All-in-one hydrogel patches with sprayed bFGF-loaded GelMA microspheres for infected wound healing studies.

The current wound healing process faces numerous challenges such as bacterial infection, inflammation and oxidative stress. However, wound dressings used to promote wound healing, are not well suited to meet the clinical needs. Hyaluronic acid (HA) not only has excellent water absorption and good biocompatibility but facilitates cell function and tissue regeneration. Dopamine, on the other hand, increases the overall viscosity of the hydrogel and possesses antioxidant property. Furthermore, chitosan exhibits outstanding performance in antimicrobial, anti-inflammatory and antioxidant activities. Basic fibroblast growth factor (bFGF) is conducive to cell proliferation and migration, vascular regeneration and wound healing. Hence, we designed an all-in-one hydrogel patch containing dopamine and chitosan framed by hyaluronic acid (HDC) with sprayed gelatin methacryloyl (GelMA) microspheres loaded with bFGF (HDC-bFGF). The hydrogel patch exhibits excellent adhesive, anti-inflammatory, antioxidant and antibacterial properties. In vitro experiments, the HDC-bFGF hydrogel patch not only showed significant inhibitory effect on RAW cell inflammation and Staphylococcus aureus (S. aureus) growth but also effectively scavenged free radicals, in addition to promoting the migration of 3 T3 cells. In the mice acute infected wound model, the HDC-bFGF hydrogel patch adhered to the wound surface greatly accelerated the healing process via its anti-inflammatory and antioxidant activities, bacterial inhibition and pro-vascularization effects. Therefore, the multifunctional HDC-bFGF hydrogel patch holds great promise for clinical application.

Endotoxin tolerance ameliorates lipopolysaccharide/D-galactosamine-induced acute liver failure by negative regulation of the NF-κB/NLRP3 and activation of Nrf2/HO-1 via Sitr1.

Acute liver failure (ALF) is a potentially fatal disorder characterized by extensive hepatocyte necrosis and rapid decline in liver function. Numerous factors, including oxidative stress, cell death, and inflammatory responses, are associated with its pathogenesis. Endotoxin tolerance (ET) refers to the phenomenon in which the body or cells exhibit low or no response to high-dose lipopolysaccharide (LPS) stimulation after pre-stimulation with low-dose LPS. However, the specific mechanism through which ET regulates LPS/D-galactosamine (D-GalN)-induced ALF remains unclear. An ALF mouse model was established by intraperitoneal injection of D-GalN (400 mg/kg) and LPS (10 mg/kg). A low dose of LPS (0.1 mg/kg/d) was continuously administered to mice for 5 d before modeling to assess the protective effect of ET. The data from this study showed that ET alleviated the inflammatory response in mice with LPS/D-GalN-induced ALF. ET inhibited LPS-induced oxidative damage and pyroptosis in macrophages in vitro. RNA sequencing analysis showed that the NF-κB/NLRP3 pathway was linked to the anti-inflammatory and antioxidative effects of ET. Furthermore, using western blot, RT-qPCR, and immunofluorescence, we verified that ET inhibited the NF-κB/NLRP3 pathway and triggered the Nrf2/HO-1 signaling pathway to attenuate oxidative stress and cell pyroptosis. Sirt1 knockdown reversed this protective effect. In summary, our research elucidates that ET prevents ALF advancement by upregulating Sirt1 levels, triggering the Nrf2/HO-1 signaling axis, and suppressing the NF-κB/NLRP3 signaling cascade to inhibit oxidative stress and cell pyroptosis. Our results provide a mechanistic explanation for the protective effect of ET against ALF.

Rocaglamide regulates iron homeostasis by suppressing hepcidin expression.

