The pathogenesis of inflammation and tumors is a focal point of scientific inquiry, with oxidative stress often serving as the primary initiator. Within the human genome, the SESN3 gene encodes the SESN3 protein, a crucial antioxidant stress protein. Acting as a regulatory factor, SESN3 intricately modulates cellular oxidative stress, actively participating in cellular protection and repair mechanisms. Its functions span antioxidative, anti-aging, and anti-tumor properties. The expression of SESN3 is closely linked to cellular and oxidative stress, metabolic status, and specific signaling pathways. This review aims to delve into the origins and functions of SESN3, its role within signaling pathways, and its contributions to inflammation and tumorigenesis.

Sestrins (SESN1-3) are a family of stress-responsive proteins that regulate cellular metabolism and redox balance, both of which are frequently disrupted in cancer. As direct targets of stress-responsive transcription factors, including tumour suppressor p53, Sestrins function as leucine-dependent inhibitors of mTORC1 and potent antioxidants. Their downregulation is widely observed across multiple cancers and is associated with increased tumour growth and poor prognosis. Despite their consistent tumour-suppressive effects through mTORC1 inhibition and promotion of p53-dependent apoptosis, Sestrins exhibit a limited role in tumour initiation, which appears to be context-dependent. Their antioxidant activity reduces oxidative damage, thereby protecting against genomic instability and other cancer-promoting events. However, in certain contexts, Sestrins may promote tumour survival and progression by stimulating pro-survival pathways, such as AKT signalling through mTORC2 activation. This review examines the molecular mechanisms underlying these dual functions, with a particular focus on mTOR signalling and oxidative stress. We also discuss Sestrin expression patterns and functional outcomes in various cancer types, including lung, liver, colon, skin, prostate, and follicular lymphomas, highlighting their potential as diagnostic markers and therapeutic targets.

Ibuprofen (IBU), a prevalent non-steroidal anti-inflammatory drug (NSAID), is extensively utilized in medical practices. Especially since the popularity of COVID-19, its use has become more widespread, coupled with its low degradation rate and high environmental residues. Thus, more focus is warranted on the possible detrimental impacts on non-target organisms, as well as the underlying mechanisms of toxicity. The present study investigated the relationships and molecular mechanisms between hepatic mitochondrial dynamics processes and lipid metabolism in the yellowstripe goby (Mugilogobius chulae) exposed to IBU at concentrations of 0.5, 5, 50, and 500 μg/L over 7 days. The results showed that IBU exposure inhibited mitochondrial biogenesis and fusion but promoted mitochondrial fission by interfering with the SESN/PGC/ULK signaling pathway, causing an imbalance in mitochondrial dynamics. Thus, high concentration of IBU exposure caused mitochondrial dysfunction and oxidative stress. Molecular biological evidences suggested that IBU caused a decrease in ATP production and lipogenesis, leading to an energetic crisis in M. chulae. Hepatic tissue also showed a significant decrease in relative weight, an increase in mitochondrial damage and adipocyte degeneration. Correspondingly, the exposed organism attempted to mitigate these crises by promoting mitophagy and lipophagy via the Pink-Parkin pathway. Overall, IBU exposure interfered with mitochondrial dynamics processes and caused abnormalities in hepatic lipid metabolism in M. chulae. The present study highlighted the discovery of mitochondrial dynamics imbalance to lipid dysregulation cascade mechanism. We emphasized the negative effects of NSAIDs such as IBU on aquatic non-target organisms at different levels. It provided valuable insights into the ecological risk assessment of IBU in aquatic environments.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease closely related to aging with unclear pathogenic mechanisms. This study aims to identify the biomarkers in RA, aging and autophagy using bioinformatics and machine learning and explore the binding stability of taurine to target utilizing computer-aided drug design (CADD).

