Injectable tissue prosthesis for instantaneous closed-loop rehabilitation.

To construct tissue-like prosthetic materials, soft electroactive hydrogels are the best candidate owing to their physiological mechanical modulus, low electrical resistance and bidirectional stimulating and recording capability of electrophysiological signals from biological tissues1,2. Nevertheless, until now, bioelectronic devices for such prostheses have been patch type, which cannot be applied onto rough, narrow or deep tissue surfaces3-5. Here we present an injectable tissue prosthesis with instantaneous bidirectional electrical conduction in the neuromuscular system. The soft and injectable prosthesis is composed of a biocompatible hydrogel with unique phenylborate-mediated multiple crosslinking, such as irreversible yet freely rearrangeable biphenyl bonds and reversible coordinate bonds with conductive gold nanoparticles formed in situ by cross-coupling. Closed-loop robot-assisted rehabilitation by injecting this prosthetic material is successfully demonstrated in the early stage of severe muscle injury in rats, and accelerated tissue repair is achieved in the later stage.

Ferritin Nanoshuttle for Long-Lasting Self-Healing of Phenolic Hydrogels.

Herein, we highlight a novel finding that ferritin can play a crucial role in the "self-healing lifetime" of soft phenolic materials. Ferritin interacts with a catechol-functionalized polymer to form a self-healable and adhesive hydrogel bidirectionally by providing and retrieving Fe3+. As a result of its unique role as a nanoshuttle to store and release iron, ferritin significantly increases the self-healing lifetime of the hydrogel compared with that afforded by catechol-Fe3+ coordination through direct Fe3+ addition without ferritin. Ferritin also induces stable oxidative coupling between catechol moieties following metal coordination, which contributes to double cross-linking networks of catechol-catechol adducts and catechol-Fe3+ coordination. Thus, ferritin-mediated cross-linking can provide phenolic hydrogels with the advantages of hydrogels prepared by both metal coordination and oxidative coupling, thereby overcoming the limitations of the current cross-linking methods of phenolic hydrogels and broadening their versatility in biomedical applications.

Pomegranate Polyphenol-Derived Injectable Therapeutic Hydrogels to Enhance Neuronal Regeneration.

Drug delivery for the treatment of neurological disorders has long been considered complex due to difficulties in ensuring the drug targeting on a specific site of the damaged neural tissues and its prolonged release. A syringe-injectable polymeric hydrogel with mechanical moduli matching those of brain tissues can provide a solution to deliver the drugs to the specific region through intracranial injections in a minimally invasive manner. In this study, an injectable therapeutic hydrogel with antioxidant pomegranate polyphenols, punicalagin, is reported for efficient neuronal repair. The hydrogels composed of tyramine-functionalized hyaluronic acid and collagen crosslinked by enzymatic reactions have great injectability with high shape fidelity and effectively encapsulate the polyphenol therapeutics. Furthermore, the punicalagin continuously released from the hydrogels over several days could enhance the growth and differentiation of the neurons. Our findings for efficacy of the polyphenol therapeutic-encapsulated injectable hydrogels on neuronal regeneration would be promising for designing a new type of antioxidative biomaterials in brain disorder therapy.

TRPM7 channels regulate breathing during sleep in obesity by acting peripherally in the carotid bodies.

Sleep-disordered breathing (SDB) affects over 50% of obese individuals. Exaggerated hypoxic chemoreflex is a cardinal trait of SDB in obesity. We have shown that leptin acts in the carotid bodies (CB) to augment chemoreflex and that leptin activates the transient receptor potential melastatin 7 (TRPM7) channel. However, the effect of leptin-TRPM7 signalling in CB on breathing and SDB has not been characterized in diet-induced obesity (DIO). We hypothesized that leptin acts via TRPM7 in the CB to increase chemoreflex leading to SDB in obesity. DIO mice were implanted with EEG/EMG electrodes and transfected with Leprb short hairpin RNA (shRNA) or Trpm7 shRNA vs. control shRNA in the CB area bilaterally. Mice underwent a full-polysomnography and metabolic studies at baseline and after transfection. Ventilatory responses to hypoxia and hypercapnia were assessed during wakefulness. Leprb and Trpm7 were upregulated and their promoters were demethylated in the CB of DIO mice. Leprb knockdown in the CB did not significantly affect ventilation. Trpm7 knockdown in the CB stimulated breathing during sleep in normoxia. These effects were not driven by changes in CB chemosensitivity or metabolism. Under sustained hypoxia, Trpm7 shRNA in the CB augmented ventilation during sleep, but decreased oxyhaemoglobin saturation. We conclude that the suppression of TRPM7 in the CB improved sleep-related hypoventilation and that the respiratory effects of CB TRPM7 channels in obesity are independent of leptin. TRPM7 signalling in the CB could be a therapeutic target for the treatment of obesity-related SDB. KEY POINTS: The leptin-TRPM7 axis in the carotid bodies may play an important role in the pathogenesis of sleep-disordered breathing. TRPM7 channels regulate breathing during sleep by acting peripherally in the carotid bodies. Suppression of TRPM7 signalling in the carotid bodies improves the obesity-induced hypoventilation in mice. Pharmacological blockade of TRPM7 channels in the carotid bodies could be a therapy for sleep-disordered breathing in obesity.

