Hydrogel forming microneedles loaded with VEGF and Ritlecitinib/polyhydroxyalkanoates nanoparticles for mini-invasive androgenetic alopecia treatment.

Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.

Temporal development and potential interactions between the gut microbiome and resistome in early childhood.

Antimicrobial resistance-associated infections have become a major threat to global health. The gut microbiome serves as a major reservoir of bacteria with antibiotic resistance genes; whereas, the temporal development of gut resistome during early childhood and the factors influencing it remain unclear. Moreover, the potential interactions between gut microbiome and resistome still need to be further explored. In this study, we found that antibiotic treatment led to destabilization of the gut microbiome and resistome structural communities, exhibiting a greater impact on the resistome than on the microbiome. The composition of the gut resistome at various developmental stages was influenced by the abundance and richness of different core microbes. First exposure to antibiotics led to a dramatic increase in the number of opportunistic pathogens carrying multidrug efflux pump encoding genes. Multiple factors could influence the gut microbiome and resistome formation. The data may provide new insights into early-life research.IMPORTANCEIn recent years, the irrational or inappropriate use of antibiotics, an important life-saving medical intervention, has led to the emergence and increase of drug-resistant and even multidrug-resistant bacteria. It remains unclear how antibiotic exposure affects various developmental stages of early childhood and how gut core microbes under antibiotic exposure affect the structural composition of the gut resistome. In this study, we focused on early antibiotic exposure and analyzed these questions in detail using samples from infants at various developmental stages. The significance of our research is to elucidate the impact of early antibiotic exposure on the dynamic patterns of the gut resistome in children and to provide new insights for early-life studies.

Synergistic horizontal transfer of antibiotic resistance genes and transposons in the infant gut microbial genome.

Transposons, plasmids, bacteriophages, and other mobile genetic elements facilitate horizontal gene transfer in the gut microbiota, allowing some pathogenic bacteria to acquire antibiotic resistance genes (ARGs). Currently, the relationship between specific ARGs and specific transposons in the comprehensive infant gut microbiome has not been elucidated. In this study, ARGs and transposons were annotated from the Unified Human Gastrointestinal Genome (UHGG) and the Early-Life Gut Genomes (ELGG). Association rules mining was used to explore the association between specific ARGs and specific transposons in UHGG, and the robustness of the association rules was validated using the external database in ELGG. Our results suggested that ARGs and transposons were more likely to be relevant in infant gut microbiota compared to adult gut microbiota, and nine robust association rules were identified, among which Klebsiella pneumoniae, Enterobacter hormaechei_A, and Escherichia coli_D played important roles in this association phenomenon. The emphasis of this study is to investigate the synergistic transfer of specific ARGs and specific transposons in the infant gut microbiota, which can contribute to the study of microbial pathogenesis and the ARG dissemination dynamics.IMPORTANCEThe transfer of transposons carrying antibiotic resistance genes (ARGs) among microorganisms accelerates antibiotic resistance dissemination among infant gut microbiota. Nonetheless, it is unclear what the relationship between specific ARGs and specific transposons within the infant gut microbiota. K. pneumoniae, E. hormaechei_A, and E. coli_D were identified as key players in the nine robust association rules we discovered. Meanwhile, we found that infant gut microorganisms were more susceptible to horizontal gene transfer events about specific ARGs and specific transposons than adult gut microorganisms. These discoveries could enhance the understanding of microbial pathogenesis and the ARG dissemination dynamics within the infant gut microbiota.

Aging-related histone modification changes in brain function.

Aging can be defined as a decline of physiological function that is more difficult to reverse, characterized by the loss of the physiological integrity of tissues, organs, and cells of an organism over time. Normal aging is associated with structural and functional changes in the brain, involving neuronal apoptosis, synaptic structure, neurotransmission, and metabolism alterations, leading to impairment in sleep, cognitive functions, memory, learning, and motor and sensory systems. Histone modification is a significant aging-related epigenetic change that influences synaptic and mitochondrial function and immune and stress responses in the brain. This review discusses the changes in histone modifications that occur during brain aging, specifically methylation and acetylation, and the associated changes in gene transcription and protein expression. We observed that genes related to synaptic and mitochondrial function are downregulated in the aging brain, while genes related to immune response and inflammatory functions are upregulated.

Gender moderates the association between resting vagally mediated heart rate variability and attentional control.