We identified differentially expressed genes (DEGs) for RA, then crossed with gene libraries for aging and autophagy to identify common genes (Co-genes). We performed Gene Ontology (GO), Kyoto Encyclopedia of the Genome (KEGG), and ClueGO analysis for Co-genes. The Co-genes were subjected to support vector machine-recursive feature elimination (SVM-RFE), Degree, and Betweenness algorithms to get hub genes, then verified by an artificial neural network (ANN). After continuing to perform least absolute shrinkage and selection operator (LASSO) and weighted gene co-expression network analysis (WGCNA) on Co-genes, the results were crossed with hub genes to obtain genes, which were imported into various validation sets for receiver operating characteristics (ROC) to identify key genes. We analyzed the microRNA/TF network, enriched pathways, and immune cell infiltration for key genes. The binding stability of taurine with the target protein was verified by CADD. Finally, we used Western blot for in vitro experimental verification.

We obtained 74 Co-genes enriched in RA, cellular senescence, and regulation of programmed cell death. The model prediction of hub genes works well in ANN. The key genes (MMP9, CXCL10, IL15, FOXO3) were tested in ROC with excellent efficacy. In RA, FOXO3 expression was down-regulated while MMP9, CXCL10, and IL15 expression were upregulated, and FOXO3 was negatively correlated with MMP9, CXCL10, and IL15. Two miRNAs (hsa-mir-21-5p, hsa-mir-129-2-3p) and four TFs (CTCF, KLF, FOXC1, TP53) were associated with key genes. The immune cells positively correlated with MMP9, CXCL10, and IL15 expression and negatively correlated with FOXO3 expression were Plasma cells, CD8 T cells, memory-activated CD4 T cells, and follicular helper T cells, aggregating in RA. The binding stability of taurine with FOXO3 was verified by molecular docking and molecular dynamics simulation. In vitro experiments have indicated that taurine can upregulate the expression of FOXO3 and treat RA through the FOXO3-Parkin signaling pathway.

MMP9, CXCL10, IL15, and FOXO3 are biomarkers of RA, cellular senescence, and autophagy. Taurine might be a promising drug against RA via targeting cellular senescence and autophagy through FOXO3.

Tuberculosis (TB), resulting from Mycobacterium tuberculosis (Mtb), is one of the leading causes of morbidity and mortality in humans worldwide. Host-directed therapy (HDT) is a novel approach for treating TB, particularly those with drug resistance. Urolithin A (UroA) produced through bioconversion of plant-derived ellagic acid by gut microbes has been proven to have multiple beneficial effects in a variety of diseases without showing undesired adverse reactions. However, whether UroA has antimycobacterial effect and the underlying mechanism has not yet been reported. Here, we found that UroA significantly inhibited Mtb growth within both macrophages and mice. Moreover, UroA promoted the activation of autophagy in Mtb-infected macrophages via the protein kinase B-Forkhead box protein O1 signaling pathway, which contributed to the antimycobacterial effect of UroA. Additionally, UroA suppressed the survival of clinically isoniazid (INH)-resistant Mtb (C2) within macrophages, and the combination of UroA and INH synergistically enhanced host elimination of Mtb H37Rv. Therefore, UroA may be utilized as a potential candidate for HDT and as an adjunctive therapy with first-line anti-TB drugs.IMPORTANCEHost-directed therapy (HDT) is a novel approach for treating tuberculosis (TB), particularly those with drug resistance. Urolithin A (UroA) produced through bioconversion of plant-derived ellagic acid by gut microbes has been proven to have multiple beneficial effects in a variety of diseases without showing undesired adverse reactions. We found that UroA significantly inhibited Mycobacterium tuberculosis (Mtb) growth within macrophages. Moreover, UroA suppressed the survival of clinically isoniazid (INH)-resistant Mtb (C2) within macrophages, and the combination of UroA and INH synergistically enhanced host elimination of Mtb H37Rv. Therefore, UroA may be utilized as a potential candidate for HDT and as an adjunctive therapy with first-line anti-TB drugs.