pH-Universal Catechol-Amine Chemistry for Versatile Hyaluronic Acid Bioadhesives.

Catechol, a major mussel-inspired underwater adhesive moiety, has been used to develop functional adhesive hydrogels for biomedical applications. However, oxidative catechol chemistry for interpolymer crosslinking and adhesion is exclusively effective under alkaline conditions, with limited applications in non-alkaline conditions. To overcome this limitation, pH-universal catechol-amine chemistry to recapitulate naturally occurring biochemical events induced by pH variation in the mussel foot is suggested. Aldehyde moieties are introduced to hyaluronic acid (HA) by partial oxidation, which enables dual-mode catechol tethering to the HA via both stable amide and reactive secondary amine bonds. Because of the presence of additional reactive amine groups, the resultant aldehyde-modified HA conjugated with catechol (AH-CA) is effectively crosslinked in acidic and neutral pH conditions. The AH-CA hydrogel exhibits not only fast gelation via active crosslinking regardless of pH conditions, but also strong adhesion and excellent biocompatibility. The hydrogel enables rapid and robust wound sealing and hemostasis in neutral and alkaline conditions. The hydrogel also mediates effective therapeutic stem cell and drug delivery even in dynamic and harsh environments, such as a motile heart and acidic stomach. Therefore, the AH-CA hydrogel can serve as a versatile biomaterial in a wide range of pH conditions in vivo.

Leptin Induces Epigenetic Regulation of Transient Receptor Potential Melastatin 7 in Rat Adrenal Pheochromocytoma Cells.

Obesity elevates the plasma level of leptin, which has been associated with hypertension. Our recent studies in mice demonstrated that leptin increases blood pressure by activating the carotid sinus nerve, which transmits the chemosensory input from carotid bodies (CBs) to the medullary centers, and that the effect of leptin is mediated via Trpm7 (TRP [transient receptor potential] melastatin 7) channels in CB glomus cells. We also found that Trpm7 overexpression and Trpm7 promoter demethylation in CBs correlate positively with the hyperleptinemia and leptin receptor overexpression in CBs. Hence, we postulated that leptin epigenetically regulates Trpm7 expression in CBs. We addressed our hypothesis by using rat adrenal pheochromocytoma (PC12) cells as a model of CB glomus cells. PC12 cells expressing LEPRb (long, active form of leptin receptor) showed dramatic induction of the promoter activity and expression of Trpm7 upon leptin treatment. The increased Trpm7 expression coincided with the reduction of CpG site-specific methylation and trimethylation of H3K27 (H3 [histone 3] K27 [lysine 27]) and the increase of acetylation of H3K27 and trimethylation of H3K4 (H3 lysine 4) at the Trpm7 promoter. The inhibitor of STAT3 (signal transducer and activator of transcription 3) signaling, SD1008, reversed the leptin-induced Trpm7 promoter activity via modulations of the binding of pSTAT3 (phosphorylated STAT3) and DNMT3B (DNA methyltransferase 3B) and modifications of H3K27 and H3K4 at the Trpm7 promoter. Our results suggest that leptin-activated pSTAT3 epigenetically regulates the transcription of Trpm7 through DNA methylation and histone modifications. Because epigenetic changes are reversible, targeting epigenetic modifications of Trpm7 may serve as a new therapeutic approach for the treatment of hypertension in obesity.

Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body.

