Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors.

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs-dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs-BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

State-of-the-art: functional fluorescent probes for bioimaging and pharmacological research.

Cardiovascular diseases, neuropsychiatric disorders, and cancers seriously endanger human health. Mechanistic and pharmacological mechanisms of candidate drugs are central to the translational paradigm. Since many signal transduction and molecular events are implicated in these diseases, a novel method to interrogate the key pharmacological mechanisms is required to accelerate innovative drug discovery. Much attention now focuses on the real-time visualization of molecular disease events to yield new insights to the pathogenesis of the diseases. This review focuses on recent advances in the development of chemical probes for imaging pathological events to facilitate the study of the underlying pharmacodynamics and toxicity involved. As reviewed here, optical imaging is now frequently viewed as an indispensable technique in the field of biological research. Promoting interdisciplinary collaboration among chemistry, biology and medicine, is necessary to further refine functional fluorescent probes for diagnostic and therapeutic applications.

Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities.

Glioblastoma is the most common brain tumor, with high recurrence and low survival rates. An integrative bioinformatics analysis demonstrated that anaplastic lymphoma kinase (ALK) is a promising therapeutic target for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole derivatives, which were further evaluated for antiproliferative activity using glioma cell lines. Among them, compound 4a significantly inhibited the viability of glioblastoma cells. With favorable pharmacokinetic characteristics and blood-brain barrier permeability, 4a improved the survival rate and inhibited the growth of orthotopic glioblastoma. The Phospho-Totum system revealed that ALK was a potential target for the antiglioblastoma activity of 4a. Further experiments indicated that 4a might be a novel ALK modulator, which interacted with the extracellular ligand-binding domain of ALK, thus selectively induced ERK-mediated autophagy and apoptosis. Our findings provide an alternative ALK-based targeting strategy and a new drug candidate for glioblastoma therapy.

The efficacy of gabapentin combined with opioids for neuropathic cancer pain: a meta-analysis.

BACKGROUND: More than 30% of cancer patients experience neuropathic pain. Opioids, as standard pain-relief agents, cannot achieve satisfactory outcomes to treat neuropathic cancer pain due to drug resistance and side effects. Meanwhile, gabapentin, a third-generation anticonvulsant drug, has great potential in providing relief for neuropathic cancer pain. However, there is currently no sufficient evidence to support the efficacy of a combination of gabapentin and opioids in ameliorating neuropathic cancer pain. Hence, the aim of the present study was to explore the analgesic efficacy of gabapentin combined with opioids in treating neuropathic cancer pain. METHODS: PubMed, EMBASE, and Web of Science (Web of Knowledge) were searched for randomized controlled trials and prospective studies via the following keywords: "gabapentin", "opioid", "cancer", and "neuropathic pain". We used a scale of 0-10 (0 denoting no pain and 10 denoting the worst pain imaginable) to estimate pain intensity and utilized Review Manager 5.3 and Stata12 to analyze data. RESULTS: Seven studies meeting our criterion were selected from 110 records that were primarily searched. The mean difference of pooled pain intensity and the 95% confidence interval (CI) was -1.75 (-2.44, -1.07) (P value <0.00001; treatment group versus control group or time to outcome assessment versus baseline). The pain intensity of cancer patients after a combined treatment of gabapentin and opioids was significantly lower than that of patients receiving opioids alone. CONCLUSIONS: Our meta-analysis showed that gabapentin combined with opioids effectively alleviated neuropathic cancer pain compared with that of opioids alone.

Targeted Regulation of Blood-Brain Barrier for Enhanced Therapeutic Efficiency of Hypoxia-Modifier Nanoparticles and Immune Checkpoint Blockade Antibodies for Glioblastoma.

Glioblastoma is the most destructive type of brain cancer. The blood-brain barrier (BBB) is a tremendous obstacle that hinders therapeutic agents, such as chemical drugs and antibodies, from reaching glioblastoma tissues. Meanwhile, the abnormal microenvironment of glioblastoma extremely restricts the expected therapeutic effects of accumulated drugs. Therefore, in the present study, BBB-regulating nanovesicles (BRN) are developed to achieve targeted and controlled BBB regulation, carrying adenosine 2A receptor (A2AR) agonists and perfluorocarbon (PF). The red-blood-cell membrane (RBCM) is included on the outside to avoid the premature release of therapeutic agents. In the presence of ultrasonication (US), A2AR agonists are released and induce effects on both F-actin and tight junctions of endothelial cells. Subsequently, BBB permeability is temporarily increased and enables small molecules and nanoparticles to enter brain parenchymal tissues. The high affinity between manganese dioxide and temozolomide (TMZ) is utilized to form multifunctional nanoparticles to ameliorate the hypoxic microenvironment, which yields improved glioblastoma inhibition combined with radiotherapy. Moreover, with the aid of targeted BBB regulation, programmed death ligand-1 (PD-L1) antibody induces a tumor-specific immune response. Taken together, the findings suggest that synergistic combination may have the potential in amplifying the therapeutic efficacies of clinical drugs and immune checkpoint blockade antibodies to overcome the therapeutic resistance of glioblastoma.

Autism spectrum disorder (ASD): Disturbance of the melatonin system and its implications.

The molecular mechanisms underlying autism spectrum disorder (ASD) remain elusive, which limits the management options available in the clinic. Accumulating evidence indicates that the pineal gland/melatonin system is associated with the progression of ASD. Here, we review recent advances in our understanding of various mechanisms involving pathological process of ASD, including the abnormal breakdown of melatonin synthesis, the disturbance of intracellular MTNR1A signaling, the effects exerted by melatonin on hippocampal protein serine/threonine kinases, and immune dysregulation/inflammation during ASD. We believe that an in-depth understanding of the interplay between the action of the melatonin system and the onset of autism could promote the development of novel therapeutic strategies against ASD. We anticipate that targeting the neurotransmitters upstream pathway and downstream of melatonin in brain will lead to potential therapeutic treatment for ASD.