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Due to overactive inflammation and hindered angiogenesis, self-healing of diabetic wounds (DW) remains challenging in the clinic. Platelet-derived exosomes (PLT-Exos), a novel exosome capable of anti-inflammation and pro-angiogenesis, show great potential in DW treatment. However, previous administration of exosomes into skin wounds is topical daub or intradermal injection, which cannot intradermally deliver PLT-Exos into the dermis layer, thus impeding its long-term efficacy in anti-inflammation and pro-angiogenesis. Herein, a dissolvable microneedle-based wound dressing (PLT-Exos@ADMMA-MN) was developed for transdermal and long-term delivery of PLT-Exos. Firstly, a photo-crosslinking methacrylated acellular dermal matrix-based hydrogel (ADMMA-GEL), showing physiochemical tailorability, fast-gelling performance, excellent biocompatibility, and pro-angiogenic capacities, was synthesized as a base material of our dressing. For endowing the dressing with anti-inflammation and pro-angiogenesis, PLT-Exos were encapsulated into ADMMA-GEL with a minimum effective concentration determined by our in-vitro experiments. Then, in-vitro results show that this dressing exhibits excellent properties in anti-inflammation and pro-angiogenesis. Lastly, in-vivo experiments showed that this dressing could continuously and transdermally deliver PLT-Exos into skin wounds to switch local macrophage into M2 phenotype while stimulating neovascularization, thus proving a low-inflammatory and pro-angiogenic microenvironment for DW healing. Collectively, this study provides a novel wound dressing capable of suppressing inflammation and stimulating vascularization for DW treatment.

Sepsis, a life-threatening syndrome of organ damage resulting from dysregulated inflammatory response, is distinguished by overexpression of inflammatory cytokines, excessive generation of reactive oxygen/nitrogen species (RONS), heightened activation of pyroptosis, and suppression of autophagy. However, current clinical symptomatic supportive treatment has failed to reduce the high mortality. Herein, we developed self-assembled multifunctional carbon monoxide nanogenerators (Nano CO), as sepsis drug candidates, which can release CO in response to ROS, resulting in clearing bacteria and activating the heme oxygenase-1/CO system. This activation strengthened endogenous protection and scavenged multiple inflammatory mediators to alleviate the cytokine storm, including scavenging RONS and cfDNA, inhibiting macrophage activation, blocking pyroptosis and activating autophagy. Animal experiments show that Nano CO has a good therapeutic effect on mice with LPS-induced sepsis, which is manifested in hypothermia recovery, organ damage repair, and a 50% decrease in mortality rates. Taken together, these results illustrated the efficacy of multifunctional Nano CO to target clearance of multiple mediators in sepsis treatment and act against other refractory inflammation-related diseases.

The lever or the lever-type mechanism can achieve an inertia amplification effect by appropriately calibrating its structural configuration, and it is also proven to be one of the most cost-effective solution for the inerter realization compared with other mechanical devices. Benefitting from this property, the present paper adopted a new type of tuned lever inerter-like mass damper (TLIMD) for attenuating stochastic load-induced structure dynamic responses. A set of closed-form formulae for the TLIMD optimal parameters are developed by the use of H2 norm optimization criterion, wherein the structure’s inherent damping is explicitly accounted for. It is theoretically demonstrated that the TLIMD optimal parameters are mainly dominated by three critical parameters, i.e., the damper mass ratio, the lever length ratio (known as the inertia amplification ratio) and also the host structural damping. The proposed formulae for the TLIMD optimization are validated through the seismic analysis, where two classic inerter-based dampers (i.e., the tuned mass damper inerter (TMDI) and the tuned inerter damper (TID)) optimized by the numerical technique are included in the discussion. It is found that the TLIMD has a superior advantage in reducing the structure responses and also exhibits stronger robustness for the detuning condition than the classic inerter-based dampers. Furthermore, the increase in the damper mass ratio and the lever length ratio can be beneficial for enhancing its performance.

