Atypical antipsychotics-induced metabolic syndrome and nonalcoholic fatty liver disease: a critical review.

The atypical antipsychotics (AAPs) have been used as first-line drugs in psychiatric practice for a wide range of psychotic disorders, including schizophrenia and bipolar mania. While effectively exerting therapeutic effects on positive and negative symptoms, as well as cognitive impairments in schizophrenia patients, these drugs are less likely to induce extrapyramidal symptoms compared to typical antipsychotics. However, the increasing application of them has raised questions on their tolerability and adverse effects over the endocrine, metabolic, and cardiovascular axes. Specifically, AAPs are associated to different extents, with weight gain, metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD). This article summarized clinical evidence showing the metabolic side effects of AAPs in patients with schizophrenia, and experimental evidence of AAPs-induced metabolic side effects observed in animals and cell culture studies. In addition, it discussed potential mechanisms involved in the APPs-induced MetS and NAFLD.

Platelet serotonin and serotonin transporter as peripheral surrogates in depression and anxiety patients.

Previous studies suggested that serotonergic neurons and platelets share similarities in serotonin (5-HT) uptake by serotonin transporter (SERT), storage, metabolism and release mechanisms, indicating that platelets may be used as a reliable peripheral surrogate to measure central SERT activity in neuropsychiatric research. In this study, platelet 5-HT content and 5-HT uptake capacity of SERT in depression and anxiety patients were measured by ELISA and flow cytometry with IDT307 at baseline and after serotonin reuptake inhibitors (SSRIs) treatment for 4 weeks. Healthy persons matched with age and gender were used as reference. The clinical presentations of the patients were assessed with Hamilton Depression (HAMD) and Anxiety Rating Scales (HAMA) at the same time points. Compared to healthy subjects, anxiety and depression patients showed higher levels of platelet 5-HT and IDT307 fluorescence intensity, but the values were comparable between the patient groups. SSRIs administration for 4 weeks significantly decreased scores of HAMD (29 vs 14) and HAMA (22 vs 14) in depression and anxiety patients, respectively; while it decreased platelet 5-HT content, but did not change the IDT307 fluorescence intensity of platelets. After incubation with fluoxetine in vitro, the IDT307 fluorescence intensity of isolated platelets from both healthy subjects and patients decreased in a dose-dependent manner. These results provide further evidence supporting the employment of platelet 5-HT content and SERT as peripheral surrogates in depression and anxiety patients, and are of help in understanding the several weeks' delay from the initiation of antidepressant medication to their full therapeutic effects in the patients.

Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites.

Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine.

TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes.

Exosomes released from tumor cells having been shown to induce interleukin-6 release from myeloid-derived suppressor cells in a Toll-like receptor 2/Stat3-dependent manner. In this study, we show that exosomes released from tumor cells re-isolated from syngeneic mice are capable of inducing interleukin-6 in a Toll-like receptor 2-independent manner, whereas the data generated from exosomes of tumor cells having undergone numerous in vitro passages induce interleukin-6 in a Toll-like receptor 2-dependent manner. This discrepancy may be due to the source of tumor cells used to generate the exosomes for this study. These results suggest that exosomes released from tumor cells that are not within a tumor microenvironment may not realistically represent the role of tumor exosomes in vivo. This is an important consideration since frequently passing tumor cells in vivo is an accepted practice for studying tumor exosome-mediated inflammatory responses.