Obesity, defined by excessive body fat accumulation, is strongly associated with dysfunction of adipose tissue, a major regulator of whole-body energy balance and metabolic health. Dysfunctional adipose tissue is characterized by altered adipokine secretion, impaired insulin sensitivity, and chronic low-grade inflammation, all of which contribute to obesity-related comorbidities such as type 2 diabetes, cardiovascular disease, and certain cancers. Understanding how obesity disrupts adipose tissue biology is essential for developing strategies to mitigate these metabolic risks. In recent years, RNA-binding proteins (RBPs) have emerged as important regulators of energy metabolism. By controlling post-transcriptional gene expression, RBPs influence RNA stability, localization, and translation, thereby shaping key cellular processes. Dysregulation of specific RBPs has been implicated in obesity and metabolic disorders, with several shown to affect adipogenesis, lipid handling, thermogenesis, and insulin sensitivity across different adipose depots. Their ability to direct the fate of transcripts involved in metabolic homeostasis positions RBPs as critical nodes linking adipose dysfunction to systemic disease. This review provides a mechanistic overview of RBP functions in adipose biology, highlights how their dysregulation can reinforce metabolic dysfunction, and identifies gaps and future directions for exploring RBPs and their RNA networks as potential therapeutic targets for obesity and related metabolic diseases.

Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging.

Heat-related mortality remains health challenges exacerbated by climate change, with sex-based differences in outcomes, yet underlying mechanisms remain poorly understood. This study examined transcriptomic responses to heat exposure in peripheral blood mononuclear cells from 19 patients with heat stroke (HS; 8 males, mean age 64.8 ± 6.6 yr; 11 females, mean age 49.7 ± 11 yr) and 19 controls (11 males, mean age 48.9 ± 9.6 yr; 8 females, mean age 44.9 ± 11.8 yr). At admission, gene expression revealed upregulation of heat shock protein genes, and pathway analysis demonstrated activation of heat shock and unfolded protein responses across both sexes consistent with proteotoxic stress. However, distinct metabolic, oxidative stress, cell cycle control, and immune responses were observed within each sex. Females displayed inhibition of protein synthesis, oxidative phosphorylation, and metabolic pathways, including glucose metabolism, indicative of a hypometabolic state. Males maintained metabolic activity precooling and enhanced adenosine triphosphate production postcooling. Females activated nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress responses and inhibited DNA replication and mitosis, potentially mitigating genomic instability, whereas these pathways showed limited regulation in males. Females promoted innate immunity via interleukin (IL)-6, inflammasome, and triggering receptor expressed on myeloid cells 1 (TREM1) signaling, whereas males showed suppression of both innate and adaptive immunity, including IL-12, Th1, and T-cell receptor pathways. Upstream analysis identified over 100 transcription factors in both sexes. Males primarily relied on transcriptional mechanisms, whereas females also exhibited translational regulation via La ribonucleoprotein 1 (LARP1), fragile X messenger ribonucleoprotein 1 (FMR1), insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), and eukaryotic translation initiation factor 6 (EIF6). These findings suggest distinct, sex-specific molecular adaptations to heat stroke, underscoring the need for targeted therapeutic strategies to mitigate heat-induced morbidity and mortality.NEW & NOTEWORTHY Heat-related mortality continues to rise with climate change. Our transcriptomic analysis reveals distinct sex-specific metabolic strategies to heat stroke: females enter a hypometabolic state, an evolutionary adaptation that conserves energy, whereas males sustain metabolic activity. Transcription factors and a subset of translation regulators in females modulate proteostasis and bioenergetics, driving these sex-specific pathways. These novel findings highlight the critical need to consider sex-specific differences in heat-related illnesses and inform carefully targeted interventions to improve patient outcomes.

Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly correlated with hyperthermia-associated neurological damage. We used an untargeted proteomic approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify and characterize time-series proteome-wide changes in dose-responsive proteotoxic stress models in medulloblastoma [Daoy], neuroblastoma [SH-SY5Y], and differentiated SH-SY5Y neuron-like cells [SH(D)]. An integrated analysis of condition-time datasets identified global proteome-wide differentially expressed proteins (DEPs) as part of the heat-induced proteotoxic stress response. The condition-specific analysis detected higher DEPs and upregulated proteins in extreme heat stress with a relatively conservative and tight regulation in differentiated SH-SY5Y neuron-like cells. Functional network analysis using ingenuity pathway analysis (IPA) identified common intercellular pathways associated with the biological processes of protein, RNA, and amino acid metabolism and cellular response to stress and membrane trafficking. The condition-wise temporal pathway analysis in the differentiated neuron-like cells detects a significant pathway, functional, and disease association of DEPs with processes like protein folding and protein synthesis, Nervous System Development and Function, and Neurological Disease. An elaborate dose-dependent stress-specific and neuroprotective cellular signaling cascade is also significantly activated. Thus, our study provides a comprehensive map of the heat-induced proteotoxic stress response associating proteome-wide changes with altered biological processes. This helps to expand our understanding of the molecular basis of the heat-induced proteotoxic stress response with potential translational connotations.

This study investigates the molecular responses to heatstroke in young and old patients by comparing whole-genome transcriptomes between age groups. We analyzed transcriptomic profiles from patients categorized into two age-defined cohorts: young (mean age = 44.9 ± 6 yr) and old (mean age = 66.1 ± 4 yr). Control subjects, exposed to similar environmental heat conditions but without developing heatstroke, were also included in the analysis to provide a baseline for comparison. Despite uniform heatstroke severity at admission, as indicated by core body temperature, consciousness level, and organ damage markers, notable gene expression differences emerged. Old patients showed 37% fewer differentially expressed genes compared with young patients at admission, with a shift toward gene upregulation, deviating from the usual downregulation seen in heat stress responses. Both age groups exhibited increased heat shock protein gene expression, activated the heat stress, and unfolded protein responses indicating comparable proteotoxic stress. Nonetheless, age-specific differences were evident in critical regulatory pathways like Sirtuin, mTOR, and p53 signaling, along with key pathways related to proteostasis, energy metabolism, oxidative stress, and immune responses. Following cooling, older adults exhibited a decline in the heat stress response and a cessation of the unfolded protein response, in contrast to the sustained responses seen in younger individuals. This pattern suggests an age-related adaptability or a diminished protective response capacity with aging. These findings provide insights into the biological mechanisms that may contribute to age-specific vulnerabilities to heat.NEW & NOTEWORTHY Our study reveals distinct molecular responses to heatstroke across age groups, with older adults showing fewer differentially expressed genes and an atypical pattern of gene upregulation, contrasting with the downregulation in usual heat stress responses. It also uncovers a reduced heat stress response and an abbreviated unfolded protein response in older adults, likely impairing their cellular repair mechanisms. This contributes to increased vulnerability during severe heat waves, underscoring the urgent need for age-specific interventions.

Abstract RNA-binding proteins (RBPs) are key regulators of various cellular processes, including mRNA splicing, transport, stability, and translation. They play a crucial role in post-transcriptional gene regulation by interacting with specific RNA sequences or structures. RBPs can also influence the localization of mRNAs within the cell and participate in the formation of RNA-protein complexes that control gene expression. Dysregulation or mutations in RBPs have been associated with a wide range of diseases, including neurodegenerative disorders, cancer, and developmental abnormalities. Recent studies have highlighted the importance of RBPs in regulating adipocyte differentiation, lipid metabolism, and insulin sensitivity. However, the global expression patterns and functional contributions of RBPs during adipogenesis and in regulating adipocyte functioning remain poorly understood. Identifying and characterizing RBPs during adipogenesis could provide valuable insights into the molecular mechanisms underlying adipocyte differentiation and potentially lead to the development of novel therapeutic strategies for obesity-related disorders. Using a combination of bioinformatics tools and experimental validation, we identified a set of novel RBPs that may have important roles in adipogenesis and adipocyte functioning. We analyzed the expression of the entire repertoire of RBPs during the adipogenic differentiation of murine adipocyte cell line, 3T3-L1 and assessed the expression of RBPs in stromal vesicular fraction (SVF) and adipocyte fraction of mouse epididymal adipose tissue. We also evaluated the impact of high fat diet on the expression of RBPs in adipocytes isolated from mouse epididymal adipose tissue. We found a number of RBPS that were significantly up- or down-regulated in 3T3-L1 cells during adipogenic differentiation and were enriched in the stromal vascular fraction (SVF) or adipocyte fraction of mouse adipose tissue. In addition, they exhibited differential expression in adipocytes isolated from diet-induced obese mice compared to control mice. The majority of these RBPs have no known role in adipogenesis or adipose metabolism. These proteins could potentially play a novel role in adipogenic differentiation and adipose metabolism, suggesting the presence of previously unknown regulatory mechanisms. Further investigation is needed to understand the specific functions of these RBPs and their potential impact on adipose tissue development and metabolism. This discovery opens up new avenues for research in uncovering the intricate regulatory networks involved in adipogenesis and adipose tissue homeostasis.