The wide application of lithium in green energy and clinical psychiatry results in ubiquitous occurrence of lithium in aquatic environments. However, researches on the toxicity of lithium are largely confined to acute and/or high-dose scenarios, with insufficient data on its impacts on non-target organisms at environmental levels. The present study investigated the neurotoxicological effects of environmentally relevant concentrations of lithium exposure on yellowstripe goby (Mugilogobius chulae) and the related molecular response mechanisms. The results showed that lithium exposure significantly inhibited the expression of the target protein GSK-3β in the brain of M. chulae, and induced a series of harmful events including oxidative stress, glutamate accumulation, and even behavioral alteration. The organism mitigated the excitotoxic effects of glutamate accumulation by down-regulating ionotropic glutamate receptors. At the same time, the organism met the energy supply and alleviated oxidative stress by altering mitochondrial function. Notably, the stress regulators FoxOs and sestrins both modulated synaptic sensitivities to enhance the neural signaling and altered the energy metabolism pattern to alleviate energy crisis, all of which were important for maintaining neuronal survival and organismal homeostasis. In conclusion, lithium exposure induced glutamate excitability and led to a series of toxic events. Meanwhile, FoxOs played an important role in neural signaling and homeostatic regulation of energy metabolism in brain. This study furthered the comprehension of the neurotoxic impacts of lithium on aquatic organisms, elucidated the associated molecular mechanisms, and underscored the environmental risks posed by increasing lithium contamination.

Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF-agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism-wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2-dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form a positive feedback loop to sustain the cancer-favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3-mediated Akt-mTOR axis in ccRCC initiation and progression.

Cardiac ischemia-reperfusion injury (IRI) occurs when blood flow is restored to the myocardium after a period of ischemia, leading to oxidative stress and subsequent myocardial cell damage, primarily due to the accumulation of reactive oxygen species (ROS). In our previous research, we identified that miR-25 is significantly overexpressed in pressure overload-induced heart failure, and its inhibition improves cardiac function by restoring the expression of SERCA2a, a key protein involved in calcium regulation. In this study, we aimed to investigate the role of miR-25 in the context of ischemia-reperfusion injury. We found that miR-25 was markedly upregulated under hypoxic conditions in both in vitro and in vivo models. Through in silico analysis, we identified Sestrin3 (SESN3), an antioxidant protein known for its protective effects against oxidative stress, as a novel target of miR-25. Based on these findings, we hypothesized that inhibiting miR-25 would restore Sestrin3 expression, thereby reducing ROS-induced myocardial cell damage and improving cardiac function. To test this hypothesis, we employed two model systems: a hypoxia/reoxygenation (H/R) stress model using H9c2 myoblasts and a surgically induced ischemia-reperfusion injury mouse model. Our results demonstrated that the use of miR-25 inhibitors significantly improved cardiac function and reduced myocardial damage in both models through the restoration of SESN3 expression. In conclusion, our findings suggest that targeting miR-25 may serve as a novel therapeutic modality to alleviate oxidative damage in the heart.

AMPK (AMP-activated protein kinase) is a crucial cellular energy sensor across all eukaryotic species. Its multiple roles in maintaining energy homeostasis, regulating cellular metabolic processes have been widely investigated in mammals. In contrast, the function of AMPK in insects has been less reported. Here, we successfully identified three AMPK subunits from Lymantria dispar (L. dispar), a Lepidoptera pest in forestry. Based on that, in particular, the role of AMPK signaling in regulating larval development, as well as chitin biosynthesis was investigated by the application of RNAi-mediated LdAMPKα2 knockdown. The results indicated that knockdown of LdAMPKα2 significantly increased the body weight of L. dispar larvae, and dramatically upregulated the expression of LdmTOR, LdS6K and LdSREBP1, the key genes in mTOR (mammalian target of rapamycin) signaling pathway. While, it significantly reduced the expression of Ld4EBP, a critical repressor of mTOR pathway. Besides, the glucose level was increased and trehalose level was decreased in L. dispar after LdAMPKα2 silencing. Furthermore, we found that the chitin content in the epidermis, as well as the expressions of four key genes in the chitin biosynthesis pathway, LdGFAT, LdPAGM, LdUAP and LdCHSA, were significantly decreased after LdAMPKα2 knockdown. Taken together, these results revealed that AMPK signaling played a pivotal role in regulating the growth and development, as well as carbohydrate metabolism and chitin biosynthesis in L. dispar larvae. The findings expand our understanding of the comprehensive regulatory role of AMPK signaling in insects.

