Calcium Peroxide-Based Hydrogel Patch with Sustainable Oxygenation for Diabetic Wound Healing.

Nonhealing diabetic wounds are predominantly attributed to the inhibition of angiogenesis, re-epithelialization, and extracellular matrix (ECM) synthesis caused by hypoxia. Although oxygen therapy has demonstrated efficacy in promoting healing, its therapeutic impact remains suboptimal due to unsustainable oxygenation. Here, this work proposes an oxygen-releasing hydrogel patch embedded with polyethylene glycol-modified calcium peroxide microparticles, which sustainably releases oxygen for 7 days without requiring any supplementary conditions. The released oxygen effectively promotes cell migration and angiogenesis under hypoxic conditions as validated in vitro. The in vivo tests in diabetic mice models show that the sustainably released oxygen significantly facilitates the synthesis of ECM, induces angiogenesis, and decreases the expression of inflammatory cytokines, achieving a diabetic wound healing rate of 84.2% on day 7, outperforming the existing oxygen-releasing approaches. Moreover, the proposed hydrogel patch is designed with porous, soft, antibacterial, biodegradable, and storage stability for 15 days. The proposed hydrogel patch is expected to be promising in clinics treating diabetic wounds.

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists.

The farnesoid X receptor (FXR) has been recognized as a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). FXR agonists benefit NAFLD by modulating bile acid synthesis and transport, lipid metabolism, inflammation, and fibrosis pathways. However, there are still great challenges involved in developing safe and effective FXR agonists. To investigate the critical factors contributing to their activity on the FXR, 3D-QSAR molecular modeling was applied to a series of isoxazole derivatives, using comparative molecular field analysis (CoMFA (q2 = 0.664, r2 = 0.960, r2pred = 0.872)) and comparative molecular similarity indices analysis (CoMSIA (q2 = 0.706, r2 = 0.969, r2pred = 0.866)) models, which demonstrated strong predictive ability in our study. The contour maps generated from molecular modeling showed that the presence of hydrophobicity at the R2 group and electronegativity group at the R3 group in these compounds is crucial to their agonistic activity. A molecular dynamics (MD) simulation was carried out to further understand the binding modes and interactions between the FXR and its agonists in preclinical or clinical studies. The conformational motions of loops L: H1/H2 and L: H5/H6 in FXR-ligand binding domain (LBD) were crucial to the protein stability and agonistic activity of ligands. Hydrophobic interactions were formed between residues (such as LEU287, MET290, ALA291, HIS294, and VAL297) in helix H3 and ligands. In particular, our study found that residue ARG331 participated in salt bridges, and HIS447 participated in salt bridges and hydrogen bonds with ligands; these interactions were significant to protein-ligand binding. Eight new potent FXR agonists were designed according to our results, and their activities were predicted to be better than that of the first synthetic FXR agonist, GW4064.

Magnetic soft microfiberbots for robotic embolization.

Cerebral aneurysms and brain tumors are leading life-threatening diseases worldwide. By deliberately occluding the target lesion to reduce the blood supply, embolization has been widely used clinically to treat cerebral aneurysms and brain tumors. Conventional embolization is usually performed by threading a catheter through blood vessels to the target lesion, which is often limited by the poor steerability of the catheter in complex neurovascular networks, especially in submillimeter regions. Here, we propose magnetic soft microfiberbots with high steerability, reliable maneuverability, and multimodal shape reconfigurability to perform robotic embolization in submillimeter regions via a remote, untethered, and magnetically controllable manner. Magnetic soft microfiberbots were fabricated by thermal drawing magnetic soft composite into microfibers, followed by magnetizing and molding procedures to endow a helical magnetic polarity. By controlling magnetic fields, magnetic soft microfiberbots exhibit reversible elongated/aggregated shape morphing and helical propulsion in flow conditions, allowing for controllable navigation through complex vasculature and robotic embolization in submillimeter regions. We performed in vitro embolization of aneurysm and tumor in neurovascular phantoms and in vivo embolization of a rabbit femoral artery model under real-time fluoroscopy. These studies demonstrate the potential clinical value of our work, paving the way for a robotic embolization scheme in robotic settings.