In this study, we aimed to explore the hypoglycemic effects of a hydrolysate on Takifugu bimaculatus skin (TBSH). The effect of the dipeptidyl peptidase-IV (DPP-IV) inhibitory activities from different TBSH fractions was investigated on basic indexes, gut hormones, blood lipid indexes, viscera, and the gut microbiota and its metabolites in rats with type 2 diabetes mellitus (T2DM). The results showed that the 50 = 0.45 ± 0.01 mg/mL). T2DM rats were induced with streptozocin, followed by the administration of TBP. The 200 mg/kg TBP mitigated weight loss, lowered fasting blood glucose levels, and increased insulin secretion by 20.47%, 25.23%, and 34.55%, respectively, rectified irregular hormonal fluctuations, lipid metabolism, and tissue injuries, and effectively remedied gut microbiota imbalance. In conclusion, TBP exerts a hypoglycemic effect in rats with T2DM. This study offers the potential to develop nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus. It will provide information for developing nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus.

As a new type of injectable biomaterials, functional microspheres have attracted increasing attention in tissue regeneration because they possess some advantageous properties compared to other biomaterials, including hydrogels. A variety of bio-inspired microspheres with unique structures and properties have been developed as cellular carriers and drug delivery vehicles in recent years. In this review, we provide a comprehensive summary of the progress of functional and biodegradable microspheres that have been used for tissue regeneration over the last two decades. First, we briefly introduce the biomaterials and general methods for microsphere fabrication. Next, we focus on the newly developed technologies for preparing functional microspheres, including macroporous microspheres, nanofibrous microspheres, hollow microspheres, core-shell structured microspheres, and surface-modified functional microspheres. After that, we discuss the application of functional microspheres for tissue regeneration, specifically for bone, cartilage, dental, neural, cardiac, and skin tissue regeneration. Last, we present our perspectives and future directions of functional microspheres as injectable carriers for the future advancement of tissue regeneration.

Influenza A virus (IAV) infection often leads to influenza-associated fatalities, frequently compounded by subsequent bacterial infections, particularly Gram-negative bacterial co-infections. Lipopolysaccharide (LPS), a primary virulence factor in Gram-negative bacteria, plays a crucial role in influenza–bacterial co-infections. However, the precise pathogenic mechanisms underlying the synergistic effects of viral–bacterial co-infections remain elusive, posing significant challenges for disease management. In our study, we administered a combination of IAV and LPS to mice and examined associated parameters, including the lung function, lung index, wet/dry ratio, serum inflammatory cytokines, Nedd4L expression in lung tissue, and mRNA levels of inflammatory cytokines. Co-infection with IAV and LPS exacerbated lung tissue inflammation and amplified M1 macrophage expression in lung tissue. Additionally, we stimulated macrophages with IAV and LPS in vitro, assessing the inflammatory cytokine content in the cell supernatant and cytokine mRNA expression within the cells. This combined stimulation intensified the inflammatory response in macrophages and upregulated Nedd4L protein and mRNA expression. Subsequently, we used siRNA to knockdown Nedd4L in macrophages, revealing that suppression of Nedd4L expression alleviated the inflammatory response triggered by concurrent IAV and LPS stimulation. Collectively, these results highlight the pivotal role of Nedd4L in mediating the exacerbated inflammatory responses observed in IAV and LPS co-infections.

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.

Abnormal melanogenesis can lead to hyperpigmentation. Tyrosinase (TYR), a key rate-limiting enzyme in melanin production, is an important therapeutic target for these disorders. We investigated the TYR inhibitory activity of hydrolysates extracted from the muscle tissue of Takifugu flavidus (TFMH). We used computer-aided virtual screening to identify a novel peptide that potently inhibited melanin synthesis, simulated its binding mode to TYR, and evaluated functional efficacy in vitro and in vivo. TFMH inhibited the diphenolase activities of mTYR, reducing TYR substrate binding activity and effectively inhibiting melanin synthesis. TFMH indirectly reduced cAMP response element-binding protein phosphorylation in vitro by downregulating melanocortin 1 receptor expression, thereby inhibiting expression of the microphthalmia-associated transcription factor, further decreasing TYR, tyrosinase related protein 1, and dopachrome tautomerase expression and ultimately impeding melanin synthesis. In zebrafish, TFMH significantly reduced black spot formation. TFMH (200 μg/mL) decreased zebrafish TYR activity by 43% and melanin content by 52%. Molecular dynamics simulations over 100 ns revealed that the FGFRSP (T-6) peptide stably binds mushroom TYR via hydrogen bonds and ionic interactions. T-6 (400 μmol/L) reduced melanin content in B16F10 melanoma cells by 71% and TYR activity by 79%. In zebrafish, T-6 (200 μmol/L) inhibited melanin production by 64%. TFMH and T-6 exhibit good potential for the development of natural skin-whitening cosmetic products.

