Such porous materials not only effectively avoid unwanted active site accumulation induced quenching (ACQ) and offer sufficient contact with guest molecules to favor their exchange and diffusion, but more importantly, finely tune their band energy and optical properties via formation of covalently linked crystalline domains. [2] In this study, this strategy was utilized to form a series of multienzyme-mimicking covalent organic frameworks by decorating metal ions (Cu, Fe and Ni) into the COF backbone, where their optical properties, including band energy, lifetime, and lightabsorption properties, were finely tuned to achieve excellent enzyme-mimicking catalytic performance, including superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPx) activities. As a result, one member, COF-909-Cu was revealed to be a good pyroptosis inducer for boosting cancer immunotherapy for the first time.As a form of noninflammatory programmed cell death (PCD), the efficacy of apoptosis is usually limited due to the existence of apoptosis resistance in cancer cells, leading to unsatisfactory therapeutic performance. [3] In contrast to apoptosis, pyroptosis and ferroptosis are immunogenic PCD and are recently proven to be a powerful strategy to combat cancer, owing to their favorable ability to prime antitumor immune responses by releasing sufficient danger-associated molecular patterns (DAMPs). [4] Attempts have been made to isolate iron ions into the building block of MOF to facilitate the pyroptosiseliciting process and activate the immune system. [5] Recently, COFs were also utilized as new photosensitizers (PSs) for chemodynamic therapy (CDT)-triggered ferroptosis. [6] The potential of inducing pyroptosis by using COF materials, however, is rarely explored due to the stringent requirement for an acute inflammatory response. Moreover, the hypoxic character in the tumor microenvironment (TME) and limited penetration depth also restrict the reactive oxygen species (ROS) generation efficiency of photodynamic therapy (PDT). [7] CDT, which involves the consumption of intracellular hydrogen peroxide (H 2 O 2 ) to produce hydroxyl radicals (•OH), the most harmful ROS, is promising for eliciting acute inflammatory responses and inducing pyroptosis due to the advantages of not relying The engineering of a series of multienzyme-mimicking covalent organic frameworks (COFs), COF-909-Cu, COF-909-Fe, and COF-909-Ni, as pyroptosis inducers, remodeling the tumor microenvironment to boost cancer immunotherapy, is reported. Mechanistic studies reveal that these COFs can serve as hydrogen peroxide (H 2 O 2 ) homeostasis disruptors to elevate intracellular H 2 O 2 levels, and they not only exhibit excellent superoxide dismutase (SOD)-mimicking activity and convert superoxide radicals (O 2 •− ) to H 2 O 2 to facilitate H 2 O 2 generation, but also possess outstanding glutathione peroxidase (GPx)-mimicking activity and deplete glutathione (GSH) to alleviate the scavenging of H 2 O 2 . Meanwhile, the outstanding photothermal the...

The nucleus tractus solitarius (NTS) integrates

Glucagon-like peptide-1 (GLP-1) increases pancreatic insulin secretion via a direct action on pancreatic beta-cells. A high density of GLP-1-containing neurons and receptors is also present in brain stem vagal circuits; therefore, the aims of the present study were to investigate 1) whether identified pancreas-projecting neurons of the dorsal motor nucleus of the vagus (DMV) respond to exogenously applied GLP-1, 2) the mechanism(s) of action of GLP-1, and 3) whether the GLP-1-responsive neurons (putative modulators of endocrine secretion) could be distinguished from DMV neurons responsive to peptides that modulate pancreatic exocrine secretion, specifically pancreatic polypeptide (PP). Whole cell recordings were made from identified pancreas-projecting DMV neurons. Perfusion with GLP-1 induced a concentration-dependent depolarization in approximately 50% of pancreas-projecting DMV neurons. The GLP-1 effects were mimicked by exendin-4 and antagonized by exendin-(9-39). In approximately 60% of the responsive neurons, the GLP-1-induced depolarization was reduced by tetrodotoxin (1 microM), suggesting both pre- and postsynaptic sites of action. Indeed, the GLP-1 effects were mediated by actions on potassium currents, GABA-induced currents, or both. Importantly, neurons excited by GLP-1 were unresponsive to PP and vice versa. These data indicate that 1) GLP-1 may act on DMV neurons to control pancreatic endocrine secretion, 2) the effects of GLP-1 on pancreas-projecting DMV neurons are mediated both via a direct excitation of their membrane as well as via an effect on local circuits, and 3) the GLP-1-responsive neurons (i.e., putative endocrine secretion-controlling neurons) could be distinguished from neurons responsive to PP (i.e., putative exocrine secretion-controlling neurons).