Background: Women typically exhibit weaker attentional control ability than men. Lower resting vagally mediated heart rate variability (vmHRV) is thought to reflect the poorer function of the neurophysiological pathways underlying attentional control and thus, poorer attentional control ability. However, existing findings are inconsistent regarding the relationship between vmHRV and attentional control. Gender may be an important moderator. Objective: To examine whether gender moderates the relationship between resting vmHRV and attentional control, and to provide neurophysiological evidence for elucidating gender differences in attentional control ability. Methods: Two hundred and twenty college students completed the Attentional Control Scale to evaluate their attentional control ability. Resting vmHRV was assessed during a 5 min baseline period using an electrocardiographic amplifier (ECG100C) of the Biopac MP150 physiological recorder. Results: (1) There was no significant difference in the total scores of the Attentional Control Scale between men and women (t = 0.498, p > 0.05), but the scores of the attentional shifting dimension of women were significantly lower than those of men (t = 1.995, p < 0.05); (2) Resting vmHRV was significantly negatively correlated with attentional control in women(r = -0.233, p < 0.01), whereas the correlation was not significant in men; (3) Gender significantly moderated the relationship between resting vmHRV and attentional control (B = -3.088, 95% boot CI [-5.431, -0.745], t = -2.598, p < 0.05); (4) Among participants with lower resting vmHRV, there was no significant difference in attentional control between men and women (B = 2.284, 95% boot CI [-0.748, 5.310], p > 0.05), but among participants with higher resting vmHRV, men scored significantly higher than women in attentional control (B = -3.377, 95% boot CI [-6.406, -0.348], p < 0.05). Conclusion: Gender moderates the relationship between resting vmHRV and attentional control, with higher resting vmHRV in women reflecting a compensatory response to deficits in attentional control.

Polyhydroxyalkanoates: the natural biopolyester for future medical innovations.

Polyhydroxyalkanoates (PHAs) are a family of natural microbial biopolyesters with the same basic chemical structure and diverse side chain groups. Based on their excellent biodegradability, biocompatibility, thermoplastic properties and diversity, PHAs are highly promising medical biomaterials and elements of medical devices for applications in tissue engineering and drug delivery. However, due to the high cost of biotechnological production, most PHAs have yet to be applied in the clinic and have only been studied at laboratory scale. This review focuses on the biosynthesis, diversity, physical properties, biodegradability and biosafety of PHAs. We also discuss optimization strategies for improved microbial production of commercial PHAs via novel synthetic biology tools. Moreover, we also systematically summarize various medical devices based on PHAs and related design approaches for medical applications, including tissue repair and drug delivery. The main degradation product of PHAs, 3-hydroxybutyrate (3HB), is recognized as a new functional molecule for cancer therapy and immune regulation. Although PHAs still account for only a small percentage of medical polymers, up-and-coming novel medical PHA devices will enter the clinical translation stage in the next few years.

Recent advances of medical polyhydroxyalkanoates in musculoskeletal system.

Infection and rejection in musculoskeletal trauma often pose challenges for natural healing, prompting the exploration of biomimetic organ and tissue transplantation as a common alternative solution. Polyhydroxyalkanoates (PHAs) are a large family of biopolyesters synthesised in microorganism, demonstrating excellent biocompatibility and controllable biodegradability for tissue remodelling and drug delivery. With different monomer-combination and polymer-types, multi-mechanical properties of PHAs making them have great application prospects in medical devices with stretching, compression, twist in long time, especially in musculoskeletal tissue engineering. This review systematically summarises the applications of PHAs in multiple tissues repair and drug release, encompassing areas such as bone, cartilage, joint, skin, tendons, ligament, cardiovascular tissue, and nervous tissue. It also discusses challenges encountered in their application, including high production costs, potential cytotoxicity, and uncontrollable particle size distribution. In conclusion, PHAs offer a compelling avenue for musculoskeletal system applications, striking a balance between biocompatibility and mechanical performance. However, addressing challenges in their production and application requires further research to unleash their full potential in tackling the complexities of musculoskeletal regeneration.

Advances in modified hyaluronic acid-based hydrogels for skin wound healing.