Adipocytes play a critical role in maintaining a healthy systemic metabolism by storing and releasing energy in the form of fat and helping to regulate glucose and lipid levels in the body. Adipogenesis is the process through which pre-adipocytes are differentiated into mature adipocytes. It is a complex process involving various transcription factors and signaling pathways. The dysregulation of adipogenesis has been implicated in the development of obesity and metabolic disorders. Therefore, understanding the mechanisms that regulate adipogenesis and the factors that contribute to its dysregulation may provide insights into the prevention and treatment of these conditions. RNA-binding motif single-stranded interacting protein 1 (RBMS1) is a protein that binds to RNA and plays a critical role in various cellular processes such as alternative splicing, mRNA stability, and translation. RBMS1 polymorphism has been shown to be associated with obesity and type 2 diabetes, but the role of RBMS1 in adipose metabolism and adipogenesis is not known. We show that RBMS1 is highly expressed during the early phase of the differentiation of the murine adipocyte cell line 3T3-L1 and is significantly upregulated in the adipose tissue depots and adipocytes of high-fat-fed mice, implying a possible role in adipogenesis and adipose metabolism. Knockdown of RBMS1 in pre-adipocytes impacted the differentiation process and reduced the expression of some of the key adipogenic markers. Transcriptomic and proteomic analysis indicated that RBMS1 depletion affected the expression of several genes involved in major metabolic processes, including carbohydrate and lipid metabolism. Our findings imply that RBMS1 plays an important role in adipocyte metabolism and may offer novel therapeutic opportunity for metabolic disorders such as obesity and type 2 diabetes.

G protein-coupled receptors (GPCRs) are expressed essentially on all cells, facilitating cellular responses to external stimuli, and are involved in nearly every biological process. Several members of this family play significant roles in the regulation of adipogenesis and adipose metabolism. However, the expression and functional significance of a vast number of GPCRs in adipose tissue are unknown. We used a high-throughput RT-PCR panel to determine the expression of the entire repertoire of non-sensory GPCRs in mouse white, and brown adipose tissue and assess changes in their expression during adipogenic differentiation of murine adipocyte cell line, 3T3-L1. In addition, the expression of GPCRs in subcutaneous adipose tissues from lean, obese, and diabetic human subjects and in adipocytes isolated from regular chow and high-fat fed mice were evaluated by re-analyzing RNA-sequencing data. We detected a total of 292 and 271 GPCRs in mouse white and brown adipose tissue, respectively. There is a significant overlap in the expression of GPCRs between the two adipose tissue depots, but several GPCRs are specifically expressed in one of the two tissue types. Adipogenic differentiation of 3T3-L1 cells had a profound impact on the expression of several GPCRs. RNA sequencing of subcutaneous adipose from healthy human subjects detected 255 GPCRs and obesity significantly changed the expression of several GPCRs in adipose tissue. High-fat diet had a significant impact on adipocyte GPCR expression that was similar to human obesity. Finally, we report several highly expressed GPCRs with no known role in adipose biology whose expression was significantly altered during adipogenic differentiation, and/or in the diseased human subjects. These GPCRs could play an important role in adipose metabolism and serve as a valuable translational resource for obesity and metabolic research.