The anemia of inflammation (AI) is characterized by the presence of inflammation and abnormal elevation of hepcidin. Accumulating evidence has proved that Rocaglamide (RocA) was involved in inflammation regulation. Nevertheless, the role of RocA in AI, especially in iron metabolism, has not been investigated, and its underlying mechanism remains elusive. Here, we demonstrated that RocA dramatically suppressed the elevation of hepcidin and ferritin in LPS-treated mice cell line RAW264.7 and peritoneal macrophages. In vivo study showed that RocA can restrain the depletion of serum iron (SI) and transferrin (Tf) saturation caused by LPS. Further investigation showed that RocA suppressed the upregulation of hepcidin mRNA and downregulation of Fpn1 protein expression in the spleen and liver of LPS-treated mice. Mechanistically, this effect was attributed to RocA's ability to inhibit the IL-6/STAT3 pathway, resulting in the suppression of hepcidin mRNA and subsequent increase in Fpn1 and TfR1 expression in LPS-treated macrophages. Moreover, RocA inhibited the elevation of the cellular labile iron pool (LIP) and reactive oxygen species (ROS) induced by LPS in RAW264.7 cells. These findings reveal a pivotal mechanism underlying the roles of RocA in modulating iron homeostasis and also provide a candidate natural product on alleviating AI.

Ultrasmall polyvinylpyrrolidone-modified iridium nanoparticles with antioxidant and anti-inflammatory activity for acute pancreatitis alleviation.

Acute pancreatitis (AP) is a common and serious acute inflammatory disease with high severity rate and mortality. Inflammation and oxidative stress play an extremely important role in the development of AP disease. Polyvinylpyrrolidone-modified iridium nanoparticles (IrNP-PVP) have multienzyme mimetic activity, and the aim of this article is to discuss the therapeutic alleviative effects of the ultrasmall nanozymes IrNP-PVP on AP through their antioxidant and anti-inflammatory effects. IrNP-PVP were proved to inhibit inflammation and scavenge reactive oxygen species (ROS) at the cellular level. The synthetic IrNP-PVP exhibit remarkable antioxidant and anti-inflammatory activities in the prevention and treatment of AP mice by establishing murine AP model, which can reduce the oxidative stress and inflammatory response. The results of this article indicated that the ultrasmall nanozymes IrNP-PVP effectively alleviate AP via scavenging ROS as well as suppressing inflammation both in vivo and in vitro, which might provide enormous promise for the AP management.

Exploring clinical applications and long-term effectiveness of benzodiazepines: An integrated perspective on mechanisms, imaging, and personalized medicine.

Benzodiazepines have been long-established treatments for various conditions, including anxiety disorders and insomnia. Recent FDA warnings emphasize the risks of misuse and dependence associated with benzodiazepines. This article highlights their benefits and potential drawbacks from various perspectives. It achieves this by explaining how benzodiazepines work in terms of neuroendocrinology, immunomodulation, sleep, anxiety, cognition, and addiction, ultimately improving their clinical effectiveness. Benzodiazepines play a regulatory role in the HPA axis and impact various systems, including neuropeptide Y and cholecystokinin. Benzodiazepines can facilitate sleep-dependent memory consolidation by promoting spindle wave activity, but they can also lead to memory deficits in older individuals due to reduced slow-wave sleep. The cognitive effects of chronic benzodiazepines use remain uncertain; however, no adverse findings have been reported in clinical imaging studies. This article aims to comprehensively review the evidence on benzodiazepines therapy, emphasizing the need for more clinical studies, especially regarding long-term benzodiazepines use.

Early-onset Alzheimer's disease with depression as the first symptom: a case report with literature review.

Background: Alzheimer's disease is a common neurodegenerative disease, and patients with early-onset Alzheimer's disease (onset age < 65 years) often have atypical symptoms, which are easily misdiagnosed and missed. Multimodality neuroimaging has become an important diagnostic and follow-up method for AD with its non-invasive and quantitative advantages. Case presentation: We report a case of a 59-year-old female with a diagnosis of depression at the age of 50 after a 46-year-old onset and a 9-year follow-up observation, who developed cognitive dysfunction manifested by memory loss and disorientation at the age of 53, and eventually developed dementia. Combined with neuropsychological scales (MMSE and MOCA scores decreased year by year and finally reached the dementia criteria) and the application of multimodal imaging. MRI showed that the hippocampus atrophied year by year and the cerebral cortex was extensively atrophied. 18F-FDG PET image showed hypometabolism in right parietal lobes, bilateral frontal lobes, bilateral joint parieto-temporal areas, and bilateral posterior cingulate glucose metabolism. The 18F-AV45 PET image showed the diagnosis of early-onset Alzheimer's disease was confirmed by the presence of Aß deposits in the cerebral cortex. Conclusion: Early-onset Alzheimer's disease, which starts with depression, often has atypical symptoms and is prone to misdiagnosis. The combination of neuropsychological scales and neuroimaging examinations are good screening tools that can better assist in the early diagnosis of Alzheimer's disease. Graphical Abstract.