RATIONALE: Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel. OBJECTIVE: To examine if leptin induces hypertension acting on the CB Trpm7. METHODS AND RESULTS: C57BL/6J (n=79), leptin receptor (LepRb) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepRb gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and Trpm7 small hairpin RNA applied to CBs. Leprb overexpression in CB of Leprb-deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression, and induced hypertension. CONCLUSIONS: We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.

Intranasal Leptin Relieves Sleep-disordered Breathing in Mice with Diet-induced Obesity.

RATIONALE: Leptin treats upper airway obstruction and alveolar hypoventilation in leptin-deficient ob/ob mice. However, obese humans and mice with diet-induced obesity (DIO) are resistant to leptin because of poor permeability of the blood-brain barrier. We propose that intranasal leptin will bypass leptin resistance and treat sleep-disordered breathing in obesity. OBJECTIVES: To assess if intranasal leptin can treat obesity hypoventilation and upper airway obstruction during sleep in mice with DIO. METHODS: Male C57BL/6J mice were fed with a high-fat diet for 16 weeks. A single dose of leptin (0.4 mg/kg) or BSA (vehicle) were administered intranasally or intraperitoneally, followed by either sleep studies (n = 10) or energy expenditure measurements (n = 10). A subset of mice was treated with leptin daily for 14 days for metabolic outcomes (n = 20). In a separate experiment, retrograde viral tracers were used to examine connections between leptin receptors and respiratory motoneurons. MEASUREMENTS AND MAIN RESULTS: Acute intranasal, but not intraperitoneal, leptin decreased the number of oxygen desaturation events in REM sleep, and increased ventilation in non-REM and REM sleep, independently of metabolic effects. Chronic intranasal leptin decreased food intake and body weight, whereas intraperitoneal leptin had no effect. Intranasal leptin induced signal transducer and activator of transcription 3 phosphorylation in hypothalamic and medullary centers, whereas intraperitoneal leptin had no effect. Leptin receptor-positive cells were synaptically connected to respiratory motoneurons. CONCLUSIONS: In mice with DIO, intranasal leptin bypassed leptin resistance and significantly attenuated sleep-disordered breathing independently of body weight.

Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response.

KEY POINTS: Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb , was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE ) and the hypoxic ventilatory response (HVR) has not been sufficiently studied. We report that LepRb is present in approximately 74% of the CB glomus cells. Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo. Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation. Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR. We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity. ABSTRACT: Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb , but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE ) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb -deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δ FIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non-rapid eye movement (20.1 vs. -27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.

Safety and efficacy evaluations of an adeno-associated virus variant for preparing IL10-secreting human neural stem cell-based therapeutics.

Gene therapy technologies are inevitably required to boost the therapeutic performance of cell therapies; thus, validating the efficacy of gene carriers specifically used for preparing cellular therapeutics is a prerequisite for evaluating the therapeutic capabilities of gene and cell combinatorial therapies. Herein, the efficacy of a recombinant adeno-associated virus derivative (rAAVr3.45) was examined to evaluate its potential as a gene carrier for genetically manipulating interleukin-10 (IL10)-secreting human neural stem cells (hNSCs) that can potentially treat ischemic injuries or neurological disorders. Safety issues that could arise during the virus preparation or viral infection were investigated; no replication-competent AAVs were detected in the final cell suspensions, transgene expression was mostly transient, and no severe interference on endogenous gene expression by viral infection occurred. IL10 secretion from hNSCs infected by rAAVr3.45 encoding IL10 did not alter the transcriptional profile of any gene by more than threefold, but the exogenously boosted IL10 was sufficient to provoke immunomodulatory effects in an ischemic brain injury animal model, thereby accelerating the recovery of neurological deficits and the reduction of brain infarction volume. This study presents evidence that rAAVr3.45 can be potentially used as a gene carrier to prepare stem cell therapeutics.

Complete prevention of blood loss with self-sealing haemostatic needles.

Bleeding is largely unavoidable following syringe needle puncture of biological tissues and, while inconvenient, this typically causes little or no harm in healthy individuals. However, there are certain circumstances where syringe injections can have more significant side effects, such as uncontrolled bleeding in those with haemophilia, coagulopathy, or the transmission of infectious diseases through contaminated blood. Herein, we present a haemostatic hypodermic needle able to prevent bleeding following tissue puncture. The surface of the needle is coated with partially crosslinked catechol-functionalized chitosan that undergoes a solid-to-gel phase transition in situ to seal punctured tissues. Testing the capabilities of these haemostatic needles, we report complete prevention of blood loss following intravenous and intramuscular injections in animal models, and 100% survival in haemophiliac mice following syringe puncture of the jugular vein. Such self-sealing haemostatic needles and adhesive coatings may therefore help to prevent complications associated with bleeding in more clinical settings.

