STAR Protoc. 2023 Sep 2;4(3):102533. doi: 10.1016/j.xpro.2023.102533. Online ahead of print.

ABSTRACT

Social isolation, a risk factor for mortality and various disease states, in mice remains poorly understood, due in part to under-consideration of housing temperature and the murine thermoneutral zone. Here, we present a housing protocol to minimize the confounding effect of chronic cold stress on socially isolated mice that are unable to socially thermoregulate. We describe steps for allocating mice to group housing or social isolation conditions, housing mice in thermoneutral cabinets, feeding mice with high-fat diet, and measuring body weight, food intake, and metabolic indicators. For complete details on the use and execution of this protocol, please refer to Queen et al..1.

PMID:37660300 | DOI:10.1016/j.xpro.2023.102533

Cell Rep. 2023 Sep 1;42(9):113082. doi: 10.1016/j.celrep.2023.113082. Online ahead of print.

ABSTRACT

Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate that is present in nearly all organisms studied to date. A remarkable function of polyP involves its attachment to lysine residues via non-enzymatic post-translational modification (PTM), which is presumed to be covalent. Here, we show that proteins containing tracts of consecutive histidine residues exhibit a similar modification by polyP, which confers an electrophoretic mobility shift on NuPAGE gels. Our screen uncovers 30 human and yeast histidine repeat proteins that undergo histidine polyphosphate modification (HPM). This polyP modification is histidine dependent and non-covalent in nature, although remarkably it withstands harsh denaturing conditions-a hallmark of covalent PTMs. Importantly, we show that HPM disrupts phase separation and the phosphorylation activity of the human protein kinase DYRK1A, and inhibits the activity of the transcription factor MafB, highlighting HPM as a potential protein regulatory mechanism.

PMID:37660293 | DOI:10.1016/j.celrep.2023.113082

Mol Plant. 2023 Sep 1:S1674-2052(23)00252-6. doi: 10.1016/j.molp.2023.08.017. Online ahead of print.

ABSTRACT

Photosynthesis in both crops and natural vegetation allows light energy to be converted into chemical energy, and thus forms the foundation for almost all terrestrial trophic networks on Earth. The efficiency of photosynthetic energy conversion plays a crucial role in determining the portion of incident solar radiation that can be used to generate plant biomass throughout a growth season. Consequently, alongside factors such as resource availability, crop management, crop selection, maintenance costs, and intrinsic yield potential, photosynthetic energy use efficiency significantly influences crop yield. Photosynthetic efficiency is relevant to sustainability and food security because it impacts water-use efficiency, nutrient-use efficiency, and land-use efficiency. This review focuses specifically on the potential for improvements in photosynthetic efficiency to drive a sustainable increase in crop yields. We will discuss bypassing photorespiration, enhancing light use efficiency, harnessing natural variation in photosynthetic parameters for breeding purposes, and adopting new-to-nature approaches that show promise for achieving unprecedented gains in photosynthetic efficiency.

PMID:37660255 | DOI:10.1016/j.molp.2023.08.017

ISME Commun. 2023 Sep 2;3(1):92. doi: 10.1038/s43705-023-00290-0.

ABSTRACT

Traditional culture techniques usually retrieve a small fraction of the marine microbial diversity, which mainly belong to the so-called rare biosphere. However, this paradigm has not been fully tested at a broad scale, especially in the deep ocean. Here, we examined the fraction of heterotrophic bacterial communities in photic and deep ocean layers that could be recovered by culture-dependent techniques at a large scale. We compared 16S rRNA gene sequences from a collection of 2003 cultured heterotrophic marine bacteria with global 16S rRNA metabarcoding datasets (16S TAGs) covering surface, mesopelagic and bathypelagic ocean samples that included 16 of the 23 samples used for isolation. These global datasets represent 60 322 unique 16S amplicon sequence variants (ASVs). Our results reveal a significantly higher proportion of isolates identical to ASVs in deeper ocean layers reaching up to 28% of the 16S TAGs of the bathypelagic microbial communities, which included the isolation of 3 of the top 10 most abundant 16S ASVs in the global bathypelagic ocean, related to the genera Sulfitobacter, Halomonas and Erythrobacter. These isolates contributed differently to the prokaryotic communities across different plankton size fractions, recruiting between 38% in the free-living fraction (0.2-0.8 µm) and up to 45% in the largest particles (20-200 µm) in the bathypelagic ocean. Our findings support the hypothesis that sinking particles in the bathypelagic act as resource-rich habitats, suitable for the growth of heterotrophic bacteria with a copiotroph lifestyle that can be cultured, and that these cultivable bacteria can also thrive as free-living bacteria.