A Laparoscopically Compatible Rapid-Adhesion Bioadhesive for Asymmetric Adhesion, Non-Pressing Hemostasis, and Seamless Seal.

Bioadhesive hydrogels offer unprecedented opportunities in hemostatic agents and tissue sealing; however, the application of existing bioadhesive hydrogels through narrow spaces to achieve strong adhesion in fluid-rich physiological environments is challenged either by undesired indiscriminate adhesion or weak wet tissue adhesion. Here, a laparoscopically compatible asymmetric adhesive hydrogel (aAH) composed of sprayable adhesive hydrogel powders and injectable anti-adhesive glue is proposed for hemostasis and to seal the bloody tissues in a non-pressing way, allowing for preventing postoperative adhesion. The powders can seed on the irregular bloody wound to rapidly absorb interfacial fluid, crosslink, and form an adhesive hydrogel to hemostatic seal (blood clotting time and tissue sealing in 10 s, ≈200 mm Hg of burst pressure in sealed porcine tissues). The aAH can be simply formed by crosslinking the upper powder with injectable glue to prevent postoperative adhesion (adhesive strength as low as 1 kPa). The aAH outperforms commercial hemostatic agents and sealants in the sealing of bleeding organs in live rats, demonstrating superior anti-adhesive efficiency. Further, the hemostatic seamless sealing by aAH succeeds in shortening the time of warm ischemia, decreasing the blood loss, and reducing the possibility of rebleeding in the porcine laparoscopic partial nephrectomy model.

Cytotoxic withanolides from the stems and leaves of Physalis ixocarpa.

The stems and leaves of the tomatillo (Physalis ixocarpa or Physalis philadelphica) were considered agricultural waste during the processing of tomatillo fruits. However, their potential value for utilization has not yet been explored. The investigation resulted in the isolation of a total of 29 withanolides, out of which 15 never reported. These newly discovered withanolides were then tested for their cytotoxicity against eight different human tumor cell lines. Compounds 2-3, 6-7, 17, 19, and 25-27 displayed encouraging cytotoxic effects. Given the potent inhibitory activity of physagulin C (25) on the proliferation of HepG2 cells in vitro, further investigation was conducted to determine its molecular mechanism. Physagulin C inhibited epithelial-mesenchymal transition (EMT) process through the down-regulation of the JAK2/STAT3 and PI3K/AKT/mTOR pathways. Withanolides presenting in the stems and leaves of tomatillo make the plant possess potential commercial importance. Therefore, tomatillos could be commercialized worldwide in the food and pharmaceutical industries.

Molecular targets and mechanisms of anti-cancer effects of withanolides.

Withanolides are a class of natural products with a steroidal lactone structure that exhibit a broad spectrum of anti-cancer effects. To date, several studies have shown that their possible mechanisms in cancer development and progression are associated with the regulation of cell proliferation, apoptosis, metastasis, and angiogenesis. Withanolides can also attenuate inflammatory responses, as well as modulate the genomic instability and energy metabolism of cancer cells. In addition, they may improve the safety and efficacy of cancer treatments as adjuvants to traditional cancer therapeutics. Herein, we summarize the molecular targets and mechanisms of withanolides in different cancers, as well as their current clinical studies on them.

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia.

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsⅢ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate AsⅢ in arsenic-nickel complex by nickel acetate gradient method. The AsⅢ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of AsⅢ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells' apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified AsⅢ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.

Structure-Based Drug Design and Synthesis of Pyrrolidine-2,5-diones as Novel TNF-α Inhibitors.

Tumor necrosis factor α (TNF-α) inhibitors are the treatment of choice for autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and Crohn's disease. Herein, some Benpyrine derivatives with stronger binding affinity, better activity, better solubility, and higher synthetic efficiency were identified using structure-based drug design and optimization strategies. Among the synthesized series of compounds, 10 directly binds to TNF-α and blocks the activation of TNF-α-trigged caspase and NF-κB signaling pathway. Compound 10 represents a promising scaffold for the further development of TNF-α inhibitors. Drug development based on compound 10 may provide a new strategy for the treatment of TNF-α-mediated autoimmune diseases.

Recent Advances in Perfluorocarbon-Based Delivery Systems for Cancer Theranostics.