Heat stroke is among the most hazardous hyperthermia-related illnesses and an emerging threat to humans from climate change. Acute brain injury and long-lasting brain damage are the hallmarks of this condition. Hyperthermic neurological manifestations are remarkable for their damage correlation with stress amplitude and long-term persistence. Hyperthermia-induced protein unfolding, and nonspecific aggregation accumulation have neurotoxic effects and contribute to the pathogenesis of brain damage in heat stroke. Therefore, we generated heat-induced, dose-responsive extreme and mild proteotoxic stress models in medulloblastoma [Daoy] and neuroblastoma [SH-SY5Y] and differentiated SH-SY5Y neuronal cells. We show that heat-induced protein aggregation is associated with reduced cell proliferation and viability. Higher protein aggregation in differentiated neurons than in neuroblastoma precursors suggests a differential neuronal vulnerability to heat. We characterized the neuronal heat shock response through RT-PCR array analysis of eighty-four genes involved in protein folding and protein quality control (PQC). We identify seventeen significantly expressed genes, five of which are Hsp70 chaperones, and four of their known complementing function proteins. Protein expression analysis determined the individual differential contribution of the five Hsp70 chaperones to the proteotoxic stress response and the significance of only two members under mild conditions. The co-expression analysis reveals significantly high co-expression between the Hsp70 chaperones and their interacting partners. The findings of this study lend support to the hypothesis that hyperthermia-induced proteotoxicity may underlie the brain injury of heat stroke. Additionally, this study presents a comprehensive map of the Hsp70 network in these models with potential clinical and translational implications.

Obesity is one of the most pressing healthcare concerns of the twenty-first century. Obesity prevalence has risen dramatically in recent decades, and in 2016, more than 1.9 billion adults were overweight (BMI ≥ 25 kg/m2) and 650 million were obese (BMI ≥ 30 kg/m2). About 50% of the world’s population is anticipated to be obese/overweight within the next decade. Obesity is a major risk factor for a variety of non-communicable diseases, including type 2 diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, and a variety of malignancies. Obesity has emerged as a substantial risk factor for hospitalization and death from viral respiratory infections such as influenza A and the ongoing pandemic SARS-CoV-2. Several independent studies have indicated that obese/overweight patients are at a higher risk of severe disease and death from these respiratory diseases. Excess fat, particularly visceral fat, contributes to the development of a variety of metabolic disorders, including persistent systemic inflammation and decreased immunological function. As a result, the immunological response to infectious pathogens is weakened, resulting in poorer outcomes post-infection. Additionally, the poor lung mechanics associated with obesity may increase the risk of more serious respiratory infections. In this review, we address the likely mechanism(s) that predispose obese people to severe diseases caused by viral respiratory infections.

Context Bariatric surgery has been shown to be effective in inducing complete remission of type 2 diabetes in adults with obesity. However, its efficacy in achieving complete diabetes remission remains variable and difficult to predict before surgery.Objectives We aimed to characterize bariatric surgery-induced transcriptome changes associated with diabetes remission and the predictive role of the baseline transcriptome.Patients and Methods We performed a whole genome microarray in peripheral mononuclear cells at baseline (before surgery) and 2 and 12 months after bariatric surgery in a prospective cohort of 26 adults with obesity and type 2 diabetes. We applied machine learning to the baseline transcriptome to identify genes that predict metabolic outcomes. We validated the microarray expression profile using a real-time polymerase chain reaction.Results Sixteen patients entered diabetes remission at 12 months and ten did not. The gene expression analysis showed similarities and differences between responders and nonresponders. The difference included the expression of critical genes (SKT4, SIRT1, and TNF superfamily), metabolic and signaling pathways (Hippo, Sirtuin, ARE-Mediated mRNA Degradation, MSP-RON, and Huntington), and predicted biological functions (beta cell growth and proliferation, insulin and glucose metabolism, energy balance, inflammation, and neurodegeneration). Modeling the baseline transcriptome identified ten genes that could hypothetically predict the metabolic outcome before bariatric surgery.Conclusions The changes in the transcriptome after bariatric surgery distinguish patients in whom diabetes enters complete remission from those who do not. The baseline transcriptome can contribute to the prediction of bariatric surgery-induced diabetes remission preoperatively.