Micro-CT scanners can generate large high-resolution three-dimensional (3D) digital images of small-animal organs, such as rat hearts. Such images enable studies of basic physiologic questions on coronary branching geometry and uid transport. Performing such an analysis requires three steps: (1) extract the arterial tree from the image; (2) compute quantitative geometric data from the extracted tree; and (3) perform a numerical analysis of the computed data. Because a typical coronary arterial tree consists of hundreds of branches and many generations, it is impractical to perform such an integrated study manually. An automatic method exists for performing step (1), extracting the tree, but little e ort has been made on the other two steps. We propose an environment for performing a complete study. Quantitative measures for arterial-lumen cross-sectional area, inter-branch segment length, branch surface area and others at the generation, inter-branch, and intra-branch levels are computed. A human user can then work with the quantitative data in an interactive visualization system. The system provides various forms of viewing and permits interactive tree editing for "on the y" correction of the quantitative data. We illustrate the methodology for 3D micro-CT rat heart images. ?

Acute hyperglycemia has profound effects on vagally mediated gastrointestinal functions. We have reported recently that the release of glutamate from the central terminals of vagal afferent neurons is correlated directly with the extracellular glucose concentration. The present study was designed to test the hypothesis that 5-HT(3) receptors present on vagal afferent nerve terminals are involved in this glucose-dependent modulation of glutamatergic synaptic transmission. Whole-cell patch-clamp recordings were made from neurons of the nucleus tractus solitarius (NTS) in thin rat brainstem slices. Spontaneous and evoked glutamate release was decreased in a concentration-dependent manner by the 5-HT(3) receptor selective antagonist, ondansetron. Alterations in the extracellular glucose concentration induced parallel shifts in the ondansetron-mediated inhibition of glutamate release. The changes in excitatory synaptic transmission induced by extracellular glucose concentration were mimicked by the serotonin uptake inhibitor, fenfluramine. These data suggest that glucose alters excitatory synaptic transmission within the rat brainstem via actions on tonically active 5-HT(3) receptors, and the number of 5-HT(3) receptors on vagal afferent nerve terminals is positively correlated with the extracellular glucose concentration. These data indicate that the 5-HT(3) receptors present on synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose acts to modulate vagovagal reflexes.

Wan S, Browning KN. D-Glucose modulates synaptic transmission from the central terminals of vagal afferent fibers. Am J Physiol Gastrointest Liver Physiol 294: G757-G763, 2008. First published January 17, 2008 doi:10.1152/ajpgi.00576.2007.-Experimental evidence suggests that glucose modulates gastric functions via vagally mediated effects. It is unclear whether glucose affects only peripheral vagal nerve activity or whether glucose also modulates vagal circuitry at the level of the brain stem. This study used whole cell patch-clamp recordings from neurons of the nucleus of the tractus solitarius (NTS) to assess whether acute variations in glucose modulates vagal brain stem neurocircuitry. Increasing D-glucose concentration induced a postsynaptic response in 40% of neurons; neither the response type (inward vs. outward current) nor response magnitude was altered in the presence of tetrodotoxin suggesting direct effects on the NTS neuronal membrane. In contrast, reducing D-glucose concentration induced a postsynaptic response (inward or outward current) in 54% of NTS neurons; tetrodotoxin abolished these responses, suggesting indirect sites of action. The frequency, but not amplitude, of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was correlated with D-glucose concentration in 79% of neurons tested (n ϭ 48). Prior surgical afferent rhizotomy abolished the ability of D-glucose to modulate spontaneous EPSC frequency, suggesting presynaptic actions at vagal afferent nerve terminals to modulate glutamatergic synaptic transmission. In experiments in which EPSCs were evoked via electrical stimulation of the tractus solitarius, EPSC amplitude correlated with D-glucose concentration. These effects were not mimicked by L-glucose, suggesting the involvement of glucose metabolism, not uptake, in the nerve terminal. These data suggest that the synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose-evoked changes in vagovagal reflexes occurs. brain stem; electrophysiology; vagus DELAYED GASTRIC EMPTYING, or gastroparesis (diabetic gastropathy) in its extreme state, is reported in ϳ35-50% of patients with Type 1 or Type 2 diabetes (17,25,44,52) and is associated with early satiety, nausea, vomiting, and abdominal pain. Autonomic nerve dysfunction(s) undoubtedly contribute to the development of this syndrome (52), but reports that physiological hyperglycemia delays gastric emptying have led to the understanding that poor glycemic control per se may be responsible for at least some of these symptoms (25,26,37,38,45). Acute changes in blood glucose concentration, even within the physiological range, have profound effects on gastrointestinal functions, including gastric emptying. In healthy subjects, gastric emptying of both solids and liquids is slower at a blood glucose concentration of 8 mM than at 4 mM, and profound hyperglycemia (15 mM) causes a clear relaxation of the proximal stomach (29, 37). Hypoglycemia,...