PMID:37660234 | DOI:10.1038/s43705-023-00290-0

Nat Commun. 2023 Sep 2;14(1):5351. doi: 10.1038/s41467-023-41114-y.

ABSTRACT

Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.

PMID:37660128 | DOI:10.1038/s41467-023-41114-y

Eur Urol. 2023 Aug 31:S0302-2838(23)03016-6. doi: 10.1016/j.eururo.2023.07.016. Online ahead of print.

ABSTRACT

BACKGROUND: The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress.

OBJECTIVE: To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa.

DESIGN, SETTING, AND PARTICIPANTS: Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance.

INTERVENTION: Metformin was administered before or after the induction of oxidative stress by treatment with paraquat.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models.

RESULTS AND LIMITATIONS: Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin.

CONCLUSIONS: Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression.

PATIENT SUMMARY: Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.

PMID:37659962 | DOI:10.1016/j.eururo.2023.07.016

Trends Pharmacol Sci. 2023 Aug 31:S0165-6147(23)00171-2. doi: 10.1016/j.tips.2023.08.001. Online ahead of print.

ABSTRACT

Psychedelic drugs have experienced an unprecedented surge in recreational use within the past few years. Among recreational users, the risks of psychedelic use by pregnant and breastfeeding women are severely understudied and there is little information on the potential teratogenic effects of these drugs. We provide an overview of the previous data on psychedelic teratogenicity from rodent studies and human surveys, discuss their limitations, and propose the utility of the zebrafish as a potential effective model for investigating psychedelic teratogenicity. Recent years have validated the use of zebrafish in the study of fetal exposure and developmental biology; we highlight these properties of the zebrafish for its suitability in psychedelic toxicity research.

PMID:37659901 | DOI:10.1016/j.tips.2023.08.001

Environ Res. 2023 Aug 31:117027. doi: 10.1016/j.envres.2023.117027. Online ahead of print.

ABSTRACT

The latest advancements in oncology involves the creation of multifunctional nanostructures. The integration of nanoparticles into the realm of cancer therapy has brought about a transformative shift, revolutionizing the approach to addressing existing challenges and limitations in tumor elimination. This is particularly crucial in combating the emergence of resistance, which has significantly undermined the effectiveness of treatments like chemotherapy and radiotherapy. GO stands as a carbon-derived nanoparticle that is increasingly finding utility across diverse domains, notably in the realm of biomedicine. The utilization of GO nanostructures holds promise in the arena of oncology, enabling precise transportation of drugs and genetic material to targeted sites. GO nanomaterials offer the opportunity to enhance the pharmacokinetic behavior and bioavailability of drugs, with documented instances of these nanocarriers elevating drug accumulation at the tumor location. The GO nanostructures encapsulate genes, shielding them from degradation and facilitating their uptake within cancer cells, thereby promoting efficient gene silencing. The capability of GO to facilitate phototherapy has led to notable advancements in reducing tumor progression. By PDT and PTT combination, GO nanomaterials hold the capacity to diminish tumorigenesis. GO nanomaterials have the potential to trigger both cellular and innate immunity, making them promising contenders for vaccine development. Additionally, types of GO nanoparticles that respond to specific stimuli have been applied in cancer eradication, as well as for the purpose of cancer detection and biomarker diagnosis. Endocytosis serves as the mechanism through which GO nanomaterials are internalized. Given these advantages, the utilization of GO nanomaterials for tumor elimination comes highly recommended.