An increasing number of methods are being used to extract rock discontinuities from 3D point cloud data of rock surfaces. In this paper, a new method for automatic extraction of rock discontinuity based on an improved Naive Bayes classifier is proposed. The method first uses principal component analysis to find the normal vectors of the points, and then generates a certain number of random point sets around the selected training points for training the classifier. The trained, improved Naive Bayes classifier is based on point normal vectors and is able to automatically remove noise points due to various reasons in conjunction with the knee point algorithm, realizing high-precision extraction of the discontinuity sets. Subsequently, the individual discontinuities are segmented using a hierarchical density-based spatial clustering method with noise application. Finally, the PCA algorithm is used to complete the orientation by plane fitting the individual discontinuities. The method was applied in two cases, Kingston and Colorado, and the reliability and advantages of the new method were verified by comparing the results with those of previous research, and the discussion and analysis determined the optimal values of the relevant parameters in the algorithm.

Macrophages play an important role in managing the onset and progression of chronic inflammatory diseases. The primary objective of this study is to explore the antioxidant potential and anti-inflammatory properties of Sargassum hemiphyllum ethanol extract (SHE) and its fraction. SHE and its five constituent fractions were assessed for overall antioxidant capabilities and inhibitory effects on LPS-induced inflammation by modulating macrophages polarization in both RAW 264.7 macrophages and bone-marrow-derived macrophages (BMDM). Among the organic solvent fractions of SHE, the ethyl acetate fraction displayed the highest total phenolic content and total antioxidant capacity. Notably, the n-hexane (Hex) fraction showed the most substantial suppression of LPS-induced tumor necrosis factor α secretion in BMDM among the five fractions of SHE. The SHE and Hex fraction significantly reduced the heightened expression of pro-inflammatory cytokines and inflammation-inducible enzymes induced by LPS in RAW 264.7 macrophages. In particular, the SHE and Hex fraction inhibited M1 macrophage polarization by reducing the mRNA expression of M1 macrophage markers in macrophages that were polarized toward the M1 phenotype. Furthermore, the SHE and Hex fraction attenuated the induction in nuclear factor E2-related factor 2 and its target genes, which was accompanied by an alteration in antioxidant gene expression in M1-polarized BMDM. The findings suggest that both SHE and its Hex fraction exhibit inhibitory effects on LPS-triggered inflammation and oxidative stress by modulating the polarization of M1 macrophages within macrophage populations.

An affinity chromatography filler of CNBr-activated Sepharose 4B-immobilized ACE was used to purify ACE-inhibitory peptides from Takifugu flavidus protein hydrolysate (50 = 93.5 µmol·L−1) was selected. Molecular docking revealed that TLRFALHGME may interact with the active site of ACE through H-bond, hydrophobic, and electrostatic interactions. The total binding energy (ΔGbinding) of TLRFALHGME was estimated to be −82.7382 kJ·mol−1 by MD simulations, indicating the favorable binding of peptides with ACE. Furthermore, the binding affinity of TLRFALHGME to ACE was determined by surface plasmon resonance (SPR) with a Kd of 80.9 µmol, indicating that there was a direct molecular interaction between them. TLRFALHGME has great potential for the treatment of hypertension.

CHCHD2 mutations have been reported to cause Parkinson’s disease (PD) by a loss of function in mitochondria. Most reported mutations, however, were missense, which was not the perfect model for a study of haploinsufficiency. Here, a truncated mutation, CHCHD2 p.Pro53Alafs*38, was identified in one familial early-onset PD patient. We generated a human-induced pluripotent stem cell (iPSC) line WCHSCUi001-A from this patient. The generated iPSCs resembled human embryonic stem cells, expressed pluripotency markers, exhibited a normal karyotype and could be differentiated into three germ layers in vitro. This line will be valuable for investigating the disease mechanisms and screening candidate drugs.