Efficacy of electrical stimulation combined with ultrasound acupuncture therapy on treatment in patients with intrauterine adhesions: Study protocol for a placebo-controlled, single-blind, single-center, randomized trial.

BACKGROUND: Recurrence of postoperative adhesions is one of the most important factors for poor reproductive outcomes after hysteroscopic surgery, particularly in cases diagnosed with severe intrauterine adhesions (IUAs), where the recurrence rate is significantly higher. This study aims to explore the effectiveness of the electrical muscle stimulation combined with ultrasound acupuncture therapy in preventing the recurrence of IUAs and improving reproductive outcomes after operative hysteroscopy. METHODS: This study is a single-center, randomized controlled trial. A total of 210 patients with IUAs will be randomly assigned into 2 groups according to the ratio of 1:1, as the treatment group and the control group. Participants will receive the electrical muscle stimulation combined with ultrasound acupuncture therapy and oral hormone supplementation or receive oral hormone supplementation only. The primary outcome was the clinical response rate. There were 3 menstrual cycles of treatment and 3 menstrual cycles of follow-up in this study. ETHICS AND DISSEMINATION: This study protocol was approved by the Ethics Committee of the Reproductive Hospital of Guangxi Zhuang Autonomous Region (approval number: KY-LL-2022-06). This trial will be conducted in accordance with the principles of the Declaration of Helsinki as well as Good Clinical Practice. Study results will be disseminated at academic presentations and publications in peer-reviewed journals. TRIAL REGISTRATION: Registry name: Clinical value of electroultrasonic instrument in the treatment of IUAs and changes of related protein expression; Registry number: ChiCTR2200058901; registration date: April 19th, 2022; http://www.chictr.org.cn/showproj.aspx?proj=166155.

To roll or not to roll: nyctinastic behavior in young leaves of sacred lotus, Nelumbo nucifera.

Foliar nyctinasty refers to the daily rhythm in leaf orientation that occurs in evolutionarily diverse taxa. Traditionally, two mechanisms have been identified for the sleep movement of leaves, namely pulvinar and non-pulvinar. Here, we report upon some novel aspects of the nyctinastic behavior of leaves of the sacred lotus (Nelumbo nucifera Gaertn., Nelumbonaceae). We discovered that expanding leaves underwent daily oscillations in leaf orientation with a more vertical position at night, which is similar to many nyctinastic species. Additionally, however, the immature leaves were observed to exhibit a second type of nyctinasty that involved nocturnal rolling of leaf blades, which has not previously been reported. These two distinct mechanisms acted synergistically to make the young leaves more compact at night during a brief period (6 days) of leaf ontogenesis, during which petiole and blade showed substantial growth. We propose that the nyctinastic behavior of immature N. nucifera leaves is an adaptation that facilitates leaf growth at night by reducing mechanical interference with other leaves and plants.

Computational Identification of Immune- and Ferroptosis-Related LncRNA Signature for Prognosis of Hepatocellular Carcinoma.

Long non-coding RNAs (lncRNAs), which were implicated in many pathophysiological processes including cancer, were frequently dysregulated in hepatocellular carcinoma (HCC). Studies have demonstrated that ferroptosis and immunity can regulate the biological behaviors of tumors. Therefore, biomarkers that combined ferroptosis, immunity, and lncRNA can be a promising candidate bioindicator in clinical therapy of cancers. Many bioinformatics methods, including Pearson correlation analysis, univariate Cox proportional hazard regression analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox proportional hazard regression analysis were applied to develop a prognostic risk signature of immune- and ferroptosis-related lncRNA (IFLSig). Finally, eight immune- and ferroptosis-related lncRNAs (IFLncRNA) were identified to develop and IFLSig of HCC patients. We found the prognosis of patients with high IFLSig will be worse, while the prognosis of patients with low IFLSig will be better. The results provide an efficient method of uniting critical clinical information with immunological characteristics, enabling estimation of the overall survival (OS). Such an integrative prognostic model with high predictive power would have a notable impact and utility in prognosis prediction and individualized treatment strategies.