Hypoxia is a key impediment encountered in the treatment of most solid tumors, leading to immune escape and therapeutic resistance. Perfluorocarbons (PFCs) have a unique electrical structure and are characterized by a high solubility for gases. PFC-based oxygen carriers have been evaluated for their ability to deliver oxygen effectively to hypoxic tissues, and significant clinical translation has been demonstrated. And due to the unique acoustic activity, PFCs have been employed to stabilize the injection of gas microbubbles (MBs) as clinical ultrasonography contrast agents. In contrast, the ultrasound and photothermally activatable PFC phase-shift nanodroplets (P-SNDs) represent a novel alternative to ultrasound imaging and hypoxia improvement. The PFC-based oxygen carriers may be utilized to improve the efficacy of cancer treatments based on synergistic radiotherapy (RT), chemotherapy (CMT), and photodynamic therapy (PDT) to reshape the tumor microenvironment through synergistic immunotherapy (IMT) and to achieve precise tumor diagnosis using acoustic imaging. This review described the characteristics of PFCs to provide an update on the design of PFC delivery systems used for oxygen delivery and ultrasound imaging to facilitate the treatment and diagnosis of tumors. The objective was to contribute to overcoming the obstacles encountered during PFC research and provide the developing prospects.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Minimally invasive bioprinting for in situ liver regeneration.

In situ bioprinting is promising for developing scaffolds directly on defect models in operating rooms, which provides a new strategy for in situ tissue regeneration. However, due to the limitation of existing in situ biofabrication technologies including printing depth and suitable bioinks, bioprinting scaffolds in deep dermal or extremity injuries remains a grand challenge. Here, we present an in vivo scaffold fabrication approach by minimally invasive bioprinting electroactive hydrogel scaffolds to promote in situ tissue regeneration. The minimally invasive bioprinting system consists of a ferromagnetic soft catheter robot for extrusion, a digital laparoscope for in situ monitoring, and a Veress needle for establishing a pneumoperitoneum. After 3D reconstruction of the defects with computed tomography, electroactive hydrogel scaffolds are printed within partial liver resection of live rats, and in situ tissue regeneration is achieved by promoting the proliferation, migration, and differentiation of cells and maintaining liver function in vivo.

Glucagon-like peptide-1 receptor agonists decrease hyperinsulinemia and hyperandrogenemia in dehydroepiandrosterone-induced polycystic ovary syndrome mice and are associated with mitigating inflammation and inducing browning of white adipose tissue†.

Polycystic ovary syndrome is a complicated hormonal and metabolic disorder. The exact pathogenesis of polycystic ovary syndrome is not clear thus far. Inflammation is involved in the progression of polycystic ovary syndrome. In addition, brown adipose tissue activity is impaired in polycystic ovary syndrome. Interestingly, glucagon-like peptide-1 receptor agonists have been reported to alleviate inflammation and promote browning of white adipose tissue. In this study, the effects of glucagon-like peptide-1 receptor agonists on polycystic ovary syndrome mice were explored. Mice were randomly assigned into four groups: control, dehydroepiandrosterone, dehydroepiandrosterone + liraglutide, and dehydroepiandrosterone + semaglutide. Relative indexes were measured after glucagon-like peptide-1 receptor agonist intervention. Glucose metabolism in polycystic ovary syndrome mice was ameliorated by glucagon-like peptide-1 receptor agonists, while the reproductive endocrine disorder of polycystic ovary syndrome mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes and the expression of inflammatory mediators in serum and ovaries of polycystic ovary syndrome mice were improved. Furthermore, toll-like receptor 4 and phosphorylation of nuclear factor-kappa B protein levels were decreased by glucagon-like peptide-1 receptor agonists in ovary. Notably, after glucagon-like peptide-1 receptor agonist intervention, the expression of brown adipose tissue marker levels was considerably raised in the white adipose tissue of polycystic ovary syndrome mice. In conclusion, the hyperinsulinemia and hyperandrogenemia of polycystic ovary syndrome mice were alleviated by glucagon-like peptide-1 receptor agonist intervention, which was associated with mitigating inflammation and stimulating adipose tissue browning.