Immune checkpoint blockade therapy is revolutionizing the traditional treatment model of multiple tumor types, but remains ineffective for a large subset of patients. Photodynamic therapy (PDT) has been shown to induce cancer cell death and provoke an immune response, and may represent a potential strategy to synergize with immune checkpoint blockade therapy. However, the limited tissue penetration of exciting light for conventional PDT largely hinders its application in the clinic and its further combination with immunotherapy. Here, a serrated packing covalent organic framework (COF), COF-606, with excellent two-photon absorption (2PA) property and photostability, largely avoids aggregation-caused quenching, therefore offering high reactive oxygen species (ROS) generation efficiency; it is used as a 2PA photo sensitizer for PDT in deep tumor tissue. COF-606 induced PDT is shown to be efficient in inducing immunogenic cell death, provoking an immune response and normalizing the immunosuppressive status for the first time. This makes it possible to combine 2PA induced PDT using COF with programmed cell death protein 1 immune checkpoint blockade therapy. Such combination leads to strong abscopal tumor-inhibiting efficiency and long-lasting immune memory effects, standing as a promising combinatorial therapeutic strategy for cancer treatment.

It is known that cholecystokinin (CCK) acts in a paracrine fashion to increase pancreatic exocrine secretion via vagal circuits. Recent evidence, however, suggests that CCK-8s actions are not restricted to afferent vagal fibers, but also affect brain stem structures directly. Within the brain stem, preganglionic neurons of the dorsal motor nucleus of the vagus (DMV) send efferent fibers to subdiaphragmatic viscera, including the pancreas. Our aims were to investigate whether DMV neurons responded to exogenously applied CCK-8s and, if so, the mechanism of action. Using whole cell patch-clamp recordings we show that perfusion with CCK-8s induced a concentration-dependent excitation in approximately 60% of identified pancreas-projecting DMV neurons. The depolarization was significantly reduced by tetrodotoxin, suggesting both direct (on the DMV membrane) and indirect (on local synaptic circuits) effects. Indeed, CCK-8s increased the frequency of miniature excitatory currents onto DMV neurons. The CCK-A antagonist, lorglumide, prevented the CCK-8s-mediated excitation whereas the CCK-B preferring agonist, CCK-nonsulfated, had no effect, suggesting the involvement of CCK-A receptors only. In voltage clamp, the CCK-8s-induced inward current reversed at -106 +/- 3 mV and the input resistance increased by 150 +/- 15%, suggesting an effect mediated by the closure of a potassium conductance. Indeed, CCK-8s reduced both the amplitude and the time constant of decay of a calcium-dependent potassium conductance. When tested with pancreatic polypeptide (which reduces pancreatic exocrine secretion), cells that responded to CCK-8s with an excitation were, instead, inhibited by pancreatic polypeptide. These data indicate that CCK-8s may control pancreas-exocrine secretion also via an effect on pancreas-projecting DMV neurons.