Biology subjects

Salimi, M.

Publications and source records attributed to Salimi, M..

10 recordsLinked to original sources

bioRxiv2026

Sobetirome, a thyroid hormone receptor beta agonist, is a potential therapeutic agent for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with limited treatment options. Our group previously identified the antifibrotic potential of thyroid hormone, triiodothyronine (T3); however, clinical translation of thyroid hormone therapy is limited by its systemic adverse effects. In this study, we investigate whether sobetirome, a selective and well tolerated thyroid hormone receptor beta (THRB) agonist, offers antifibrotic benefits of thyroid hormone while minimizing systemic toxicity. Our study reveals that sobetirome, administered via intraperitoneal or inhalational routes, effectively mitigates bleomycin-induced pulmonary fibrosis in mice, with no evidence of toxicity. We identified that sobetirome restores mitochondrial homeostasis via activating the THRB-PPARGC1a axis. This protects alveolar type II epithelial cells from injury-induced apoptosis while selectively inducing apoptosis and metabolic reprogramming in apoptosis resistant IPF fibroblasts. Cell-specific deletion of Ppargc1a in either alveolar epithelial cells or fibroblasts abolishes sobetirome-mediated protection, establishing PPARGC1a as an essential mediator of therapeutic response. Importantly, sobetirome reverses fibrosis-associated transcriptional programs in human IPF lung tissue, reducing expression of key fibrosis-associated genes, including collagen I alpha 1 (COL1A1), collagen III alpha 1 (COL3A1), periostin (POSTN), cathepsin K (CTSK), and Chitinase 3 Like 1 (CHI3L1), while promoting extracellular matrix remodeling, epithelial restoration, and tissue homeostasis. Collectively, our findings identify THRB activation as a novel metabolic strategy for reversing pulmonary fibrosis. Across complementary in vitro, in vivo, and human ex vivo models, sobetirome restores mitochondrial function, modulates apoptotic pathways in pathogenic cells, and promotes fibrosis resolution, highlighting its potential as a lung-targeted therapeutic approach for IPF and other fibrotic lung diseases.

systems biology↗

bioRxiv2026

Cortical oscillations reflect opponent ensemble dynamics through coordinated multifrequency activity

Neural oscillations are widely used as proxies for neuronal activity, where power in individual frequency bands is commonly interpreted as functionally indexing neural circuit engagement. However, power in individual frequency bands shows heterogeneous and sometimes opposing relationships with neuronal activity across regions and behavioral contexts, challenging the assumption of a stable frequency-to-circuit mapping. Here we show that glutamatergic population activity in rat medial prefrontal cortex is not stably linked with power in isolated frequency bands, but rather with dynamically recurring multi-frequency amplitude co-fluctuations. These multi-frequency patterns, termed spectral motifs, occurred in opponent pairs with nearly identical frequency composition but inverted relationships to population calcium activity. This opponent motif structure, observed across cortical regions and species, provides a key component for understanding how oscillations are linked to neuronal activity. We found that shifts in motif opponency balance explained changes in glutamatergic activity that occur during brain-computer interface learning better than models based on frequency band power alone. Furthermore, opponent motifs map selectively onto opponent cell ensembles and enable bidirectional mapping between local field potentials and ensemble activity. These findings identify multi-frequency opponent motifs as a conserved organizational principle linking oscillatory dynamics to population-level circuit states and challenge the notion that individual frequency bands can serve as interpretable functional units mapping onto neural circuit activity.

neuroscience↗

bioRxiv2025

Methylphenidate-induced reductions in choice impulsivity are associated with alterations in cortico-striatal beta oscillations.

Impulsive choice- preferring small, immediate rewards over larger, delayed reward- is a hallmark of many psychiatric disorders. Methylphenidate, a dopamine and noradrenaline transporter inhibitor, reduces impulsivity, but the neural mechanisms underlying this effect remain unclear. Identifying a neurophysiological signature of methylphenidates action could be used clinically to predict treatment response and guide drug development. To this end, we recorded local field potentials (LFP) from 32 electrodes spanning cortico-striatal circuits in rats performing a temporal discounting task, under saline or methylphenidate treatment conditions. Methylphenidate decreased beta frequency (15-30 Hz) power and connectivity for small, immediate rewards while simultaneously increasing beta power for large, delayed rewards. Reduced connectivity in cortico-striatal networks during small rewards predicted increased preference for delayed rewards. These findings suggest that methylphenidate influences discounting behavior by modulating reward-evoked beta oscillations in cortico-striatal networks. Thus, beta oscillations may serve as a translational biomarker of treatment responsivity to monoaminergic drugs, providing a circuit-level assay to measure and predict changes in impulsive behavior.

neuroscience↗

bioRxiv2025

Differential glutamatergic and GABAergic responses drive divergent prefrontal cortex neural outcomes to low and high frequency stimulation