Hyaluronic acid (HA) is a natural linear anionic polysaccharide with many unique characteristics such as excellent biocompatibility and biodegradability, native biofunctionality, hydrophilicity, and non-immunoreactivity. HA plays crucial roles in numerous biological processes, including the inflammatory response, cell adhesion, migration, proliferation, differentiation, angiogenesis, and tissue regeneration. All these properties and biological functions of HA make it an appealing material for the synthesis of biomedical hydrogels for skin wound healing. Since HA is not able to be gelate alone, it must be processed and functionalized through chemical modifications and crosslinking to generate versatile HA-based hydrogels. In recent years, different physical and chemical crosslinking strategies for HA-based hydrogels have been developed and designed, such as radical polymerization, Schiff-base crosslinking, enzymatic crosslinking, and dynamic covalent crosslinking, and they have broad and promising applications in skin wound healing and tissue engineering. In this review, we focus on chemical modification and crosslinking strategies for HA-based hydrogels, aiming to provide an overview of the latest advances in the development of HA-based hydrogels for skin wound healing. We summarize and propose feasible measures for the application of HA-based hydrogels for skin treatment, and discuss future application trends, which may ultimately promote HA-based hydrogels as a promising biomaterial for clinical applications.

Black SnO2-x based nanotheranostic for imaging-guided photodynamic/photothermal synergistic therapy in the second near-infrared window.

The shallow penetration depth of photothermal agents in the first near-infrared (NIR-I) window significantly limits their therapeutic efficiency. Multifunctional nanotheranostic agents in the second near-infrared (NIR-II) window have drawn extensive attention for their combined treatment of tumors. Here, for the first time, we created oxygen-deficient black SnO2-x with strong NIR (700-1200 nm) light absorption with NaBH4 reduction from white SnO2. Hyaluronic acid (HA) could selectively target cancer cells overexpressed CD44 protein. After modification with HA, the obtained nanotheranostic SnO2-x@SiO2-HA showed high dispersity in aqueous solution and good biocompatibility. SnO2-x@SiO2-HA was confirmed to simultaneously generate enough hyperthermia and reactive oxygen species with single NIR-II (1064 nm) light irradiation. Because HA is highly affined to CD44 protein, SnO2-x@SiO2-HA has specific uptake by overexpressed CD44 cells and can be accurately transferred to the tumor site. Furthermore, tumor growth was significantly inhibited following synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) with targeted specificity under the guidance of photoacoustic (PA) imaging using 1064 nm laser irradiation in vivo. Moreover, SnO2-x@SiO2-HA accelerated wound healing. This work prominently extends the therapeutic utilization of semiconductor nanomaterials by changing their nanostructures and demonstrates for the first time that SnO2-x based therapeutic agents can accelerate wound healing. STATEMENT OF SIGNIFICANCE: The phototherapeutic efficacy of nanotheranostics by NIR-I lightirradiation was restricted owing to the limitation of tissue penetration and maximum permissible exposure. To overcome these limitations, we hereby fabricated a NIR-IIlight-mediated multifunctional nanotheranostic based on SnO2-x. The introduction of oxygen vacancy strategy was employed to construct full spectrum responsive oxygen-deficient SnO2-x, endowing outstanding photothermal conversion, and remarkable production activity of reactive oxygen species under NIR-II light activation. Tumor growth was significantly inhibited following synergistic PDT/PTT with targeted specificity under the guidance of photoacoustic imaging using 1064 nm laser irradiation in vivo. Our strategy not only expands the biomedical application of SnO2, but also providea method to develop other inorganic metal oxide-based nanosystems for NIR-II light-activated phototheranostic of cancers.

Mechanisms of Reactive Oxygen Species Generated by Inorganic Nanomaterials for Cancer Therapeutics.

Recently, inorganic nanomaterials have received considerable attention for use in biomedical applications owing to their unique physicochemical properties based on their shapes, sizes, and surface characteristics. Photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemical dynamic therapy (CDT), which are cancer therapeutics mediated by reactive oxygen species (ROS), have the potential to significantly enhance the therapeutic precision and efficacy for cancer. To facilitate cancer therapeutics, numerous inorganic nanomaterials have been developed to generate ROS. This mini review provides an overview of the generation mechanisms of ROS by representative inorganic nanomaterials for cancer therapeutics, including the structures of engineered inorganic nanomaterials, ROS production conditions, ROS types, and the applications of the inorganic nanomaterials in cancer PDT, SDT, and CDT.