Effects of glutenin and gliadin on the surface tackiness of frozen cooked noodles.

The mechanism of glutenin and gliadin on the surface tackiness of recooked frozen cooked noodles (FCNs) is unclear. In this study, the effects of glutenin and gliadin addition on the surface tackiness of FCNs were investigated. The addition of glutenin and gliadin reduced the surface tackiness (3.60 and 3.50 N) of recooked FCNs stored for 0 min. The addition of glutenin increased the rigidity of the gluten network and the compactness of FCNs and made the FCNs have a moisture-distribution with multilayers. The addition of gliadin increased the tensile distance of FCNs, restricted water migration during frozen storage, and increased the membranous structure of the gluten network to wrap starch particles. Glutenin had a stronger effect on reducing the surface tackiness of FCNs than gliadin. In the future, the synergistic effects of different proportions of glutenin and gliadin on the gluten network of FCNs could be further studied.

Shorter Cilia Length and Aberrant Ciliated Marker DNAI1 in Allergic Rhinitis.

Purpose: This study aimed to investigate whether the impaired ciliary length and aberrant ciliary ultrastructure marker, dynein axonemal intermediate chain 1 (DNAI1), are important pathological characteristics in nasal mucosa from patients with allergic rhinitis (AR). Patients and Methods: Biopsies were taken from the inferior turbinate (IT) of controls (n = 20) and patients with AR (n = 20). The ciliary length and the DNAI1 location patterns were assessed by using immunofluorescent staining. Three patterns of DNAI1 localization were defined using a semi-quantitative scoring system: normal (N), partial (P) and absence (A). Every individual section was assigned a score between 0 and 2 in each high-power field (5 fields per sample). The score of 0 = pattern N >70%; 1 = patterns N + P >70%; and 2 = pattern A ≥30%. The receiver operating characteristic (ROC) curve was used to evaluate the predicted value of DNAI1 score for AR. Results: The ciliary length was reduced by 33.3% in patients with AR compared with controls (P < 0.0001). The higher DNAI1 score was found in the AR group, with a median (first and third quartile) of 0.9 (0.4 and 1.08), which was 0.1 (0 and 0.76) in the control group (P = 0.0071). The ROC of DNAI1 was calculated based on the area under the curve of 0.74 (P = 0.0094). The cutoff value of ROC was 0.5833, with a sensitivity and specificity of 70%. Conclusion: These results suggested that the shorter ciliary length and aberrant localization of DNAI1 are potentially important pathological characteristics of the allergic nasal mucosa. The aberrant localization of DNAI1 may provide a novel candidate target for clinical management of AR.

Data-independent acquisition mass spectrometry identification of extracellular vesicle biomarkers for gastric adenocarcinoma.

Early diagnosis of gastric adenocarcinoma (GAC) can effectively prevent the progression of the disease and significantly improve patient survival. Currently, protein markers in clinical practice barely meet patient needs; it is therefore imperative to develop new diagnostic biomarkers with high sensitivity and specificity. In this study, we extracted extracellular vesicles (EV) from the sera of 33 patients with GAC and 19 healthy controls, then applied data-independent acquisition (DIA) mass spectrometry to measure protein expression profiles. Differential protein expression analysis identified 23 proteins showing expression patterns across different cancer stages, from which 15 proteins were selected as candidate biomarkers for GAC diagnosis. From this subset of 15 proteins, up to 6 proteins were iteratively selected as features and logistic regression was used to distinguish patients from healthy controls. Furthermore, serum-derived EV from a new cohort of 12 patients with gastric cancer and 18 healthy controls were quantified using the same method. A classification panel consisting of GSN, HP, ORM1, PIGR, and TFRC showed the best performance, with a sensitivity and negative predictive value (NPV) of 0.83 and 0.82. The area under curve (AUC) of the receiver operating characteristic (ROC) is 0.80. Finally, to facilitate the diagnosis of advanced stage GAC, we identified a 3-protein panel consisting of LYZ, SAA1, and F12 that showed reasonably good performance with an AUC of 0.83 in the validation dataset. In conclusion, we identified new protein biomarker panels from serum EVs for early diagnosis of gastric cancer that worth further validation.