PMID:37659647 | DOI:10.1016/j.envres.2023.117027

EBioMedicine. 2023 Aug 31;96:104771. doi: 10.1016/j.ebiom.2023.104771. Online ahead of print.

ABSTRACT

BACKGROUND: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans.

METHODS: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed.

FINDINGS: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40-266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94-277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69-4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52-3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments.

INTERPRETATION: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes.

FUNDING: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

PMID:37659283 | DOI:10.1016/j.ebiom.2023.104771

Water Res. 2023 Aug 14;244:120490. doi: 10.1016/j.watres.2023.120490. Online ahead of print.

ABSTRACT

Research on harmful algal blooms has focused on macronutrients, yet recent research increasingly indicates that understanding micronutrient roles is also important in the development of effective environmental management interventions. Here, we report results on metallophore production from mesocosms amended with copper and iron (enzymatic co-factors in photosynthetic electron transport) to probe questions of how cyanobacteria navigate the divide between copper nutrition, copper toxicity, and issues with iron bioavailability. These experiments utilized Microcystis, Chlorella and Desmodesmus spp., in mono- and mixed-cultures in lake water from a large, hypereutrophic lake (Taihu, China). To initiate experiments, copper and iron amendments were added to mesocosms containing algae that had been acclimated to achieve a state of copper and iron limitation. Mesocosms were analyzed over time for a range of analytes including algal growth parameters, algal assemblage progression, copper/iron concentrations and biomolecule production of chalkophore, siderophore and total microcystins. Community Trajectory Analysis and other multivariate methods were used for analysis resulting in our findings: 1) Microcystis spp. manage copper/iron requirements though a dynamically phased behavior of chalkophore/siderophore production according to their copper and iron limitation status (chalkophore correlates with Cu concentration, R2 = 0.99, and siderophore correlates with the sum of Cu and Fe concentrations, R2 = 0.98). 2) A strong correlation was observed between the production of chalkophore and the cyanobacterial toxin microcystin (R2 = 0.76)-Chalkophore is a predictor of microcystin production. 3) Based on our results and literature, we posit that Microcystis spp. produces microcystin in response to copper/iron availability to manage photosystem productivity and effect an energy-saving status. Results from this work underscore the importance of micronutrients in influencing harmful algal bloom progression and represents a major advance in understanding the ecological function for the cyanobacterial toxin microcystin as a hallmark of micronutrient limitation stress.

PMID:37659180 | DOI:10.1016/j.watres.2023.120490

Bioorg Chem. 2023 Aug 21;140:106782. doi: 10.1016/j.bioorg.2023.106782. Online ahead of print.

ABSTRACT

The study investigated the structure-activity relationship of newly synthesized dye-linker-macrocycle (DLM) conjugates and the effect of each component on various biological properties, including cytotoxicity, cellular uptake, intracellular localization, interaction with DNA and photodynamic effects. The conjugates were synthesized by combining 1,8-naphthalimide and thioxanthone dyes with 1,4,7,10-tetraazacyclododecane (cyclen) and 1-aza-12-crown-4 (1A12C4) using alkyl linkers of different lengths. The results revealed significant differences in biological activity among the various series of conjugates. Particularly, 1A12C4 conjugates exhibited notably higher cytotoxicity compared to cyclen conjugates. Conjugation with 1A12C4 proved to be an effective strategy for increasing cellular uptake and cytotoxicity of small-molecule conjugates. In addition, the results highlighted the critical role of linker length in modulating the biological activity of DLM conjugates. It became clear that the choice of each component (dye, macrocycle and linker) could significantly alter the biological activity of the conjugates.

PMID:37659149 | DOI:10.1016/j.bioorg.2023.106782

Cell Rep. 2023 Sep 1;42(9):113048. doi: 10.1016/j.celrep.2023.113048. Online ahead of print.

