Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity.

The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Application of soil amendments for reducing PFAS leachability and bioavailability.

In this study, changes in PFAS leachability and bioavailability were determined following the application of RemBind®100 (R100) and RemBind®300 (R300; 1-10% w/w) to PFAS-contaminated soil (Æ©28 PFAS 3.093-32.78 mg kg-1). Small differences were observed in PFAS immobilization efficacy when soil was amended with RemBind® products although adding 5% w/w of either product resulted in a >98% reduction in ASLP PFAS leachability. Variability in immobilization efficacy was attributed to differences in activated carbon composition which influenced physicochemical properties of RemBind® formulations and PFAS sorption. PFOS, PFHxS and PFOA relative bioavailability was also assessed in unamended and amended soil (5% w/w) using an in vivo mouse model. In unamended soil, PFAS relative bioavailability was >60% with differences attributed to physicochemical properties of soil which influenced electrostatic and hydrophobic interactions. However, when PFAS relative bioavailability was assessed in soil amended with 5% w/w R100, individual PFAS relative bioavailability was reduced to 16.1 ± 0.8% to 26.1 ± 0.9% with similar results observed when R300 (5% w/w) was utilised (14.4 ± 1.6% to 24.3 ± 0.8%). Results from this study highlight that soil amendments have the potential to reduce both PFAS leachability and relative bioavailability thereby decreasing mobility and potential exposure to soil-borne contaminants.

Treatment-induced mood switching in affective disorders.

Many patients under treatment for mood disorders, in particular patients with bipolar mood disorders, experience episodes of mood switching from one state to another. Various hypotheses have been proposed to explain the mechanism of mood switching, spontaneously or induced by drug treatment. Animal models have also been used to test the role of psychotropic drugs in the switching of mood states. We examine the possible relationship between the pharmacology of psychotropic drugs and their reported incidents of induced mood switching, with reference to the various hypotheses of mechanisms of mood switching.

Plumbojarosite formation in contaminated soil to mitigate childhood exposure to lead, arsenic and antimony.

In this study, a novel method for lead (Pb) immobilization was developed in contaminated soils using iron (III) (Fe3+) in conjunction with 0.05 M H2SO4. During method optimization, a range of microwave treatment times, solid to solution ratios, and Fe2(SO4)3/H2SO4 concentrations were assessed using a mining/smelting impacted soil (BHK2, Pb: 3031 mg/kg), followed by treatment of additional Pb contaminated soils (PP, Pb: 1506 mg/kg, G10, Pb: 2454 mg/kg and SoFC-1, Pb: 6340 mg/kg) using the optimized method. Pb bioaccessibility was assessed using USEPA Method 1340, with Pb speciation determined by X-ray Absorption (XAS) spectroscopy. Treatment efficacy was also validated using an in vivo mouse assay, where Pb accumulation in femur, kidney and liver was assessed to confirm in vitro bioaccessibility outcomes. Results showed that Pb bioaccessibility could be reduced by 77.4-97.0% following treatment of soil with Fe2(SO4)3 (0.4-1.0 M), H2SO4 (0.05 M) at 150 °C for 60 min in a closed microwave system. Results of bioavailability assessment demonstrated treatment effect ratio of 0.06-0.07 in femur, 0.06-0.27 in kidney and 0.06-0.11 in liver (bioavailability reduction between 73% and 93%). Formation of plumbojarosite in treated soils was confirmed by XAS analysis.

Hallucinations: diagnosis, neurobiology and clinical management.

Hallucinations are important diagnostic symptoms in schizophrenia, but also occur in other medical and neuropsychiatric conditions. Not all patients with hallucinations are psychotic. There has been a surge of interest in the topic of hallucinations, as new research data have begun to reveal their neurobiology. Hallucinogenic molecules may also serve as new scaffolds for the development of new psychotropic drugs. We searched and reviewed recent literature, focusing on the refinement of clinical management, which was inspired by new data regarding the neurobiology of hallucination subtypes. We concluded that the successful management of hallucinations depends on accurate differential diagnosis to identify subtypes, which would then determine the most appropriate treatment.

Safety of traditional medicine and natural product supplements in psychiatry.

Traditional medicines in the form of health food and supplements are highly popular nowadays. They are often aggressively promoted with unsubstantiated health benefit claims. Patients suffering from chronic illness, such as psychiatric disorders may be attracted to these products and use them concurrently with their prescribed drugs. The potential danger of these health supplements and traditional medicines containing products have prompted repeated warnings by the US Food and Drug Administration in recent years. A new initiative by the Food and Drug Administration in 2019 was also implemented to strengthen the oversight of these supplements. The WHO global compendium will include traditional medicines in 2019, which has generated much debate about their safety. Many practising psychiatrists are not familiar with traditional medicines, and clinically useful information is also not easily available. In this review, we examine the nature and safety of commonly encountered traditional medicine in these health food products and supplements.

Opportunities in Novel Psychotropic Drug Design from Natural Compounds.

