Disruption in the autophagic process underlies the sensory neuropathy in dystonia musculorum mice

Introduction: The infiltration of HIV into the brain alters the functions of the nervous system known as NeuroAIDS. It leads to neuronal defects clinically manifested by motor and cognitive dysfunctions. Materials/Methods: Current antiretroviral therapy can prevent viral replication but cannot cure the disease completely. HAART-Highly active antiretroviral therapy used for the treatment of HIV infection. Challenges in neuro-AIDS therapy are as shown in the graphical abstract. One of the challenges is latent viral reservoirs like the brain; which acts as a sanctuary site for viruses. Nearly ~50% of HIV patients show neuropathological signs. Nervous system related disorders including AIDS dementia, sensory neuropathy, and myelopathy have a 25% of prevalence in patients having access to a highly active combination antiretroviral therapy. Results/Conclusions: Brain is one of the viral sanctuary sites for HIV. The current need of neuro-AIDS therapy is to target the brain as a viral reservoir. Drugs should cross or bypass the blood-brain barrier to reach the brain with effective concentrations. Current research on novel drug delivery approaches may prove helpful to treat neuro-AIDS and related disorders effectively.

Download Full-text

Post-translational regulation of autophagy is involved in intra-microbiome suppression of fungal pathogens

Microbiome ◽

10.1186/s40168-021-01077-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Jing Wang ◽

Chaoyun Xu ◽

Qiming Sun ◽

Jinrong Xu ◽

Yunrong Chai ◽

...

Keyword(s):

Translational Regulation ◽

Fungal Pathogens ◽

Fungal Growth ◽

Fungal Species ◽

26S Proteasome ◽

Healthy Plant ◽

Autophagy Induction ◽

Histone Acetyltransferase Gcn5 ◽

Plant Microbiota ◽

Autophagic Process

Abstract Background Microbiome interactions are important determinants for ecosystem functioning, stability, and health. In previous studies, it was often observed that bacteria suppress potentially pathogenic fungal species that are part of the same plant microbiota; however, the underlying microbe-microbe interplay remains mostly elusive. Here, we explored antagonistic interactions of the fungus Fusarium graminearum and bacterium Streptomyces hygroscopicus at the molecular level. Both are ubiquitous members of the healthy wheat microbiota; under dysbiosis, the fungus causes devastating diseases. Results In co-cultures, we found that Streptomyces alters the fungal acetylome leading to substantial induction of fungal autophagy. The bacterium secrets rapamycin to inactivate the target of rapamycin (TOR), which subsequently promotes the degradation of the fungal histone acetyltransferase Gcn5 through the 26S proteasome. Gcn5 negatively regulates fungal autophagy by acetylating the autophagy-related protein Atg8 at the lysine site K13 and blocking cellular relocalization of Atg8. Thus, degradation of Gcn5 triggered by rapamycin was found to reduce Atg8 acetylation, resulting in autophagy induction in F. graminearum. Conclusions Autophagy homeostasis plays an essential role in fungal growth and competition, as well as for virulence. Our work reveals a novel post-translational regulation of autophagy initiated by a bacterial antibiotic. Rapamycin was shown to be a powerful modulator of bacteria–fungi interactions with potential importance in explaining microbial homeostasis in healthy plant microbiomes. The autophagic process provides novel possibilities and targets to biologically control pathogens.

Download Full-text

Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma

Cell Death and Disease ◽

10.1038/s41419-021-03510-4 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Renjie Dou ◽

Jinjun Qian ◽

Wei Wu ◽

Yanxin Zhang ◽

Yuxia Yuan ◽

...

Keyword(s):

Multiple Myeloma ◽

Type I ◽

Disease Course ◽

Mtor Signaling Pathway ◽

Hairpin Rna ◽

Aberrant Expression ◽

Transcriptomic Sequencing ◽

Family Protein ◽

Cellular Apoptosis ◽

Autophagic Process

AbstractSteroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.

Download Full-text

Phase II study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study)

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04232-2 ◽

2021 ◽

Author(s):

Keiichiro Ishibashi ◽

Toru Aoyama ◽

Masahito Kotaka ◽

Hironaga Satake ◽

Yasushi Tsuji ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Sensory Neuropathy ◽

Progression Free Survival ◽

First Line ◽

Secondary Endpoints ◽

Grade 3 ◽

Peripheral Sensory ◽

Line Chemotherapy

Abstract Background The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX. Methods Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity. Results A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3–16.0), the median OS was 45.4 months (95% CI 37.4–NA), and the RR was 56.0% (95% CI 42.3–68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%). Conclusions First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.

Download Full-text

MR imaging in hypertrophic neuropathy: A case of hereditary motor and sensory neuropathy, type i (charcot-marie-tooth)

Clinical Imaging ◽

10.1016/0899-7071(90)90073-k ◽

1990 ◽

Vol 14 (3) ◽

pp. 204-207 ◽

Cited By ~ 17

Author(s):

Samuel K. Choi ◽

Roger P. Bowers ◽

Paul E. Buckthal

Keyword(s):

Mr Imaging ◽

Sensory Neuropathy ◽

Type I ◽

Charcot Marie Tooth ◽

Hypertrophic Neuropathy ◽

Hereditary Motor ◽

Motor And Sensory Neuropathy

Download Full-text

A Rare Case of Sensory Neuropathy Associated with Transitional Cell Carcinoma of the Bladder

Case Reports in Oncology ◽

10.1159/000510742 ◽

2020 ◽

Vol 13 (3) ◽

pp. 1397-1401

Author(s):

Sujitha Ketineni ◽

Sreenath Kodali ◽

Sasikanth Gorantla

Keyword(s):

Lymph Nodes ◽

Transitional Cell Carcinoma ◽

Cell Carcinoma ◽

Rare Case ◽

Transitional Cell ◽

Sensory Neuropathy ◽

Endobronchial Ultrasound ◽

Whole Body ◽

Initial Symptoms ◽

Carcinoma Of The Bladder

Malignancies can trigger an autoimmune response against the nervous system and manifest as paraneoplastic neurological syndromes (PNS). Initial symptoms of PNS may develop up to 5 years prior to the diagnosis of the underlying malignancy. We report a rare case of PNS associated with transitional cell carcinoma of the bladder in a 70-year-old male with a 6-month history of rapidly progressive symmetric sensory neuropathy. Peripheral neuropathy serological workup was unremarkable. A paraneoplastic neuropathy panel revealed anti-Hu autoantibodies. Further evaluation with a whole-body PET scan could not identify the primary malignancy, but it showed hypermetabolic hilar lymph nodes. An endobronchial ultrasound biopsy of the hilar lymph nodes was negative for cancer. The patient developed painless hematuria 2.5 years after the onset of the sensory neuropathy. Cystoscopy with biopsy revealed non-muscle-invasive transitional cell carcinoma of the bladder. Progression of the sensory neuropathy stopped after tumor resection. This case highlights the importance of a diligent and systematic approach to diagnose PNS. A relentless search is often required to detect PNS-associated occult malignancies.

Download Full-text