bims-tubesc 2022-05-08 papers

Issue of 2022‒05‒08
five papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu

Mod Rheumatol Case Rep. 2022 May 05. pii: rxac033. [Epub ahead of print]

A Mechanistic Target of Rapamycin (mTOR) Inhibitor, Everolimus Safely Ameliorated Lupus Nephritis in a Patient Complicated with Tuberous Sclerosis.

Yasutaka Okita, Maiko Yoshimura, Yoshinori Katada, Yukihiko Saeki, Shiro Ohshima.

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting edema in bilateral lower legs for three days. The urinalysis showed massive proteinuria with a lot of WBC casts. The blood tests revealed hypoalbuminemia, hypercholesterolemia, hypocomplementemia and elevated anti-ds-DNA antibody titer. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis (LN). Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil (MMF) and tacrolimus, complete remission had not been achieved leading to steroid-dependent nephrotic syndrome. During the following-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and MMF and tacrolimus were terminated instead. The activity of LN was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for six years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

Keywords: SLE; everolimus; lupus nephritis; mTOR; tuberous sclerosis

DOI: https://doi.org/10.1093/mrcr/rxac033

Mol Biol Rep. 2022 May 02.

Interplay between PI3K/AKT pathway and heart disorders.

Soudeh Ghafouri-Fard, Ali Khanbabapour Sasi, Bashdar Mahmud Hussen, Hamed Shoorei, Afshan Siddiq, Mohammad Taheri, Seyed Abdulmajid Ayatollahi.

The PI3K/AKT signaling has crucial role in the regulation of numerous physiological functions through activation of downstream effectors and modulation of cell cycle transition, growth and proliferation. This pathway participates in the pathogenesis of several human disorders such as heart diseases through regulation of size and survival of cardiomyocytes, angiogenic processes as well as inflammatory responses. Moreover, PI3K/AKT pathway participates in the process of myocardial injury induced by a number of substances such as H2O2, Mercury, lipopolysaccharides, adriamycin, doxorubicin and epirubicin. In this review, we describe the contribution of this pathway in the pathoetiology of myocardial ischemia/reperfusion injury and myocardial infarction, heart failure, cardiac hypertrophy, cardiomyopathy and toxins-induced cardiac injury.

Keywords: Cardiac hypertrophy; Expression; Heart disease; Myocardial infarction; PI3K/AKT pathway

DOI: https://doi.org/10.1007/s11033-022-07468-0

Transl Psychiatry. 2022 May 04. 12(1): 184

Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder.

Sung Woo Park, Mi Kyoung Seo, Maree J Webster, Jung Goo Lee, Sanghyeon Kim.

Bipolar disorder (BPD) is a severe mental illness characterized by episodes of depression and mania. To investigate the molecular mechanisms underlying the pathophysiology of bipolar disorder, we performed transcriptome studies using RNA-seq data from the prefrontal cortex (PFC) of individuals with BPD and matched controls, as well as data from cell culture and animal model studies. We found 879 differentially expressed genes that were also replicated in an independent cohort of post-mortem samples. Genes involving the mechanistic target of rapamycine (mTOR) pathway were down-regulated, while genes interrelated with the mTOR pathway such as Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were up-regulated. Gene co-expression network analyses identified a module related to the mTOR pathway that was up-regulated in BPD and also enriched for markers of endothelial cells. We also found a down-regulated co-expression module enriched for genes involved in mTOR signalling and in mTOR related pathways and enriched with neuronal markers. The mTOR related modules were also replicated in the independent cohort of samples. To investigate whether the expression of the modules related to mTOR signalling pathway could be differentially regulated in different cell types we performed comparative network analyses in experimental models. We found both up-regulated modules in the PFC significantly overlapped with an up-regulated module in the brain endothelial cells from mice treated with lipopolysaccharides (LPS) and mTOR related pathways such as JAK-STAT, PI3K-Akt and ribosome were enriched in the common genes. In addition, the down-regulated module in the PFC significantly overlapped with a down-regulated module from neurons treated with the mTOR inhibitor, Torin1 and mTOR signalling, autophagy, and synaptic vesicle cycles were significantly enriched in the common genes. These results suggest that co-expression networks related to mTOR signalling pathways may be up- or down-regulated in different cell types in the PFC of BPD. These results provide novel insights into the molecular mechanisms underlying the pathophysiology of BPD.

DOI: https://doi.org/10.1038/s41398-022-01944-8