Kynurenine-3-monooxygenase (KMO): From its biological functions to therapeutic effect in diseases progression.

Kynurenine-3-monooxygenase (KMO) is a mitochondrial enzyme involved in the eukaryotic kynurenine pathway (KP), which is the major catabolic route of tryptophan. KMO can convert the substrate kynurenine into the neurotoxin 3-hydroxykynurenine and quinolinic acid, which promote the production of toxic metabolites and formation of free radical in the blood, while decrease the neuroprotective metabolite kynurenic acid. As a result of branch point, KMO is predicted as an attractive drug target for several diseases, especially neurodegenerative diseases, psychosis, and cancer. This review mainly pays attention to KMO structure and the research of mechanisms and functions, with a particular emphasis on the roles of KMO in the pathogenesis of various conditions. Furthermore, we also summarized important KMO inhibitors to supporting their effects on these diseases, indicating the prospect to find novel KMO inhibitors for diseases therapy.

Magnetic soft robotic bladder for assisted urination.

The poor contractility of the detrusor muscle in underactive bladders (UABs) fails to increase the pressure inside the UAB, leading to strenuous and incomplete urination. However, existing therapeutic strategies by modulating/repairing detrusor muscles, e.g., neurostimulation and regenerative medicine, still have low efficacy and/or adverse effects. Here, we present an implantable magnetic soft robotic bladder (MRB) that can directly apply mechanical compression to the UAB to assist urination. Composed of a biocompatible elastomer composite with optimized magnetic domains, the MRB enables on-demand contraction of the UAB when actuated by magnetic fields. A representative MRB for a UAB in a porcine model is demonstrated, and MRB-assisted urination is validated by in situ computed tomography imaging after 14-day implantation. The urodynamic tests show a series of successful urination with a high pressure increase and fast urine flow. Our work paves the way for developing MRB to assist urination for humans with UABs.

Moderate Dose Irradiation Induces DNA Damage and Impairments of Barrier and Host Defense in Nasal Epithelial Cells in vitro.

Purpose: Radiotherapy (RT) is the mainstay treatment for head and neck cancers. However, chronic and recurrent upper respiratory tract infections and inflammation have been commonly reported in patients post-RT. The underlying mechanisms remain poorly understood. Method and Materials: We used a well-established model of human nasal epithelial cells (hNECs) that forms a pseudostratified layer in the air-liquid interface (ALI) and exposed it to single or repeated moderate dose γ-irradiation (1Gy). We assessed the DNA damage and evaluated the biological properties of hNECs at different time points post-RT. Further, we explored the host immunity alterations in irradiated hNECs with polyinosinic-polycytidylic acid sodium salt (poly [I:C]) and lipopolysaccharides (LPS). Results: IR induced DNA double strand breaks (DSBs) and triggered DNA damage response in hNECs. Repeated IR significantly reduced basal cell proliferation with low expression of p63/KRT5 and Ki67, induced cilia loss and inhibited mucus secretion. In addition, IR decreased ZO-1 expression and caused a significant decline in the transepithelial electrical resistance (TEER). Moreover, hyperreactive response against pathogen invasion and disrupted epithelial host defense can be observed in hNECs exposed to repeated IR. Conclusion: Our study suggests that IR induced prolonged structural and functional impairments of hNECs may contribute to patients post-RT with increased risk of developing chronic and recurrent upper respiratory tract infection and inflammation.

SIRT6 mediates multidimensional modulation to maintain organism homeostasis.

As a member of the silent information regulators (sirtuins) family, SIRT6 can regulate a variety of biological processes, including DNA repair, glucose and lipid metabolism, oxidative stress and lifespan, and so forth. SIRT6 maintains organism homeostasis in a variety of phenotypes by mediating epigenetic regulation and posttranslational modification of functional proteins. In this review, we outline the structural basis of SIRT6 enzyme activity and its mechanism of maintaining organism homeostasis in a variety of phenotypes, with an emphasis on the upstream that regulates SIRT6 expression and the downstream substrates. And how SIRT6 achieves multidimensional coordination to maintain organism homeostasis and even extend lifespan. We try to understand the regulatory mechanism of SIRT6 in different phenotypes from the perspective of protein interaction.