An evolutionary heat shock response (HSR) protects most living species, including humans, from heat-induced macromolecular damage. However, its role in the pathogenesis of heat stroke is unknown. We examined the whole genome transcriptome in peripheral blood mononuclear cells of a cohort of subjects exposed to the same high environmental heat conditions, who developed heat stroke (n = 19) versus those who did not (n = 19). Patients with heat stroke had a mean rectal temperature at admission of 41.7 ± 0.8°C, and eight were in deep coma (Glasgow Coma Score = 3). The transcriptome showed that genes involved in more than half of the entire chaperome were differentially expressed relative to heat stress control. These include the heat shock protein, cochaperone, and chaperonin genes, indicating a robust HSR. Differentially expressed genes also encoded proteins related to unfolded protein response, DNA repair, energy metabolism, oxidative stress, and immunity. The analysis predicted perturbations of the proteome network and energy production. Cooling therapy attenuated these alterations without complete restoration of homeostasis. We validated the significantly expressed genes by a real-time polymerase chain reaction. The findings reveal the molecular signature of heat stroke. They also suggested that a powerful HSR may not be sufficient to protect against heat injury. The overwhelming proteotoxicity and energy failure could play a pathogenic role. KEY POINTS: Most living species, including humans, have inherent heat stress response (HSR) that shields them against heat-induced macromolecular damage. The role of the HSR in subjects exposed to environmental heat who progressed to heat stroke versus those that did not is unknown. Our findings suggest that heat stroke induces a broad and robust HSR of nearly half of the total heat shock proteins, cochaperones, and chaperonin genes. Heat stroke patients exhibited inhibition of genes involved in energy production, including oxidative phosphorylation and ATP production. Significant enrichment of neurodegenerative pathways, including amyloid processing signalling, the Huntington's and Parkinson's disease signalling suggestive of brain proteotoxicity was noted. The data suggests that more than a powerful HSR may be required to protect against heat stroke. Overwhelming proteotoxicity and energy failure might contribute to its pathogenesis.

Context:Bariatric surgery has been shown to be effective in inducing complete remission of type 2 diabetes in adults with obesity. However, its efficacy in achieving complete diabetes remission remains variable and difficult to predict before surgery.Objective:We aimed to characterize bariatric surgery-induced transcriptome changes associated with diabetes remission and the predictive role of the baseline transcriptome.Methods:We performed a whole-genome microarray in peripheral mononuclear cells at baseline (before surgery) and 2 and 12 months after bariatric surgery in a prospective cohort of 26 adults with obesity and type 2 diabetes. We applied machine learning to the baseline transcriptome to identify genes that predict metabolic outcomes. We validated the microarray expression profile using a real-time polymerase chain reaction.Results:Sixteen patients entered diabetes remission at 12 months and 10 did not. The gene-expression analysis showed similarities and differences between responders and nonresponders. The difference included the expression of critical genes (SKT4, SIRT1, and TNF superfamily), metabolic and signaling pathways (Hippo, Sirtuin, ARE-mediated messenger RNA degradation, MSP-RON, and Huntington), and predicted biological functions (β-cell growth and proliferation, insulin and glucose metabolism, energy balance, inflammation, and neurodegeneration). Modeling the baseline transcriptome identified 10 genes that could hypothetically predict the metabolic outcome before bariatric surgery.Conclusion:The changes in the transcriptome after bariatric surgery distinguish patients in whom diabetes enters complete remission from those who do not. The baseline transcriptome can contribute to the prediction of bariatric surgery-induced diabetes remission preoperatively.

Placenta-derived stem cells (PDSCs), due to unique traits such as mesenchymal and embryonic characteristics and the absence of ethical constraints, are in a clinically and therapeutically advantageous position. To aid in stemness maintenance, counter pathophysiological stresses, and withstand post-differentiation challenges, stem cells require elevated protein synthesis and consequently augmented proteostasis. Stem cells exhibit source-specific proteostasis traits, making it imperative to study them individually from different sources. These studies have implications for understanding stem cell biology and exploitation in the augmentation of therapeutic applications. Here, we aim to identify the primary determinants of proteotoxic stress response in PDSCs. We generated heat-induced dose-responsive proteotoxic stress models of three stem cell types: placental origin cells, the placenta-derived mesenchymal stem cells (pMSCs), maternal origin cells, the decidua parietalis mesenchymal stem cells (DPMSCs), and the maternal–fetal interface cells, decidua basalis mesenchymal stem cells (DBMSCs), and measured stress induction through biochemical and cell proliferation assays. RT-PCR array analysis of 84 genes involved in protein folding and protein quality control led to the identification of Hsp70 members HSPA1A and HSPA1B as the prominent ones among 17 significantly expressed genes and with further analysis at the protein level through Western blotting. A kinetic analysis of HSPA1A and HSPA1B gene and protein expression allowed a time series evaluation of stress response. As identified by protein expression, an active stress response is in play even at 24 h. More prominent differences in expression between the two homologs are detected at the translational level, alluding to a potential higher requirement for HSPA1B during proteotoxic stress response in PDSCs.

Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein-coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid-activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids like acetate, propionate, and butyrate, whereas FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids like palmitate, oleate, linoleate, and others. FFARs have attracted considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here, we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR-based therapies to treat patients with obesity and Type 2 diabetes.

Aim: The study aims to understand the role of tumor suppressor genes in colorectal cancer initiation and progression. Background: Sporadic colorectal cancer (CRC) develops through distinct molecular events. Loss of the 18q chromosome is a conspicuous event in the progression of adenoma to carcinoma. There is limited information regarding the molecular effectors of this event. Earlier, we had reported ATP8B1 as a novel gene associated with CRC. ATP8B1 belongs to the family of P-type ATPases (P4 ATPase) that primarily function to facilitate the translocation of phospholipids. Objective: In this study, we attempt to implicate the ATP8B1 gene located on chromosome 18q as a tumor suppressor gene. Methods: Cells culture, Patient data analysis, Generation of stable ATP8B1 overexpressing SW480 cell line, Preparation of viral particles, Cell Transduction, Generation of stable ATP8B1 knockdown HT29 cell line with CRISPR/Cas9, Generation of stable ATP8B1 knockdown HT29 cell line with shRNA, Quantification of ATP8B1 gene expression, Real-time cell proliferation and migration assays, Cell proliferation assay, Cell migration assay, Protein isolation and western blotting, Endpoint cell viability assay, Uptake and efflux of sphingolipid, Statistical and computational analyses. Results: We studied indigenous patient data and confirmed the reduced expression of ATP8B1 in tumor samples. CRC cell lines were engineered with reduced and enhanced levels of ATP8B1, which provided a tool to study its role in cancer progression. Forced reduction of ATP8B1 expression either by CRISPR/Cas9 or shRNA was associated with increased growth and proliferation of CRC cell line - HT29. In contrast, overexpression of ATP8B1 resulted in reduced growth and proliferation of SW480 cell lines. We generated a network of genes that are downstream of ATP8B1. Further, we provide the predicted effect of modulation of ATP8B1 levels on this network and the possible effect on fatty acid metabolism-related genes. Conclusion: Tumor suppressor gene (ATP8B1) located on chromosome 18q could be responsible in the progression of colorectal cancer. Knocking down of this gene causes an increased rate of cell proliferation and reduced cell death, suggesting its role as a tumor suppressor. Increasing the expression of this gene in colorectal cancer cells slowed down their growth and increased cell death. These evidences suggest the role of ATP8B1 as a tumor suppressor gene.

Placenta-derived stem cells (PDSCs) offer the advantages of possessing mesenchymal and embryonic traits, broad differentiation potential, large-scale availability, and no ethical constraints in their utilization in therapeutic applications. Elevated protein synthesis and consequently enhanced protein maintenance networks become necessary both due to the requirement to maintain stemness and respond to different stresses. This study aimed to identify the primary determinants of proteotoxic stress response in PDSCs. We generated heat-induced dose-responsive proteotoxic stress models of three stem cell types DBMSCs, DPMSCs, and pMSCs, and measured stress induction through biochemical and cell proliferation assays. RT-PCR array analysis of 84 genes involved in protein folding and protein quality control led to the identification of Hsp70 isoforms HSPA1A and HSPA1B as the prominent ones among 17 significantly expressed genes and with further analysis at the protein level through western blotting. A 24-hours’ time series analysis of stress-response allowed a detailed kinetic analysis of HSPA1A and HSPA1B gene and protein expression. More prominent differences between the two Hsp70 isoforms were detected at the translational level eluding to a potential higher requirement for HSPA1B during proteotoxic stress in PDSCs. To conclude, consideration should be given to the manipulation of definitely characterized chaperones at their expression or functional levels when utilizing PDSCs in therapeutic and regenerative applications.