Corticonigral projections recruit substantia nigra pars lateralis dopaminergic neurons for auditory threat memories.

Dopaminergic neurons (DANs) in the lateral substantia nigra project to the tail of striatum (TS), which is involved in threat conditioning. Auditory cortex also contributes to threatening behaviors, but whether it directly interacts with midbrain DANs and how these interactions might influence threat conditioning remain unclear. Here, functional mapping revealed robust excitatory input from auditory and temporal association cortexes to substantia nigra pars lateralis (SNL) DANs, but not to pars compacta (SNc) DANs.

Presynaptic GABA receptors control integration of nicotinic input onto dopaminergic axons in the striatum.

Axons of dopaminergic neurons express gamma-aminobutyric acid type-A receptors (GABARs) and nicotinic acetylcholine receptors (nAChRs) which are both independently positioned to shape striatal dopamine release. Using electrophysiology and calcium imaging, we investigated how interactions between GABARs and nAChRs influence dopaminergic axon excitability. Direct axonal recordings showed that benzodiazepine application suppresses subthreshold axonal input from cholinergic interneurons (CINs).

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis.

Melanoma is the most lethal skin malignant tumor with a short survival once stepping into the metastatic status and poses a therapeutic challenge. Apatinib (a tyrosine kinase inhibitor) is a promising antiangiogenic agent for the treatment of metastatic melanoma. However, antiangiogenic monotherapy is prone to acquired drug resistance and has a limited therapeutic effect.

Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers.

Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear.

The real-world clinical outcomes and treatment patterns of patients with unresectable locally advanced or metastatic soft tissue sarcoma treated with anlotinib in the post-ALTER0203 trial era.

Background: The ALTER0203 clinical trial showed that anlotinib, a multitargeted tyrosine kinase inhibitor, had antitumor effects on advanced soft tissue sarcoma (STS) after the failure of standard chemotherapy. We aimed to evaluate the real-world efficacy and explore prognostic factors and treatment patterns of anlotinib in patients with advanced STS.

Methods: We retrospectively analyzed the data of patients with unresectable locally advanced or metastatic STS who received at least one dose of anlotinib from June 2018 to March 2021.

Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons.

Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of inhibitory synaptic inputs onto SNc neurons from genetically defined populations in dorsal striatum (striosome and matrix) and external globus pallidus (GPe; parvalbumin- and Lhx6-positive), and examined their contribution to pause-rebound firing. Activation of striosome projections, which target "dendron bouquets" in the pars reticulata (SNr), consistently quiets firing and relief from striosome inhibition triggers rebound activity.

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release.

Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice.

A combination of inhibiting microglia activity and remodeling gut microenvironment suppresses the development and progression of experimental autoimmune uveitis.

Noninfectious (autoimmune and immune-mediated) uveitis is an ocular inflammatory disease which can lead to blindness in severe cases. Due to the potential side effects of first-line drugs for clinical uveitis, novel drugs and targets against uveitis are still urgently needed. In the present study, using rat experimental autoimmune uveitis (EAU) model, we first found that minocycline treatment can substantially inhibit the development of EAU and improve the retinal function by suppressing the retinal microglial activation, and block the infiltration of inflammatory cells, including Th17, into the retina by decreasing the major histocompatibility complex class II (MHC II) expression in resident and infiltrating cells.

Tandem Molecular Self-Assembly Selectively Inhibits Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress.

The selective formation of nanomaterials in cancer cells and tumors holds great promise for cancer diagnostics and therapy. Until now, most strategies rely on a single trigger to control the formation of nanomaterials . The combination of two or more triggers may provide for more sophisticated means of manipulation.

Enhanced cellular uptake and nuclear accumulation of drug-peptide nanomedicines prepared by enzyme-instructed self-assembly.

Subcellular delivery of nanomedicines has emerged as a promising approach to enhance the therapeutic efficacy of anticancer drugs. Nuclear accumulation of anticancer drugs are essential for its therapeutic efficacy because their targets are generally located within the nucleus. However, strategies for the nuclear accumulation of nanomedicines with anticancer drugs rarely reported.

A novel thermogel system of self-assembling peptides manipulated by enzymatic dephosphorylation.

Supramolecular hydrogels of self-assembling peptides and thermogels are very promising for biomedical applications. However, there were no thermogels of self-assembling peptides. In this study, we reported on a novel and versatile strategy to prepare thermogels of self-assembling peptides by enzyme-instructed peptide folding and self-assembly.

A Facile Strategy to Generate High Drug Payload Celecoxib Micelles for Enhanced Corneal Permeability.

Topical ocular drug administration aimed at providing a high drug concentration at the precorneal site accompanied with enhanced corneal permeability to avoid systemic side effects is a very important therapeutic goal in ocular disorder therapy. In the present study, the solubility of the poorly soluble drug celecoxib (CXB) was significantly improved using a facile strategy to generate a high drug payload micellar formulation. By varying the drug/polymer feed ratios, the mean diameter of the formed CXB micelles ranged from 21.

High drug payload nanoparticles formed from dexamethasone-peptide conjugates for the treatment of endotoxin-induced uveitis in rabbit.

Purpose: To develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis.

Materials And Methods: We designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis.

Results: An in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period.

Calcium ion cross-linking alginate/dexamethasone sodium phosphate hybrid hydrogel for extended drug release.

Combining a low-molecular-weight hydrogel (LMWH) with a polymeric hydrogel overcomes the disadvantages of the LMWH (e.g., its low mechanical property) and is associated with the enhancement of materials performance, which is useful in a variety of biomedical applications.