BackgroundRepetitive brain stimulation is hypothesized to bidirectionally modulate excitability, with low-frequency trains decreasing and high-frequency (>5 Hz) trains increasing activity. Most insights on the neuroplastic effects of repetitive stimulation protocols stem from non-invasive human studies (TMS/EEG) or data from rodent slice physiology. Here, we developed a rodent experimental preparation enabling simultaneous imaging of cellular activity during stimulation in vivo to understand the mechanisms by which brain stimulation modulates excitability of prefrontal cortex. MethodsRepetitive trains of intracortical stimulation were applied to the medial prefrontal cortex using current parameters mapped to human rTMS electric-field estimates. Calcium imaging of glutamatergic (CamKII) and GABAergic (mDLX) neurons was performed before, during, and after stimulation in awake rodents (n=9 females). Protocols included low-frequency (1 Hz, 1000 pulses) and high-frequency (10 Hz, 3000 pulses), with sham stimulation as a control. ResultsGlutamatergic neurons were differentially modulated by stimulation frequency, with 10 Hz increasing and 1 Hz decreasing activity. Post-stimulation, 1 Hz suppressed both glutamatergic and GABAergic activity, whereas 10 Hz selectively suppressed GABAergic neurons. ConclusionsThese findings provide direct evidence that clinical brain stimulation protocols induce long-term modulation of cortical excitability, with low-frequency stimulation broadly suppressing activity and high-frequency stimulation preferentially inhibiting GABAergic neurons after stimulation.

neuroscience↗

bioRxiv2024

Intermittent Theta Burst Stimulation Drives Bi-Directional Changes in Excitability in Prefrontal Cortex

Intermittent Theta Burst Stimulation (iTBS) is a patterned stimulation protocol FDA-cleared to treat depression, yet its outcomes are variable and mechanistically unclear. Here, using a combination of calcium imaging, histology, optogenetics and behavior, we show that one parameter of iTBS, the inter-train interval (ITI) between stimulation trains, plays a critical role in modulating GABAergic (and especially parvalbumin) neuronal activity, modulating subsequent neuronal plasticity and antidepressant effects. Shorter ITI stimulation protocols (4-10Ssinter-train intervals) activate GABA neurons, limiting resulting changes in cortical excitability and plasticity compared to extended interval TBS protocols (eTBS, with a 20s ITI). eTBS also drives the largest changes in synaptic / spine plasticity and leads to rapid and durable antidepressant-like effects after only a single stimulation session. Optogenetic activation of GABAergic neurons during eTBS blocks synaptic plasticity and rapid antidepressant effects. Together, these findings reveal a temporal control principle for TBS-induced cortical plasticity and provides a physiology-based strategy to improve TBS efficacy. HighlightsO_LIInter-train interval (ITI) controls excitatory-inhibitory balance during theta burst stimulation C_LIO_LIShort ITIs strongly activate PV interneurons limiting longer-term changes in glutamatergic excitatory plasticity C_LIO_LIExtended ITI (20s in particular) reduces inhibitory activity while maintaining sufficient activation of glutamatergic neurons to promote post-stimulation plasticity C_LIO_LIeTBS produces rapid and durable antidepressant-like effects that are blocked by GABAergic co-activation C_LI Graphical AbstractInter-train interval (ITI) determines the balance between excitation and inhibition during theta burst stimulation (TBS), an FDA-cleared treatment for depression. (A) Short ITIs (4s) drive concurrent glutamatergic and GABAergic activation, with inhibitory dominance during stimulation and suppressed long-term modulation of excitability. Extending the ITI to 20s (eTBS) reduces GABAergic recruitment during stimulation, promoting sustained long-term glutamatergic modulation resulting cortical disinhibition, leading to rapid and durable antidepressant-like effects (B). Optogenetic activation of GABAergic interneurons during eTBS abolishes synaptic and antidepressant effects, demonstrating that reduced inhibitory recruitment during eTBS is required for the rapid and durable behavioral effects observed with that protocol. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/608693v3_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@15a7decorg.highwire.dtl.DTLVardef@1220forg.highwire.dtl.DTLVardef@63258forg.highwire.dtl.DTLVardef@13707e7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Olfactory bulb stimulation mitigates Alzheimer-like disease progression

BackgroundDeep brain stimulation (DBS) has demonstrated potential in mitigating Alzheimers disease (AD). However, the invasive nature of DBS presents challenges for its application. The olfactory bulb (OB), showing early AD-related changes and extensive connections with memory regions, offers an attractive entry point for intervention, potentially restoring normal activity in deteriorating memory circuits. AimsOur study examined the impact of electrically stimulating the OB on working memory as well as pathological and electrophysiological alterations in the OB, medial prefrontal cortex, hippocampus, and entorhinal cortex in amyloid beta (A{beta}) AD model rats. MethodsMale Wistar rats underwent surgery for electrode implantation in brain regions, inducing Alzheimers-like disease. Bilateral olfactory bulb (OB) electrical stimulation was performed for 1 hour daily to the OB of stimulation group animals for 18 consecutive days, followed by evaluations of histological, behavioral, and local field potential signal processing. ResultsOB stimulation counteracted A{beta} plaque accumulation and prevented AD-induced working memory impairments. Furthermore, it prompted an increase in power across diverse frequency bands and enhanced functional connectivity, particularly in the gamma band, within the investigated regions during a working memory task. ConclusionThis preclinical investigation highlights the potential of olfactory pathway-based brain stimulation to modulate the activity of deep-seated memory networks for AD treatment. Importantly, the accessibility of this pathway via the nasal cavity lays the groundwork for the development of minimally invasive approaches targeting the olfactory pathway for brain modulation.