ABSTRACT

Current biochemical approaches have only identified the most well-characterized kinases for a tiny fraction of the phosphoproteome, and the functional assignments of phosphosites are almost negligible. Herein, we analyze the substrate preference catalyzed by a specific kinase and present a novel integrated deep neural network model named FuncPhos-SEQ for functional assignment of human proteome-level phosphosites. FuncPhos-SEQ incorporates phosphosite motif information from a protein sequence using multiple convolutional neural network (CNN) channels and network features from protein-protein interactions (PPIs) using network embedding and deep neural network (DNN) channels. These concatenated features are jointly fed into a heterogeneous feature network to prioritize functional phosphosites. Combined with a series of in vitro and cellular biochemical assays, we confirm that NADK-S48/50 phosphorylation could activate its enzymatic activity. In addition, ERK1/2 are discovered as the primary kinases responsible for NADK-S48/50 phosphorylation. Moreover, FuncPhos-SEQ is developed as an online server.

PMID:37659078 | DOI:10.1016/j.celrep.2023.113048

Angew Chem Int Ed Engl. 2023 Sep 1:e202308292. doi: 10.1002/anie.202308292. Online ahead of print.

ABSTRACT

Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10e, a first-in-class small molecule degrader of PDCD2. We discovered PDCD2 degrader by serendipity using a chemical proteomics approach in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights using chemical proteomics to discover selective small molecule degraders of unanticipated targets.

PMID:37658265 | DOI:10.1002/anie.202308292

Nat Genet. 2023 Sep 1. doi: 10.1038/s41588-023-01478-9. Online ahead of print.

NO ABSTRACT

PMID:37658185 | DOI:10.1038/s41588-023-01478-9

Sci Rep. 2023 Sep 1;13(1):14406. doi: 10.1038/s41598-023-41600-9.

ABSTRACT

Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson's disease, and addiction. Synthetic phenethylamines can have psychoactive and hallucinogenic effects due to their high affinity with the 5-HT2A receptor. Evidence indicates phenethylamines can directly alter the microtubule cytoskeleton being structurally similar to the microtubule destabilizing agent colchicine, however little work has been done on this interaction. As microtubules provide neuron structure, intracellular transport, and influence synaptic plasticity the interaction of phenethylamines with microtubules is important for understanding the potential harms, or potential pharmaceutical use of phenethylamines. We investigated 110 phenethylamines and their interaction with microtubules. Here we performed molecular docking of these compounds at the colchicine binding site and ranked them via binding energy. The top 10% of phenethylamines were further screened based on pharmacokinetic and physicochemical properties derived from SwissADME and LightBBB. Based on these properties 25B-NBF, 25C-NBF, and DMBMPP were tested in in vitro microtubule polymerization assays showing that they alter microtubule polymerization dynamics in a dose dependent manner. As these compounds can rapidly cross the blood brain barrier and directly affect cytoskeletal dynamics, they have the potential to modulate cytoskeletal based neural plasticity. Further investigations into these mechanisms are warranted.

PMID:37658096 | DOI:10.1038/s41598-023-41600-9

Nat Commun. 2023 Sep 1;14(1):5325. doi: 10.1038/s41467-023-41167-z.

ABSTRACT

The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38- blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142-/-BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142-/-BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142-/-BCR-ABL mice and patient-derived xenografts.

PMID:37658085 | DOI:10.1038/s41467-023-41167-z

Trends Genet. 2023 Aug 30:S0168-9525(23)00163-4. doi: 10.1016/j.tig.2023.07.005. Online ahead of print.

ABSTRACT

Cancer treatment strategies have evolved significantly over the years, with chemotherapy, targeted therapy, and immunotherapy as major pillars. Each modality leads to unique treatment outcomes by interacting with the tumor microenvironment (TME), which imposes a fundamental selective pressure on cancer progression. The advent of single-cell profiling technologies has revolutionized our understanding of the intricate and heterogeneous nature of the TME at an unprecedented resolution. This review delves into the commonalities and differential manifestations of how cancer therapies reshape the microenvironment in diverse cancer types. We highlight how groundbreaking immune checkpoint blockade (ICB) strategies alone or in combination with tumor-targeting treatments are endowed with comprehensive mechanistic insights when decoded at the single-cell level, aiming to drive forward future research directions on personalized treatments.