Maternal diabetes increases the risk of adverse maternal, perinatal and offspring outcomes. This study aimed to address whether alterations in uterine decidualization are programmed in the prepubertal offspring from diabetic rats fed diets enriched or not in extra virgin olive oil (EVOO).

Control and mild pregestational diabetic female rats (F0) were mated with control males and fed diets enriched or not with 6 % EVOO during pregnancy. Offspring (F1) were evaluated on postnatal day 30, after induction of uterine decidualization (PMSG 50 IU- hCG 50 IU). Signaling pathways involved in decidualization, including prolactin, PPAR and mTOR pathways as well as microRNAs (miRs) regulating these pathways were evaluated by Western blot or qPCR in the decidualized uteri.

The offspring from diabetic rats evidenced reduced prolactin and prolactin receptor levels in the decidualized uteri. Additionally, these tissues showed increased PPARγ levels and reduced levels of its negative regulators miR-19b and miR-155. MiR-21, a microRNA that targets both PPARα and mTOR pathway regulators was reduced, whereas PPARα, PTEN and FOXO1 mRNA levels were increased in the decidualized uteri of the offspring from diabetic rats. The mTOR pathway activity was reduced in the decidualized uteri of the offspring from diabetic rats. Most of the observed alterations were prevented by the EVOO-enriched maternal diet.

Impaired pathways relevant to decidualization are programmed in the uteri of prepubertal offspring from diabetic dams, alterations capable of being prevented by maternal diets enriched in EVOO.

Sestrins are a conserved family of stress-responsive proteins that play a crucial role in cellular metabolism, stress response, and ageing. Vertebrates have three Sestrin genes (SESN1, SESN2, and SESN3), while invertebrates encode only one. Initially identified as antioxidant proteins that regulate cell viability, Sestrins are now recognised as crucial inhibitors of the mechanistic target of rapamycin complex 1 kinase (mTORC1), a central regulator of anabolism, cell growth, and autophagy. Sestrins suppress mTORC1 through an inhibitory interaction with the GATOR2 protein complex, which, in concert with GATOR1, signals to inhibit the lysosomal docking of mTORC1. A leucine-binding pocket (LBP) is found in most vertebrate Sestrins, and when bound with leucine, Sestrins do not bind GATOR2, prompting mTORC1 activation. This review examines the evolutionary conservation of Sestrins and their functional motifs, focusing on their origins and development. We highlight that the most conserved regions of Sestrins are those involved in GATOR2 binding, and while analogues of Sestrins exist in prokaryotes, the unique feature of eukaryotic Sestrins is their structural presentation of GATOR2-binding motifs.

Reactive oxygen species are involved in the pathogenesis of cancers and metabolic diseases, including diabetes, obesity, and fatty liver disease. Thus, inhibiting the generation of free radicals is a promising strategy to control the onset of metabolic diseases and cancer progression. Various synthetic drugs and natural product-derived compounds that exhibit antioxidant activity have been reported to have a protective effect against a range of metabolic diseases and cancer. This review highlights the development and aggravation of cancer and metabolic diseases due to the imbalance between pro-oxidants and endogenous antioxidant molecules. In addition, we discuss the function of proteins that regulate the production of reactive oxygen species as a strategy to treat metabolic diseases. In particular, we summarize the role of proteins such as nuclear factor-like 2, Sestrin, and heme oxygenase-1, which regulate the expression of various antioxidant genes in metabolic diseases and cancer. We have included recent literature to discuss the latest research on identifying novel signals of antioxidant genes that can control metabolic diseases and cancer.

Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. Peptidyl-prolyl cis/trans isomerase, NIMA-Interacting 1 (PIN1) is a peptidyl-prolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 over-expression is linked to cancer. Death-associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis as a result of increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum, and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high-level signaling molecules, such as nuclear factor erythroid 2-related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. It is imperative that further research be conducted to experimentally validate whether the mechanisms described here take place in response to chronic glyphosate exposure and whether this ultimately leads to autism.

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.

Heat stress induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2-/- and Sestrin3-/- mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after heat stress. Our data showed that Sestrin2-/- and Sestrin3-/- mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after heat stress. Notably, Sestrin2-/- and Sestrin3-/- mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Furthermore, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2 and Sestrin3 exacerbated meiotic failure by compromising DNA double-strand breaks repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.

Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool for monitoring mTORC1 inhibition in living cells or tissues is lacking.

We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense the physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1.

TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.

A model explaining the dietary-protein-driven post-natal skeletal muscle growth and protein turnover in the rat is updated, and the mechanisms involved are described, in this narrative review. Dietary protein controls both bone length and muscle growth, which are interrelated through mechanotransduction mechanisms with muscle growth induced both from stretching subsequent to bone length growth and from internal work against gravity. This induces satellite cell activation, myogenesis and remodelling of the extracellular matrix, establishing a growth capacity for myofibre length and cross-sectional area. Protein deposition within this capacity is enabled by adequate dietary protein and other key nutrients. After briefly reviewing the experimental animal origins of the growth model, key concepts and processes important for growth are reviewed. These include the growth in number and size of the myonuclear domain, satellite cell activity during post-natal development and the autocrine/paracrine action of IGF-1. Regulatory and signalling pathways reviewed include developmental mechanotransduction, signalling through the insulin/IGF-1-PI3K-Akt and the Ras-MAPK pathways in the myofibre and during mechanotransduction of satellite cells. Likely pathways activated by maximal-intensity muscle contractions are highlighted and the regulation of the capacity for protein synthesis in terms of ribosome assembly and the translational regulation of 5-TOPmRNA classes by mTORC1 and LARP1 are discussed. Evidence for and potential mechanisms by which volume limitation of muscle growth can occur which would limit protein deposition within the myofibre are reviewed. An understanding of how muscle growth is achieved allows better nutritional management of its growth in health and disease.

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.

Acne vulgaris is a common dermatological condition that can present across different ages but predominantly affects adolescents and young adults. Characterized by various lesion types, the pathogenesis of acne is complex, involving genetic, hormonal, microbial, and inflammatory factors. This review comprehensively addresses current and emerging acne management strategies, emphasizing both topical and systemic treatments, procedural therapies, and dietary modifications. Key topical agents include retinoids, benzoyl peroxide, antibiotics, and other specialized compounds. Systemic options like antibiotics, hormonal therapies, and retinoids offer significant therapeutic benefits, particularly for moderate to severe cases. Procedural treatments such as laser devices, photodynamic therapy, chemical peels, and intralesional injections present viable alternatives for reducing acne symptoms and scarring. Emerging therapies focus on novel biologics, bacteriophages, probiotics, and peptides, providing promising future options. This review underscores the importance of personalized approaches to treatment due to the multifaceted nature of acne, highlighting the potential of innovative therapies for improving patient outcomes.

