Brain deficit patterns of metabolic illnesses overlap with those for major depressive disorder: A new metric of brain metabolic disease

Metabolic illnesses (MET) are detrimental to brain integrity and are common comorbidities in patients with mental illnesses, including major depressive disorder (MDD). We quantified effects of MET on standard regional brain morphometric measures from 3D brain MRI as well as diffusion MRI in a large sample of UK BioBank participants. The pattern of regional effect sizes of MET in non-psychiatric UKBB subjects was significantly correlated with the spatial profile of regional effects reported by the largest meta-analyses in MDD but not in bipolar disorder, schizophrenia or Alzheimer\u27s disease. We used a regional vulnerability index (RVI) for MET (RVI-MET) to measure individual\u27s brain similarity to the expected patterns in MET in the UK Biobank sample. Subjects with MET showed a higher effect size for RVI-MET than for any of the individual brain measures. We replicated elevation of RVI-MET in a sample of MDD participants with MET versus non-MET. RVI-MET scores were significantly correlated with the volume of white matter hyperintensities, a neurological consequence of MET and age, in both groups. Higher RVI-MET in both samples was associated with obesity, tobacco smoking and frequent alcohol use but was unrelated to antidepressant use. In summary, MET effects on the brain were regionally specific and individual similarity to the pattern was more strongly associated with MET than any regional brain structural metric. Effects of MET overlapped with the reported brain differences in MDD, likely due to higher incidence of MET, smoking and alcohol use in subjects with MDD

Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers

Orally Ingested Probiotics, Prebiotics, and Synbiotics as Countermeasures for Respiratory Tract Infections in Non-elderly Adults: A Systematic Review and Meta-analysis

BACKGROUND: The impact of gut microbiota-targeted interventions on the incidence, duration, and severity of respiratory tract infections (RTI) in non-elderly adults, and factors moderating any such effects, are unclear. OBJECTIVES: This systematic review and meta-analysis aimed to determine the effects of orally ingested probiotics, prebiotics, and synbiotics versus placebo on RTI incidence, duration, and severity in non-elderly adults, and to identify potential sources of heterogeneity. METHODS: Studies were identified by searching CENTRAL, PubMed, Scopus, and Web of Science up to December 2021. English-language peer-reviewed publications of randomized, placebo-controlled studies that tested an orally ingested probiotic, prebiotic or synbiotic intervention of any dose for ≥ 1 week in adults 18-65 yr were included. Results were synthesized using intention-to-treat and per protocol random effects meta-analysis. Heterogeneity was explored by sub-group meta-analysis and meta-regression. Risk of bias (RoB) was assessed using the Cochrane RoBv.2 tool for randomized trials. RESULTS: Forty-two manuscripts reporting effects of probiotics (n = 38), prebiotics (n = 2), synbiotics (n = 1) or multiple -biotic types (n = 1) were identified (n = 9,179 subjects). Probiotics reduced the risk of experiencing ≥ 1 RTI (relative risk = 0.91 [95%CI: 0.84, 0.98] P = 0.01), and total days (rate ratio = 0.77 [0.71, 0.83] P \u3c 0.001), duration (Hedges\u27s g = -0.23 [-0.39, -0.08] P = 0.004) and severity (Hedges\u27s g = -0.16 [-0.29, -0.03] P = 0.02) of RTI. Effects were relatively consistent across different strain combinations, doses and durations, though reductions in RTI duration were larger with fermented dairy as the delivery matrix, and beneficial effects of probiotics were not observed in physically active populations. Overall RoB was rated as some concerns for most studies. CONCLUSIONS: Orally ingested probiotics, relative to placebo, modestly reduce the incidence, duration and severity of RTI in non-elderly adults. Physical activity and delivery matrix may moderate some of these effects. Whether prebiotic and synbiotic interventions confer similar protection remains unclear due to few relevant studies. PROSPERO registration: CRD42020220213

Orally Ingested Probiotic, Prebiotic, and Synbiotic Interventions as Countermeasures for Gastrointestinal Tract Infections in Non-elderly Adults: A Systematic Review and Meta-analysis

