Effect of probiotics or prebiotics on thyroid function: A meta-analysis of eight randomized controlled trials.

BACKGROUND: Microbiome-directed therapies are increasingly utilized to optimize thyroid function in both healthy individuals and those with thyroid disorders. However, recent doubts have been raised regarding the efficacy of probiotics, prebiotics, and synbiotics in improving thyroid function. This systematic review aimed to investigate the potential relationship between probiotics/prebiotics and thyroid function by analyzing the impact on thyroid hormone levels. METHODS: We conducted a comprehensive systematic review and meta-analysis of randomized controlled trials that investigated the effects of probiotics, prebiotics, and synbiotics on free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), and thyroid stimulating hormone receptor antibody (TRAb) levels. We searched for articles from PubMed, Scopus, Web of Science, and Embase up until April 1st, 2023, without any language restriction. Quantitative data analysis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval as summary statistics. The methods and results were reported according to the PRISMA2020 statement. RESULTS: A total of eight articles were included in this review. The meta-analysis showed no significant alterations in TSH (SMD: -0.01, 95% CI: -0.21, 0.20, P = 0.93; I2: 0.00%), fT4 (SMD: 0.04, 95% CI: -0.29, 0.21, P = 0.73; I2: 0.00%) or fT3 (SMD: 0.45, 95% CI: -0.14, 1.03, P = 0.43; I2: 78.00%), while a significant reduction in TRAb levels was observed (SMD: -0.85, 95% CI: -1.54, -0.15, P = 0.02; I2: 18.00%) following probiotics/prebiotics supplementation. No indication of publication bias was found. CONCLUSIONS: Probiotics/prebiotics supplementation does not influence thyroid hormone levels, but may modestly reduce TRAb levels in patients with Graves' disease.

The deubiquitinating enzyme USP20 regulates the stability of the MCL1 protein.

Chemoresistance is a major obstacle faced by oesophageal cancer patients and is synonymous with a poor prognosis. MCL1 is a pivotal member of the anti-apoptotic Bcl-2 protein family, which has been found to play an important role in cell survival, proliferation, differentiation and chemoresistance. Thus, it might be an ideal target for treating oesophageal cancer patients. Although it is known that MCL1 is degraded via the ubiquitin-proteasome system, the deubiquitylating enzyme (DUB) responsible for stabilizing MCL1 remains elusive to date. Herein, we demonstrate that Ubiquitin-Specific Protease 20 (USP20) is a novel regulator of the apoptotic signaling pathway. Moreover, USP20 could regulate the deubiquitination of MCL1 to, in turn, regulate its stability. Increased expression of USP20 was correlated with increased levels of MCL1 protein in human patient samples. In addition, depletion of USP20 could increase the polyubiquitination of MCL1, thereby increasing the conversion rate of MCL1 and the sensitivity of cells to chemotherapy. Overall, our findings indicate that the USP20-MCL1 axis might play a key role in the apoptotic signaling pathway.

Regulation of survivin protein stability by USP35 is evolutionarily conserved.

Survivin is the key component of the chromosomal passenger complex and plays important roles in the regulation of cell division. Survivin has also been implicated in the regulation of apoptosis and tumorigenesis. Although the survivin protein has been reported to be degraded by a ubiquitin/proteasome-dependent mechanism, whether there is a DUB that is involved in the regulation of its protein stability is largely unknown. Using an expression library containing 68 deubiquitinating enzymes, we found that ubiquitin-specific-processing protease 35 (USP35) regulates survivin protein stability in an enzymatic activity-dependent manner. USP35 interacted with and promoted the deubiquitination of the survivin protein. USP38, an ortholog of USP35 encoded by the human genome, is also able to regulate survivin protein stability. Moreover, we found that the deubiquitinating enzyme DUBAI, the Drosophila homolog of human USP35, is able to regulate the protein stability of Deterin, the Drosophila homolog of survivin. Interestingly, USP35 also regulated the protein stability of Aurora B and Borealin which are also the component of the chromosomal passenger complex. By regulating protein stabilities of chromosomal passenger complex components, USP35 regulated cancer cell proliferation. Taken together, our work uncovered an evolutionarily conserved relationship between USP35 and survivin that might play an important role in cell proliferation.

Self-stabilizing regulation of deubiquitinating enzymes in an enzymatic activity-dependent manner.

Deubiquitinating enzymes (DUBs) play important roles in many physiological and pathological processes by modulating the ubiquitination of their substrates. DUBs undergo post-translational modifications including ubiquitination. However, whether DUBs can reverse their own ubiquitination and regulate their own protein stability requires further investigation. To answer this question, we screened an expression library of DUBs and their enzymatic activity mutants and found that some DUBs regulated their own protein stability in an enzymatic activity- and homomeric interaction-dependent manner. Taking Ubiquitin-specific-processing protease 29 (USP29) as an example, we found that USP29 deubiquitinates itself and protects itself from proteasomal degradation. We also revealed that the N-terminal region of USP29 is critical for its protein stability. Taken together, our work demonstrates that at least some DUBs regulate their own ubiquitination and protein stability. Our findings provide novel molecular insight into the diverse regulation of DUBs.

The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein.

BACKGROUND: Myeloid cell leukaemia 1 (MCL1) is a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumourigenesis. MCL1 is a fast-turnover protein that is degraded via an ubiquitination/proteasome-dependent mechanism. Although several E3 ligases have been discovered to promote the ubiquitination of MCL1, the deubiquitinating enzyme (DUB) that regulates its stability requires further investigation. METHODS: The immunoprecipitation was used to determine the interaction between OTUD1 and MCL1. The ubiquitination assays was performed to determine the regulation of MCL1 by OTUD1. The cell viability was used to determine the regulation of BH3-mimetic inhibitor induced cell death by OTUD1. The survival analysis was used to determine the relationship between OTUD1 expression levels and the survival rate of cancer patients. RESULTS: By screening a DUB expression library, we determined that the deubiquitinating enzyme OTUD1 regulates MCL1 protein stability in an enzymatic-activity dependent manner. OTUD1 interacts with MCL1 and promotes its deubiquitination. Knockdown of OTUD1 increases the sensitivity of tumour cells to the BH3-mimetic inhibitor ABT-263, while overexpression of OTUD1 increases tumour cell tolerance of ABT-263. Furthermore, bioinformatics analysis data reveal that OTUD1 is a negative prognostic factor for liver cancer, ovarian cancer and specific subtypes of breast and cervical cancer. CONCLUSIONS: The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Thus, OTUD1 could be considered as a therapeutic target for curing these cancers.