The management of diabetic wounds is a therapeutic challenge in clinical settings. Current tissue engineering strategies for diabetic wound healing are insufficient, owing to the lack of an appropriate scaffold that can load a large number of stem cells and induce the interaction of stem cells to form granulation tissue. Herein we fabricated a book-shaped decellularized dermal matrix (BDDM), which shows a high resemblance to native dermal tissue in terms of its histology, microstructure, and ingredients, is non-cytotoxic and low-immunogenic, and allows adipose-derived stromal cell (ASC) attachment and proliferation. Then, a collagen-binding domain (CBD) capable of binding collagen was fused into basic fibroblast growth factor (bFGF) to synthetize a recombinant growth factor (termed as CBD–bFGF). After that, CBD–bFGF was tethered onto the collagen fibers of BDDM to improve its endothelial inducibility. Finally, a functional scaffold (CBD–bFGF/BDDM) was fabricated. In vitro and in vivo experiments demonstrated that CBD–bFGF/BDDM can release tethered bFGF with a sustained release profile, steadily inducing the interaction of stem cells down to endothelial differentiation. ASCs were cultured to form a cell sheet and then sandwiched by CBD–bFGF/BDDM, thus enlarging the number of stem cells loaded into the scaffold. Using a rat model, the ASC sheets sandwiched with CBD–bFGF/BDDM (ASCs/CBD–bFGF/BDDM) were capable of enhancing the formation of granulation tissue, promoting angiogenesis, and facilitating collagen deposition and remodeling. Therefore, the findings of this study demonstrate that ASCs/CBD–bFGF/BDDM could be applicable for diabetic wound healing.

RIG-I plays important roles in pathogen sensing and activation of antiviral innate immune responses in response to RNA viruses. RIG-I-mediated signaling must be precisely controlled to maintain innate immune signaling homeostasis. Previous studies demonstrated that lysine 63 (K63)-linked polyubiquitination of RIG-I is vital for its activation, but the mechanisms through which RIG-I is deubiquitinated to control innate immune responses are not well understood. Here we identified USP27X as a negative regulator of antiviral signaling in response to RNA viruses through siRNA library screening. Further functional studies indicated that USP27X negatively modulated RIG-I-mediated antiviral signaling in a deubiquitinase-dependent manner. Mechanistically, we found that USP27X removed K63-linked polyubiquitin chains from RIG-I to negatively modulate type I interferon signaling. Collectively, these studies uncover a novel negative regulatory role of USP27X in targeting RIG-I to balance innate immune responses.

Pufferfish is increasingly regarded by many as a delicacy. However, the tetrodotoxin (TTX) that accumulates in its body can be lethal upon consumption by humans. TTX is known to mainly accumulate in pufferfish skin, but the accumulation mechanisms are poorly understood. In this study, we aimed to explore the possible mechanism of TTX accumulation in the skin of the pufferfish Takifugu flavidus following treatment with TTX. Through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we detected 37.3% of toxin accumulated in the skin at the end of the rearing period (168 h). Transcriptome and proteome analyses revealed the mechanism and pathways of TTX accumulation in the skin of T. flavidus in detail. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes analyses strongly suggest that cardiac muscle contraction and adrenergic signaling in cardiomyocyte pathways play an important role in TTX accumulation. Moreover, some upregulated and downregulated genes, which were determined via RNA-Seq, were verified with qPCR analysis. This study is the first to use multi-omics profiling data to identify novel regulatory network mechanisms of TTX accumulation in the skin of pufferfish.

Alcalase, neutral protease, and pepsin were used to hydrolyze the skin of Takifugu flavidus. The T. flavidus hydrolysates (TFHs) with the maximum degree of hydrolysis (DH) and angiotensin-I-converting enzyme (ACE)-inhibitory activity were selected and then ultra-filtered to obtain fractions with components of different molecular weights (MWs) (50 kDa). The components with MWs < 1 kDa showed the strongest ACE-inhibitory activity with a half-maximal inhibitory concentration (IC50) of 0.58 mg/mL. Purification and identification using semi-preparative liquid chromatography, Sephadex G-15 gel chromatography, RP-HPLC, and LC–MS/MS yielded one new potential ACE-inhibitory peptide, PPLLFAAL (non-competitive suppression mode; IC50 of 28 μmmol·L−1). Molecular docking and molecular dynamics simulations indicated that the peptides should bind well to ACE and interact with amino acid residues and the zinc ion at the ACE active site. Furthermore, a short-term assay of antihypertensive activity in spontaneously hypertensive rats (SHRs) revealed that PPLLFAAL could significantly decrease the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of SHRs after intravenous administration. These results suggested that PPLLFAAL may have potential applications in functional foods or pharmaceuticals as an antihypertensive agent.