Directing the nanoparticle formation by the combination with small molecular assembly and polymeric assembly for topical suppression of ocular inflammation.

In this paper, we presented a simple yet versatile strategy to generate a high drug payload nanoparticles by the combination with small molecular assembly and polymeric assembly for topical suppression of ocular inflammation. Upon physical mixing of the succinated triamcinolone acetonide (TA-SA) supramolecular hydrogel with the poly (ethylene glycol)-poly (ɛ-caprolactone)-poly (ethylene glycol) (PECE) aqueous solution at 37 °C, TA-SA/PECE nanoparticles formed spontaneously and characterized thoroughly by transmission electron microscopy (TEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The formed TA-SA/PECE nanoparticles displayed a comparable in vitro anti-inflammatory efficacy to that of native triamcinolone acetonide (TA), through a significant downregulation of various proinflammatory cytokines levels (e.

Self-Assembly of Succinated Paclitaxel into Supramolecular Hydrogel for Local Cancer Chemotherapy.

In the present study, we reported the generation of a molecular hydrogel of succinated paclitaxel (PTX-SA) by a self-hydrolytic strategy for potential local cancer chemotherapy. Upon self-hydrolysis of the ester bond of PTX-SA in phosphate-buffered saline (pH = 7.4) for 24 h, a PTX-SA supramolecular hydrogel formed spontaneously with a minimal gelation concentration of 0.

Cation instructed steroidal prodrug supramolecular hydrogel.

In the present study, we propose an ionic coordination strategy for the design of a steroidal prodrug supramolecular hydrogel. The hydrogel composed of nanofibril networks formed spontaneously by the introduction of divalent cations (e.g.

Glycosylation-enhanced biocompatibility of the supramolecular hydrogel of an anti-inflammatory drug for topical suppression of inflammation.

Unlabelled: Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but it displays a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity).

Supramolecular nanofibers of dexamethasone derivatives to form hydrogel for topical ocular drug delivery.

The low bioavailability exhibits by conventional ocular formulation owing to rapid precorneal clearance and lower corneal permeability can be overcame by the application of the gelling system. In the present study, a prodrug supramolecular hydrogel derived from succinated dexamethasone (Dex-SA) was fabricated using a pH hydrolytic strategy and explored as a "self-delivery" system for ophthalmic drugs. The self-assembled Dex-SA supramolecular hydrogel exhibited a typical nano-fibrous microstructure and was thixotropic.

Relationship Between Aerobic Fitness, the Serum IGF-1 Profiles of Healthy Young Adult African American Males, and Growth of Prostate Cancer Cells.

The growth of prostate tumors is mediated by the bioavailability of androgens and insulin-like growth factors. This study tested the hypothesis that healthy young adult African American men exhibiting low aerobic capacity (fitness) have serum insulin-like growth Factor-1 (IGF-1) and testosterone levels that promote growth of prostate cancer cells. A cross-sectional data research design was used to study groups of 18- to 26-year-old healthy men exhibiting low and moderate aerobic fitness, based on their peak oxygen consumption (VO).

Evaluation of Tumor Cell Response to Hyperthermia with Bioluminescent Imaging.

Background: Hyperthermia is used in combination with radiotherapy and/or chemotherapy in the treatment of various types of cancer. Currently, the tumor cell response to hyperthermia is determined largely based on the size reduction of tumor mass, which is insensitive.

Methods: We tested the feasibility of bioluminescent imaging (BLI) in evaluation of the tumor cell response to hyperthermia by exposing luciferase-expressing MDA-MB-231-luc human breast cancer cells to high temperature (43 °C) for 10 minutes to 2 hours.

Image-based evaluation of the molecular events underlying HC11 mammary epithelial cell differentiation.

We have developed an image-based technique for signal pathway analysis, target validation, and compound screening related to mammary epithelial cell differentiation. This technique used the advantages of optical imaging and the HC11-Lux model system. The HC11-Lux cell line is a subclone of HC11 mammary epithelial cells transfected stably with a luciferase construct of the beta-casein gene promoter (p-344/-1betac-Lux).

Cytotoxicity of etidronic acid to human breast cancer cells.

Introduction: Bisphosphonates have been used to treat Paget's disease, osteoporosis, and cancer metastases to the bone. The cancer chemotherapeutic potential of a first-generation bisphosphonate, etidronic acid, was evaluated by using MCF-7 human breast cancer cells.

Methods: In vitro cytotoxicity of etidronic acid to MCF-7 cells was estimated on the basis of clonogenicity assays, while cell cycle effects were determined by using flow cytometry.

Visualizing head and neck tumors in vivo using near-infrared fluorescent transferrin conjugate.

Transferrin receptor (TfR) is overexpressed in human head and neck squamous cell carcinomas (HNSCCs). This study was carried out to investigate the feasibility of imaging HNSCC by targeting TfR using near-infrared fluorescent transferrin conjugate (TfNIR). Western blot analysis of four HNSCC cell lines revealed overexpression of TfR in all four lines compared with that in normal keratinocytes (OKFL).

Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo.

Purpose: Vitamin E succinate (alpha-TOS) inhibits the growth of cancer cells without unacceptable side effects. Therefore, the mechanisms associated with the anticancer action of alpha-TOS, including ceramide-mediated apoptosis, were investigated using head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo.

Experimental Design: Five different human HNSCC cell lines (JHU-011, JHU-013, JHU-019, JHU-022, and JHU-029) were treated with alpha-TOS, and its effects on cell proliferation, cell cycle progression, ceramide-mediated apoptosis, and ceramide metabolism were evaluated.