neuroscience↗

bioRxiv2022

Gene Expression Profiles Reveal Potential Targets for Breast Cancer Diagnosis and Treatment

Figuring out the molecular mechanisms underlying breast cancer is essential for the diagnosis and treatment of this invasive disorder. Hence it is important to identify the most significant genes correlated with molecular events and to study their interactions in order to identify breast cancer mechanisms. Here we focus on the gene expression profiles, which we have detected in breast cancer. High-throughput genomic innovations such as microarray have helped us understand the complex dynamics of multisystem diseases such as diabetes and cancer. We performed an analysis using microarray datasets by the Networkanalyst bioinformatics tool, based on a random effect model (REM). We achieved pivotal differential expressed genes like ADAMTS5, SCARA5, IGSF10, and C2orf40 that had the most down-regulation, and also COL10A1, COL11A1, and UHRF1 that they had the most up-regulation in four-stage of breast cancer. We used CentiScape and AllegroMCODE plugins in CytoScape software in order to figure out hub genes in the protein-protein interactions network. Besides, we utilized DAVID online software to find involved biological pathways and Gene ontology, also used Expression2kinase software in order to find upstream regulatory transcription factors and kinases. In conclusion, we have found that the statistical network inference approach is useful in gene prioritization and is capable of contributing to practical network signature discovery and providing insights into the mechanisms relevant to the disease. Our research has also identified novel transcription factors, kinases, pathways, and genes that may serve as important targets for the development of diagnostic biomarkers and treatments.

cancer biology↗

bioRxiv2019

Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Circular RNAs (circRNAs) along other complementary regulatory elements in ceRNAs networks possess valuable characteristics for both diagnosis and treatment of several human cancers including breast cancer (BC). In this study, we combined several systems biology tools and approaches to identify influential BC circRNAs, RNA binding proteins (RBPs), miRNAs, and related mRNAs to study and decipher the BC triggering biological processes and pathways.\n\nRooting from the identified total of 25 co-differentially expressed circRNAs (DECs) between triple negative (TN) and luminal A subtypes of BC from microarray analysis, five hub DECs (hsa_circ_0003227, hsa_circ_0001955, hsa_circ_0020080, hsa_circ_0001666, and hsa_circ_0065173) and top eleven RBPs (AGO1, AGO2, EIF4A3, FMRP, HuR (ELAVL1), IGF2BP1, IGF2BP2, IGF2BP3, EWSR1, FUS, and PTB) were explored to form the upper stream regulatory elements. All the hub circRNAs were regarded as super sponge having multiple miRNA response elements (MREs) for numerous miRNAs. Then four leading miRNAs (hsa-miR-149, hsa-miR-182, hsa-miR-383, and hsa-miR-873) accountable for BC progression were also introduced from merging several ceRNAs networks. The predicted 7- and 8-mer MREs matches between hub circRNAs and leading miRNAs ensured their enduring regulatory capability. The mined downstream mRNAs of the circRNAs-miRNAs network then were presented to STRING database to form the PPI network and deciphering the issue from another point of view. The BC interconnected enriched pathways and processes guarantee the merits of the ceRNAs networks members as targetable therapeutic elements.\n\nThis study suggested extensive panels of novel covering therapeutic targets that are in charge of BC progression in every aspect, hence their impressive role cannot be excluded and needs deeper empirical laboratory designs.

bioinformatics↗

bioRxiv2018

Type-2 CD8+ T lymphocytes responsive to PGD2 and LTE4 in severe eosinophilic asthma

The functions and in vivo roles of type-2 CD8+ T cells in humans have not been well defined and this cell type has been largely overlooked in models of disease. We investigated this in the context of severe asthma with persistent airway eosinophilia - a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

immunology↗

bioRxiv2017

A Rational Drug Combination Design Proves to Inhibit Epithelial-Mesenchymal Transition in a Three-Dimensional Microenvironment

Epithelial-Mesenchymal Transition (EMT) is a major player of tumor invasiveness whose inhibition is challenged by redundancy of multiple inducing factors. We applied a systems-pharmacology approach by integrating network-based analyses with multiple bioinformatic resources to design a drug combination regimen reversing EMT phenotype in aggressive cancers. We observed that histone deacetylases were critical targets to tune expression of multiple epithelial versus mesenchymal genes. Moreover, SRC and IKBK were the principal intracellular kinases regulating multiple signaling pathways. To validate the anti-EMT efficacy of the target combinations, we inhibited the pinpointed proteins with already prescribed drugs and observed that whereas low dose mono-therapy failed to limit cell dispersion from collagen spheroids in a microfluidic device as a metric of EMT, the combination fully inhibited dissociation and invasion of cancer cells toward co-cultured endothelial cells. Given the approval status and safety profiles of the suggested drugs, the proposed combination set can be considered in clinical trials.

systems biology↗