Meta-analyses have not examined the prophylactic use of orally ingested probiotics, prebiotics, or synbiotics for preventing gastrointestinal tract infections (GTI) of various etiologies in adult populations despite evidence that these gut microbiota-targeted interventions can be effective in treating certain GTI. This systematic review and meta-analysis aimed to estimate the effects of prophylactic use of orally ingested probiotics, prebiotics, and synbiotics on GTI incidence, duration, and severity in non-elderly, non-hospitalized adults. CENTRAL, PubMed, Scopus, and Web of Science were searched through January 2022. English-language, peer-reviewed publications of randomized, placebo-controlled studies testing an orally ingested probiotic, prebiotic, or synbiotic intervention of any dose for ≥1 week in adults who were not hospitalized, immunosuppressed, or taking antibiotics were included. Results were analyzed using random-effects meta-analyses of intention-to-treat (ITT) and complete case (CC) cohorts. Heterogeneity was explored by subgroup meta-analysis and meta-regression. Risk of bias was assessed using the Cochrane RoB2 tool. Seventeen publications reporting 20 studies of probiotics (n=16), prebiotics (n=3), and synbiotics (n=1) were identified (n\u3e6,994 subjects). In CC and ITT analyses, risk of experiencing ≥1 GTI was reduced with probiotics (CC analysis: risk ratio=0.86 [95%CI: 0.73, 1.01]) and prebiotics (risk ratio=0.80 [95%CI: 0.66, 0.98]). No effects on GTI duration or severity were observed. Sources of heterogeneity included study population and number of probiotic strains administered, but were often unexplained, and a high risk of bias was observed for most studies. Specific effects of individual probiotic strains and prebiotic types could not be assessed due to a lack of confirmatory studies. Findings indicated that orally ingested probiotics and prebiotics, relative to placebo, both demonstrated modest benefit for reducing GTI risk in non-elderly adults. However, results should be interpreted cautiously due to the low number of studies, high risk of bias, and unexplained heterogeneity that may include probiotic strain- or prebiotic-specific effects. PROSPERO REGISTRATION: CRD42020200670

Variability of PD-L1 expression in mastocytosis

Mastocytosis is a rare disease with heterogeneous clinical manifestations and few effective therapies. Programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) protect tissues from immune-mediated damage and permit tumors to evade immune destruction. Therapeutic antibodies against PD-1 and PD-L1 are effective in the treatment of a variety of neoplasms. In the present study, we sought to systematically analyze expression of PD-1 and PD-L1 in a large number of patients with mastocytosis using immunohistochemistry and multiplex fluorescence staining. PD-L1 showed membrane staining of neoplastic mast cells (MCs) in 77% of systemic mastocytosis (SM) cases including 3 of 3 patients with MC leukemia, 2 of 2 with aggressive SM, 1 of 2 with smoldering SM, 3 of 4 with indolent SM, and 9 of 12 with SM with an associated hematologic neoplasm (SM component only). Ninety-two percent (23 of 25) of cutaneous mastocytosis (CM) cases and 1 of 2 with myelomastocytic leukemia expressed PD-L1, with no expression found in 15 healthy/reactive marrows, 18 myelodysplastic syndromes (MDSs), 16 myeloproliferative neoplasms (MPNs), 5 MDS/MPNs, and 3 monoclonal MC activation syndromes. Variable PD-L1 expression was observed between and within samples, with PD-L1 staining of MCs ranging from 10% to 100% (mean, 50%). PD-1 dimly stained 4 of 27 CM cases (15%), with no expression in SM or other neoplasms tested; PD-1 staining of MCs ranged from 20% to 50% (mean, 27%). These results provide support for the expression of PD-L1 in SM and CM, and PD-1 expression in CM. These data support the exploration of agents with anti-PD-L1 activity in patients with advanced mastocytosis

The additive impact of cardio-metabolic disorders and psychiatric illnesses on accelerated brain aging

Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio-metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning BrainAge index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD- (N = 964), SMI-/CMD+ (N = 3,765), SMI-/CMD- (N = 8,083). SMI (F = 40.47, p = 2.06 × 10 ) and CMD (F = 24.69, p = 6.82 × 10 ) significantly, independently impacted whole-brain QRI in SMI+. SSD had the largest effect (Cohen\u27s d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI- (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole-brain QRI was significantly (p \u3c 10 ) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p \u3c 10 ). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio-metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age-related cognitive decline

Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis

The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, in part due to the absence of cultured cell lines that faithfully represent adrenal cell precursors in the early stages of transformation. Here, Human Adrenocortical Adenoma (HAA1) cell line derived from a patient’s macronodular adrenocortical hyperplasia and was treated with histone deacetylase inhibitors (HDACis) and gene expression was examined. We describe a patient-derived HAA1 cell line derived from the zona reticularis, the innermost zone of the adrenal cortex. The HAA1 cell line is unique in its ability to exit a latent state and respond with steroidogenic gene expression upon treatment with histone deacetylase inhibitors. The gene expression pattern of differentiated HAA1 cells partially recreates the roster of genes in the adrenal layer that they have been derived from. Gene ontology analysis of whole genome RNA-seq corroborated increased expression of steroidogenic genes upon HDAC inhibition. Surprisingly, HDACi treatment induced broad activation of the Tumor Necrosis Factor (TNF) alpha pathway. This novel cell line we developed will hopefully be instrumental in understanding the molecular and biochemical mechanisms controlling adrenocortical differentiation and steroidogenesis