PMID:37658004 | DOI:10.1016/j.tig.2023.07.005

Trends Biochem Sci. 2023 Aug 30:S0968-0004(23)00204-9. doi: 10.1016/j.tibs.2023.08.001. Online ahead of print.

ABSTRACT

Intrinsically disordered proteins and protein regions (IDRs) are abundant in eukaryotic proteomes and play a wide variety of essential roles. Instead of folding into a stable structure, IDRs exist in an ensemble of interconverting conformations whose structure is biased by sequence-dependent interactions. The absence of a stable 3D structure, combined with high solvent accessibility, means that IDR conformational biases are inherently sensitive to changes in their environment. Here, we argue that IDRs are ideally poised to act as sensors and actuators of cellular physicochemistry. We review the physical principles that underlie IDR sensitivity, the molecular mechanisms that translate this sensitivity to function, and recent studies where environmental sensing by IDRs may play a key role in their downstream function.

PMID:37657994 | DOI:10.1016/j.tibs.2023.08.001

J Immunother Cancer. 2023 Sep;11(9):e006782. doi: 10.1136/jitc-2023-006782.

ABSTRACT

Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios-KLRG1+ subset of tumor-infiltrating regulatory T cells was associated with tumor progression from immune equilibrium to escape and was also lost in tumors responding to ICB. Validation studies confirmed KLRG1 signatures in human tumor-infiltrating CD4 T cells associate with disease progression in renal cancer. These findings nominate KLRG1+ CD4 T cell populations as subsets for further investigation in cancer immunity and demonstrate the utility of longitudinal spectral flow profiling as an engine of dynamic biomarker discovery.

PMID:37657842 | DOI:10.1136/jitc-2023-006782

Medicine (Baltimore). 2023 Sep 1;102(35):e34570. doi: 10.1097/MD.0000000000034570.

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) has caused a great threat to human health. Metabolic associated fatty liver disease (MAFLD) is a liver disease with a high prevalence rate. Previous studies indicated that MAFLD led to increased mortality and severe case rates of COVID-19 patients, but its mechanism remains unclear.

METHODS: This study analyzed the transcriptional profiles of COVID-19 and MAFLD patients and their respective healthy controls from the perspectives of bioinformatics and systems biology to explore the underlying molecular mechanisms between the 2 diseases. Specifically, gene expression profiles of COVID-19 and MAFLD patients were acquired from the gene expression omnibus datasets and screened shared differentially expressed genes (DEGs). Gene ontology and pathway function enrichment analysis were performed for common DEGs to reveal the regulatory relationship between the 2 diseases. Besides, the hub genes were extracted by constructing a protein-protein interaction network of shared DEGs. Based on these hub genes, we conducted regulatory network analysis of microRNA/transcription factors-genes and gene - disease relationship and predicted potential drugs for the treatment of COVID-19 and MAFLD.

RESULTS: A total of 3734 and 589 DEGs were screened from the transcriptome data of MAFLD (GSE183229) and COVID-19 (GSE196822), respectively, and 80 common DEGs were identified between COVID-19 and MAFLD. Functional enrichment analysis revealed that the shared DEGs were involved in inflammatory reaction, immune response and metabolic regulation. In addition, 10 hub genes including SERPINE1, IL1RN, THBS1, TNFAIP6, GADD45B, TNFRSF12A, PLA2G7, PTGES, PTX3 and GADD45G were identified. From the interaction network analysis, 41 transcription factors and 151 micro-RNAs were found to be the regulatory signals. Some mental, Inflammatory, liver diseases were found to be most related with the hub genes. Importantly, parthenolide, luteolin, apigenin and MS-275 have shown possibility as therapeutic agents against COVID-19 and MAFLD.

CONCLUSION: This study reveals the potential common pathogenesis between MAFLD and COVID-19, providing novel clues for future research and treatment of MAFLD and severe acute respiratory syndrome coronavirus 2 infection.

PMID:37657050 | DOI:10.1097/MD.0000000000034570