Angiotensin-I-converting enzyme (ACE) is a crucial enzyme or receptor that catalyzes the generation of potent vasopressor angiotensin II (Ang II). ACE inhibitory peptides from fish showed effective ACE inhibitory activity. In this study, we reported an ACE inhibitory peptide from Takifugu bimaculatus (T. bimaculatus), which was obtained by molecular docking with acid-soluble collagen (ASC) hydrolysate of T. bimaculatus. The antihypertensive effects and potential mechanism were conducted using Ang-II-induced human umbilical vein endothelial cells (HUVECs) as a model. The results showed that FNLRMQ alleviated the viability and facilitated apoptosis of Ang-II-induced HUVECs. Further research suggested that FNLRMQ may protect Ang-II-induced endothelial injury by regulating Nrf2/HO-1 and PI3K/Akt/eNOS signaling pathways. This study, herein, reveals that collagen peptide FNLRMQ could be used as a potential candidate compound for antihypertensive treatment, and could provide scientific evidence for the high-value utilization of marine resources including T. bimaculatus.

Platycladus orientalis L. (Cupressaceae) has a lifespan of thousands of years. Ancient trees have very high scientific, economic and cultural values. The senescence of ancient trees is a new research area but is poorly understood. Leaves are the primary and the most sensitive organ of a tree. To understand leaf structural response to tree senescence in ancient trees, experiments investigating the morphology, anatomy and ultrastructure were conducted with one-year leaves of ancient P. orientalis (ancient tree >2,000 years) at three different tree senescent levels (healthy, sub-healthy and senescent) at the world’s largest planted pure forest in the Mausoleum of Yellow Emperor, Shaanxi Province, China. Observations showed that leaf structure significantly changed with the senescence of trees. The chloroplast, mitochondria, vacuole and cell wall of mesophyll cells were the most significant markers of cellular ultrastructure during tree senescence. Leaf ultrastructure clearly reflected the senescence degree of ancient trees, confirming the visual evaluation from above-ground parts of trees. Understanding the relationships between leaf structure and tree senescence can support decision makers in planning the protection of ancient trees more promptly and effectively by adopting the timely rejuvenation techniques before the whole tree irreversibly recesses.

The von Willebrand factor type D (VWD) domain in vitellogenin has recently been found to bind tetrodotoxin. The way in which this protein domain associates with tetrodotoxin and participates in transporting tetrodotoxin in vivo remains unclear. A cDNA fragment of the vitellogenin gene containing the VWD domain from pufferfish (Takifugu flavidus) (TfVWD) was cloned. Using in silico structural and docking analyses of the predicted protein, we determined that key amino acids (namely, Val115, ASP116, Val117, and Lys122) in TfVWD mediate its binding to tetrodotoxin, which was supported by in vitro surface plasmon resonance analysis. Moreover, incubating recombinant rTfVWD together with tetrodotoxin attenuated its toxicity in vivo, further supporting protein–toxin binding and indicating associated toxicity-neutralizing effects. Finally, the expression profiling of TfVWD across different tissues and developmental stages indicated that its distribution patterns mirrored those of tetrodotoxin, suggesting that TfVWD may be involved in tetrodotoxin transport in pufferfish. For the first time, this study reveals the amino acids that mediate the binding of TfVWD to tetrodotoxin and provides a basis for further exploration of the molecular mechanisms underlying the enrichment and transfer of tetrodotoxin in pufferfish.

In this paper, we characterized and compared signal transmission performances of traces with different specifications of fiber weave. Measurements demonstrated that the dielectric constant, impedance fluctuation, and differential skew were all affected by fiber weave style. For flattened fiber weaves, the dielectric constant fluctuation reached 0.18, the impedance fluctuation amplitude was 1.0 Ω, and the differential skew was 2 ps/in. For conventional fiber weaves, the three parameters were 0.44, 2.5 Ω, and 4 ps/inch respectively. Flattened fiber weave was more favorable for high-speed signal control. We also discussed the other methods to improve the fiber weave effect. It turned out that NE-glass (new electronic glass) fiber weave also had better performance in reducing impedance fluctuation and differential skew. Furthermore, made the signal traces and fiber weave bundles with an angle or designing the long signal line parallel to the weft direction both are simple and effective methods to solve this problem.