Dynamic Bonds between Boronic Acid and Alginate: Hydrogels with Stretchable, Self-Healing, Stimuli-Responsive, Remoldable, and Adhesive Properties.

For the increasing demand of soft materials with wide ranges of applications, hydrogels have been developed exhibiting variety of functions (e.g., stretchable, self-healing, stimuli-responsive, and etc.). So far, add-in components such as inorganic nanoparticles, carbon materials, clays, and many others to main polymers have been used to achieve various unique functions of hydrogels. The multicomponent hydrogel systems often exhibit batch-dependent inconsistent results and problems in multicomponent mixings, require labors during preparations, and accompany unpredictable cross-talk between the added components. Here, we developed 'single polymeric component', alginate-boronic acid (alginate-BA) hydrogel to overcome the aforementioned problems. It exhibits unprecedented multifunctionalities simultaneously, such as high stretchability, self-healing, shear-thinning, pH- and glucose-sensitivities, adhesive properties, and reshaping properties. Multifunctionalities of alginate-BA hydrogel is resulted from the reversible inter- and intramolecular interactions by dynamic equilibrium of boronic acid-diol complexation and dissociation, which was proved by single molecule level Atomic Force Microscopy (AFM) pulling experiments. We also found that the alginate-BA gel showed enhanced in vivo retentions along gastrointestinal (GI) tract. Our findings suggest that rational polymer designs can result in minimizing the number of a participating component for multifunctional hydrogels, instead of increasing complexity by adding various additional components.

SpONGE: spontaneous organization of numerous-layer generation by electrospray.

Advanced technologies that can mimic hierarchical architectures found in nature can provide pivotal clues for elucidating numerous biological mechanisms. Herein, a novel technology, spontaneous organization of numerous-layer generation by electrospray (SpONGE), was developed to create self-assembled and multilayered fibrous structures. The simple inclusion of salts in a polymer solution prior to electrospraying was key to mediating the structural versatilities of the fibrous structures. The SpONGE matrix demonstrated great potential as a crucial building block capable of inducing sequential, localized drug delivery or orchestrating cellular distribution in vivo, thereby expanding its scope of use to cover a variety of biomedical applications.

Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy.

Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and is associated with dysregulation of glucose metabolism. We developed a novel model of clinically realistic IH in mice to test the hypothesis that IH causes hyperglycemia, glucose intolerance, and insulin resistance via activation of the sympathetic nervous system. Mice were exposed to acute hypoxia of graded severity (21, 14, 10, and 7% O2) or to IH of graded frequency [oxygen desaturation index (ODI) of 0, 15, 30, or 60, SpO2 nadir 80%] for 30 min to measure levels of glucose fatty acids, glycerol, insulin, and lactate. Glucose tolerance tests and insulin tolerance tests were then performed under each hypoxia condition. Next, we examined these outcomes in mice that were administered phentolamine (α-adrenergic blockade) or propranolol (ß-adrenergic blockade) or that underwent adrenal medullectomy before IH exposure. In all experiments, mice were maintained in a thermoneutral environment. Sustained and IH induced hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent fashion. Only severe hypoxia (7% O2) increased lactate, and only frequent IH (ODI 60) increased plasma fatty acids. Phentolamine or adrenal medullectomy both prevented IH-induced hyperglycemia and glucose intolerance. IH inhibited glucose-stimulated insulin secretion, and phentolamine prevented the inhibition. Propranolol had no effect on glucose metabolism but abolished IH-induced lipolysis. IH-induced insulin resistance was not affected by any intervention. Acutely hypoxia causes hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent manner. During IH, circulating catecholamines act upon α-adrenoreceptors to cause hyperglycemia and glucose intolerance.

Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4.

RATIONALE: Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown. OBJECTIVES: To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1). METHODS: ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle. MEASUREMENTS AND MAIN RESULTS: In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue. CONCLUSIONS: HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.

Meta-analysis of single-case design research: Application of multilevel modeling.