Multiple initiatives at the national and international level support natural drug discovery. Psychiatrists and patients are not well informed about natural psychotropics in general. Existing antidepressant and antipsychotic drugs were developed from atropine, a natural product. Subsequent drug developments were largely based on extension and modification of earlier molecular scaffolds. This limits their mechanisms of action to similar neuropathways. Natural psychotropic substances, particularly those with hallucinogenic and psychedelic properties and different chemical structures, may serve as new paths to novel psychotropic drug development.

Herbal medicine for psychiatric disorders: Psychopharmacology and neuroscience-based nomenclature.

Objectives: Herbs are frequently and concurrently used with prescribed drugs by patients worldwide. While clinical trials have found some herbs to be as useful as standard psychiatric drugs, most clinicians are unaware of their pharmacological mechanisms.Methods: We searched English language and other language literature with English abstracts listed in PubMed website, supplemented by additional through Google Scholar's free academic paper abstract website for publications on herbs, focussing on their clinical use in mental disorders, their neurobiology and their pharmacology.Results: A major reason for herbs remaining outside of mainstream psychiatry is that the terminology and concepts in herbal medicine are not familiar to psychiatrists in general. Many publications regarding the use of herbal medicine for psychiatric disorders are deficient in details regarding diagnosis, criteria for response and the neurobiology details compared with publications on standard psychotropic drugs. Nomenclature for herbal medicine is usually confusing and is not conducive to an easy understanding of their mode of action in psychiatric disorders.Conclusions: The recent neuroscience-based nomenclature (NbN) for psychotropics methodology would be a logical application to herbal medicine in facilitating a better understanding of the use of herbal medicine in psychiatry.

Multitarget botanical pharmacotherapy in major depression: a toxic brain hypothesis.

A significant number of patients with major depression do not respond optimally to current antidepressant drugs. As depression is likely to be a heterogeneous disorder, it is possible that existing neurotransmitter-based antidepressant drugs do not fully address other pathologies that may exist in certain cases. Biological pathologies related to depression that have been proposed and studied extensively include inflammation and immunology, hypercortisolemia, oxidative stress, and impaired angiogenesis. Such pathologies may induce neurodegeneration, which in turn causes cognitive impairment, a symptom increasingly being recognized in depression. A neurotoxic brain hypothesis unifying all these factors may explain the heterogeneity of depression as well as cognitive decline and antidepressant drug resistance in some patients. Compared with neurotransmitter-based antidepressant drugs, many botanical compounds in traditional medicine used for the treatment of depression and its related symptoms have been discovered to be anti-inflammatory, immunoregulatory, anti-infection, antioxidative, and proangiogenic. Some botanical compounds also exert actions on neurotransmission. This multitarget nature of botanical medicine may act through the amelioration of the neurotoxic brain environment in some patients resistant to neurotransmitter-based antidepressant drugs. A multitarget multidimensional approach may be a reasonable solution for patients resistant to neurotransmitter-based antidepressant drugs.

Managing interactions between cognitive enhancers and other psychotropics.

Polypharmacy is common in psychiatry. Usage of cognitive enhancers is increasing in the psychiatric population. Many clinicians are not familiar with these new psychoactive compounds. This paper reviews the potential drug-drug interactions when these cognitive enhancers are used together with psychotropic drugs and their confounding effects on diagnosis and clinical management.

Patients on psychotropic medications and herbal supplement combinations: clinical considerations.

Populations using herbs and herbal preparations are widespread and growing. As many herbal ingredients exert actions on psychotropic drug targets, psychiatrists should be well informed and aware of potential drug-drug interactions in clinical practice. Reliable and clinically useful information in this area, however, is fragmented, if not deficient. This paper reviewed the clinical aspects of herb-drug interactions, focusing in particular on the monoamine oxidase enzyme and P450 cytochrome enzyme-inhibitory properties of herbs and their potential interference with psychotropic drug actions and clinical judgement.

Using in vitro bioaccessibility to refine estimates of human exposure to PAHs via incidental soil ingestion.

PAH bioaccessibility in contaminated soil was determined using the organic physiologically based extraction test with the inclusion of a sorption sink. Silicone cord was incorporated into the assay in order to overcome the limited capacity of the in vitro medium to accommodate desorbable PAHs. Initially, silicone cord sorption efficacy was determined by assessing sorption kinetics using PAH-spiked sand (phenanthrene, pyrene and benzo[a]pyrene; 10-1000mgkg(-1)). Irrespective of PAH and concentration, >95% of the initial PAH mass partitioned into the silicone cord within 12h although rates were lower at higher concentration and with increasing hydrophobicity. When PAH bioaccessibility was assessed in contaminated soil (n=18), contamination source (i.e. pyrogenic versus petrogenic) influenced PAH bioaccessibility. Individual PAH bioaccessibility ranged up to 81.7±2.7% although mean values ranged from 2.1 (acenaphthalene) to 20.8% (benzo[k]fluoranthene) with upper 95% confidence intervals of the means of 4.5 and 28.3% respectively. Although a PAH in vivo-in vitro correlation is yet to be established, bioaccessibility approaches incorporating sorption sinks represent a robust approach for estimating PAH bioavailability as the desorbable fraction may be a conservative measure of the absorbable fraction.