Changes and Clinical Significance of PIVKA-II in Hepatitis E Patients.

Increased protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels had been widely reported in patients with hepatocellular carcinoma (HCC) and chronic hepatitis. However, the role of PIVKA-II in hepatitis E is unclear. The aim of this study was to clarify the changes related with PIVKA-II and its clinical significance in hepatitis E. We enrolled 84 patients with hepatitis E hospitalized in two hospitals from December 2019 to June 2021. The levels of serum PIVKA-II and related serological indicators in the patients were determined to elucidate the role of PIVKA-II in hepatitis E. We observed that 59.51% (50/84) of patients showed an increase in PIVKA-II levels. Compared with the normal PIVKA-II group (<32 mAU/L), patients in the elevated PIVKA-II group (>32 mAU/L) had much higher serum total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), and total bile acid (TBA) levels (p < 0.05 for each). Compared with the slightly elevated PIVKA-II group (32-125 mAU/L), patients in the significantly elevated PIVKA-II group (>125 mAU/L) had much lower serum albumin, alanine aminotransferase (ALT), aspartate transaminase (AST) levels, and longer days for the hospital stay (p < 0.05 for each). The association of PIVKA-II with TBIL and DBIL was an inverted U-shaped curve with an inflection point at 199.1 mAU/L). The association of PIVKA-II with IBIL was a U-shaped curve with an inflection point at 18.6 mAU/L while the association of PIVKA-II with albumin was an inverted U-shaped curve with an inflection point at 18.6 mAU/L. With the improvement of the disease, PIVKA-II levels were gradually decreased and finally returned to normal. This trend was consistent with that of bilirubin, and a peak appeared in the third week. Therefore, findings from our study show that the increase in PIVKA-II levels can be related to the degree of hepatic insufficiency in patients with hepatitis E, wherein PIVKA-II levels are transiently increased, and the trend of change can be related to the disease course.

Bioinspired Ultrasensitive and Stretchable MXene-Based Strain Sensor via Nacre-Mimetic Microscale "Brick-and-Mortar" Architecture.

The development of wearable strain sensors with simultaneous large stretchability (strain >55%) and high sensitivity (gauge factor >100) remains a grand challenge to this day. Drawing on inspiration from nature, nacre has demonstrated outstanding mechanical properties, especially combining high strength and toughness, which is due in part to its delicate hierarchical layered architecture with rich interfacial interactions. We demonstrate that strain sensors based on this nacre-mimetic microscale "brick-and-mortar" architecture can simultaneously achieve ultrahigh sensitivity and large stretchability while performing well in linearity, reliability, long-term durability, and monotonicity. The bioinspired sensor demonstrated a gauge factor >200 over a range of working strains up to 83% and achieved a high gauge factor exceeding 8700 in the strain region of 76-83%. This successful combination of high sensitivity and large stretchability is attributed to (1) the microscale hierarchical architecture derived from the amalgamation of 2D titanium carbide (MXene) Ti3C2T x/1D silver nanowire "brick" and poly(dopamine)/Ni2+ "mortar" and (2) the synergistic toughing effects from interfacial interactions of hydrogen and coordination bonding, layer slippage, and molecular chain stretching. The synergistic behavior of the "brick" and "mortar" allows for controlled crack generation for high sensitivity but can also dissipate considerable loading energy to promote the stepwise propagation of cracks while stretching, guaranteeing the significant comprehensive sensing performance. Moreover, this bioinspired strain sensor is employed to monitor human activities under different motion states to demonstrate its feasibility for wearable, full-spectrum human health and motion monitoring systems.