptor antagonist sulpiride blocked the promotion of DA. Besides, D2-like receptors exerted an inhibitory effect on somatostatin secretion, in contrast to their effect on pepsinogen secretion. Furthermore, D2R-/- mice showed much lower basal pepsinogen secretion but significantly increased somatostatin release and an increased number of D cells in gastric mucosa. Only SKF38393, not quinpirole, increased pepsinogen secretion in D2R-/- mice. DA promotes gastric pepsinogen secretion directly through D1-like receptors on chief cells and indirectly through D2R-mediated suppression of somatostatin release.

Light manipulation for fabrication of hydrogels and their biological applications.

The development of biocompatible materials with desired functions is essential for tissue engineering and biomedical applications. Hydrogels prepared from these materials represent an important class of soft matter for mimicking extracellular environments. In particular, dynamic hydrogels with responsiveness to environments are quite appealing because they can match the dynamics of biological processes. Among the external stimuli that can trigger responsive hydrogels, light is considered as a clean stimulus with high spatiotemporal resolution, complete bioorthogonality, and fine tunability regarding its wavelength and intensity. Therefore, photoresponsiveness has been broadly encoded in hydrogels for biological applications. Moreover, light can be used to initiate gelation during the fabrication of biocompatible hydrogels. Here, we present a critical review of light manipulation tools for the fabrication of hydrogels and for the regulation of physicochemical properties and functions of photoresponsive hydrogels. The materials, photo-initiated chemical reactions, and new prospects for light-induced gelation are introduced in the former part, while mechanisms to render hydrogels photoresponsive and their biological applications are discussed in the latter part. Subsequently, the challenges and potential research directions in this area are discussed, followed by a brief conclusion. STATEMENT OF SIGNIFICANCE: Hydrogels play a vital role in the field of biomaterials owing to their water retention ability and biocompatibility. However, static hydrogels cannot meet the dynamic requirements of the biomedical field. As a stimulus with high spatiotemporal resolution, light is an ideal tool for both the fabrication and operation of hydrogels. In this review, light-induced hydrogelation and photoresponsive hydrogels are discussed in detail, and new prospects and emerging biological applications are described. To inspire more research studies in this promising area, the challenges and possible solutions are also presented.

Activation of α7nAChR Protects Against Gastric Inflammation and Dysmotility in Parkinson's Disease Rats.

The cholinergic anti-inflammatory pathway (CAIP) has been proposed to regulate gastrointestinal inflammation via acetylcholine released from the vagus nerve activating α7 nicotinic receptor (α7nAChR) on macrophages. Parkinson's disease (PD) patients and PD rats with substantia nigra (SN) lesions exhibit gastroparesis and a decayed vagal pathway. To investigate whether activating α7nAChR could ameliorate inflammation and gastric dysmotility in PD rats, ELISA, western blot analysis, and real-time PCR were used to detect gastric inflammation. In vitro and in vivo gastric motility was investigated. Proinflammatory mediator levels and macrophage numbers were increased in the gastric muscularis of PD rats. α7nAChR was located on the gastric muscular macrophages of PD rats. The α7nAChR agonists PNU-282987 and GTS-21 decreased nuclear factor κB (NF-κB) activation and monocyte chemotactic protein-1 mRNA expression in the ex vivo gastric muscularis of PD rats, and these effects were abolished by an α7nAChR antagonist. After treatment with PNU-282987 in vivo, the PD rats showed decreased NF-κB activation, inflammatory mediator production, and contractile protein expression and improved gastric motility. The present study reveals that α7nAChR is involved in the development of gastroparesis in PD rats and provides novel insight for the treatment of gastric dysmotility in PD patients.

Identification and a phased pH control strategy of diosgenin bio-synthesized by an endogenous Bacillus licheniformis Syt1 derived from Dioscorea zingiberensis C. H. Wright.

Diosgenin is widely used as one precursor of steroidal drugs in pharmaceutical industry. Currently, there is no choice but to traditionally extract diosgenin from Dioscorea zingiberensis C. H. Wright (DZW) or other plants. In this work, an environmentally friendly approach, in which diosgenin can be bio-synthesized by the endophytic bacterium Bacillus licheniformis Syt1 isolated from DZW, is proposed. Diosgenin produced by the strain was identified by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and Fourier transform infrared spectroscopy (FTIR). The thermal gravimetric analysis (TGA) showed that the melting point of the diosgenin product was 204 °C. The optical rotation measurement exhibited that the optical rotation was α20589 = - 126.1° ± 1.5° (chloroform, c = 1%): negative sign means that the product is left-handed, which is very important to further produce steroid hormone drugs. Cholesterol may be the intermediate product in the diosgenin biosynthesis pathway. In the batch fermentation process to produce diosgenin using the strain, pH values played an important role. A phased pH control strategy from 5.5 to 7.5 was proved to be more effective to improve production yield than any single pH control, which could get the highest diosgenin yield of 85 ± 8.6 mg L-1. The proposed method may replace phyto-chemistry extraction to produce diosgenin in the industry in the future.Key points• An endophytic Bacillus licheniformis Syt1 derived from host can produce diosgenin.• A dynamic pH industrial control strategy is better than any single pH control.• Proposed diosgenin-produced method hopefully replaces phyto-chemistry extraction.