This study describes the benefits and challenges of meta-analyses of single-case design research using multilevel modeling. The researchers illustrate procedures for conducting meta-analyses using four-level multilevel modeling through open-source R code. The demonstration uses data from multiple-baseline or multiple-probe across-participant single-case design studies (n = 21) on word problem instruction for students with learning disabilities published between 1975 and 2023. Researchers explore changes in levels and trends between adjacent phases (baseline vs. intervention and intervention vs. maintenance) using the sample data. The researchers conclude that word problem solving of students with learning disabilities varies based on the complexity of the word problem measures involving single-word problem, mixed-word problem, and generalization questions. These moderating effects differed across adjacent phases. These findings extend previous literature on meta-analyses methodology by describing how multilevel modeling can be used to compare the impacts of time-varying predictors within and across cases when analyzing single-case design studies. Future researchers may want to use this methodology to explore the roles of time-varying predictors as well as case or study-level moderators. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Carotid body denervation improves hyperglycemia in obese mice.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr.NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.

Smart Contact Lens for Colorimetric Visualization of Glucose Levels in the Body Fluid.

Frequent blood glucose monitoring is a crucial routine for diabetic patients. Traditional invasive methods can cause discomfort and pain and even pose a risk of infection. As a result, researchers have been exploring noninvasive techniques. However, a limited number of products have been developed for the market due to their high cost. In this study, we developed a low-cost, highly accessible, and noninvasive contact lens-based glucose monitoring system. We functionalized the surface of the contact lens with boronic acid, which has a strong but reversible binding affinity to glucose. To achieve facile conjugation of boronic acid, we utilized a functional coating layer called poly(tannic acid). The functionalized contact lens binds to glucose in body fluids (e.g., tear) and releases it when soaked in an enzymatic cocktail, allowing for the glucose level to be quantified through a colorimetric assay. Importantly, the transparency and oxygen permeability of the contact lens, which are crucial for practical use, were maintained after functionalization, and the lenses showed high biocompatibility. Based on the analysis of colorimetric data generated by the smartphone application and ultraviolet-visible (UV-vis) spectra, we believe that this contact lens has a high potential to be used as a smart diagnostic tool for monitoring and managing blood glucose levels.

Trackable Liposomes for In Vivo Delivery Tracing toward Personalized Medicine Care under NIR Light on Skin Tumor.

We report an near-infrared (NIR)-trackable and therapeutic liposome with skin tumor specificity. Liposomes with a hydrodynamic diameter of ∼20 nm are tracked under the vein visualization imaging system in the presence of loaded paclitaxel and NIR-active agents. The ability to track liposome nanocarriers is recorded on the tissue-mimicking phantom model and in vivo mouse veins after intravenous administration. The trackable liposome delivery provides in vitro and in vivo photothermal heat (∼40 °C) for NIR-light-triggered area-specific chemotherapeutic release. This approach can be linked with a real-time vein-imaging system to track and apply area-specific local heat, which hitchhikes liposomes from the vein and finally releases them at the tumor site. We conducted studies on mice skin tumors that indicated the disappearance of tumors visibly and histologically (H&E stains). The ability of nanocarriers to monitor after administration is crucial for improving the effectiveness and specificity of cancer therapy, which could be achieved in the trackable delivery system.

Sticky and Strain-Gradient Artificial Epineurium for Sutureless Nerve Repair in Rodents and Nonhuman Primates.

The need for the development of soft materials capable of stably adhering to nerve tissues without any suturing followed by additional damages is at the fore at a time when success in postoperative recovery depends largely on the surgical experience and/or specialized microsuturing skills of the surgeon. Despite fully recognizing such prerequisite conditions, designing the materials with robust adhesion to wet nerves as well as acute/chronic anti-inflammation remains to be resolved. Herein, a sticky and strain-gradient artificial epineurium (SSGAE) that overcomes the most critically challenging aspect for realizing sutureless repair of severely injured nerves is presented. In this regard, the SSGAE with a skin-inspired hierarchical structure entailing strain-gradient layers, anisotropic Janus layers including hydrophobic top and hydrophilic bottom surfaces, and synergistic self-healing capabilities enables immediate and stable neurorrhaphy in both rodent and nonhuman primate models, indicating that the bioinspired materials strategy significantly contributes to translational medicine for effective peripheral nerve repair.