Aging is inevitable, but the lifespan (duration of life) and healthspan (healthy aging) vary greatly among individuals and across species. Unlocking the secrets behind these differences has captivated scientific curiosity for ages. This review presents relevant recent advances in genetics and cell biology that are shedding new light by untangling how subtle changes in conserved genes, pathways, and epigenetic factors influence organismal senescence and associated declines. Biogerontology is a complex and rapidly growing field aimed at elucidating genetic modifications that extend lifespan and healthspan. This review explores gerontogenes, genes influencing lifespan and healthspan across species. Though subtle differences exist, long-lived individuals such as centenarians demonstrate extended healthspans, and numerous studies confirm the heritability of longevity/healthspan genes. Importantly, genes and gerontogenes are directly and indirectly involved in DNA repair, insulin/IGF-1 and mTOR signaling pathways, long non-coding RNAs, sirtuins, and heat shock proteins. The complex interactions between genetics and epigenetics are teased apart. While more research into optimizing healthspan is needed, conserved gerontogenes offer synergistic potential to forestall aging and age-related diseases. Understanding complex longevity genetics brings closer the goal of extending not only lifespan but quality years of life. The primary aim of human Biogerontology is to enhance lifespan and healthspan, but the question remains: are current genetic modifications effectively promoting healthy aging? This article collates the advancements in gerontogenes that enhance lifespan and improve healthspan alongside their potential challenges.

Sestrins are a type of highly conserved stress-inducing protein that has antioxidant and mTORC1 inhibitory functions. Metabolic dysfunction and aging are the main risk factors for development of human diseases, such as diabetes, neurodegenerative diseases, and cancer. Sestrins have important roles in regulating glucose and lipid metabolism, anti-tumor functions, and aging by inhibiting the reactive oxygen species and mechanistic target of rapamycin complex 1 pathways. In this review, the structure and biological functions of sestrins are summarized, and how sestrins are activated and contribute to regulation of the downstream signal pathways of metabolic and aging-related diseases are discussed in detail with the goal of providing new ideas and therapeutic targets for the treatment of related diseases.

Sestrins have been implicated in regulating aging in various organs through multiple pathways. However, their roles in ovarian aging remain unrevealed.

Female Sestrin1-/-, Sestrin2-/-, and Sestrin3-/- mice were generated using the CRISPR-Cas9 system. Body weights, little sizes, ovarian weights, estrous cyclicity, and follicle number in female mice were observed. ELISA was utilized to measure serum anti-Müllerian hormone (AMH) levels. Real time PCR, western blot, immunofluorescence, and Masson trichrome staining were employed for assessment of aging-related change.

The deletion of Sestrin 1, 2, or 3 had no discernible impact on body weights,or serum AMH levels in female mice at the age of 12 months. And there were no discernible differences in litter sizes or estrous cyclicity which were assessed at the age of 8 months. At the age of 12 months, no significant differences were observed in ovarian weights or follicle numbers among the knockout mice. Consistently, the extent of fibrosis within the ovaries remained comparable across all experimental groups at this age. Additionally, autophagy, apoptosis, DNA damage, and inflammation within the ovaries were also found to be comparable to those in wild-type mice of the same age.

The loss of Sestrin 1, 2, or 3 does not exert a noticeable influence on ovarian function during the aging process. Sestrin1, 2, and 3 are not essential for female fertility in mice.

Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML.

IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression.

FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.

Bone marrow mesenchymal stem cells (MSCs) may have contrasting impacts on the progression of multiple myeloma (MM). Priming normal MSCs, by culturing them with MM cells, mimics the MSC-induced MM growth. We studied the contrasting effects of conditioned medium (CM) from unprimed or primed MSCs on growth of MM cells from newly diagnosed cases. We elucidated potential molecular pathways using global gene expression profiling and focused on the role of the mTOR2 component, RICTOR, as a novel mediator of dormancy in MM. Primed MSCs CM consistently increased proportions of proliferating cells and supported MM growth in 3-day (n = 20) and 10-day (n = 12) cultures, effects that were partially mediated through the IGF1 axis. In contrast, unprimed MSCs CM inhibited growth of MM cells in cases mainly from stages I/II MM. The genes most overexpressed in MM cells treated with primed MSCs CM were associated with cell cycle, DNA-damage repair, and proliferation; genes most overexpressed in MM cells treated with unprimed MSCs CM were associated with dormancy pathways including RICTOR (mTOR2 pathway), CXCR4, and BCL2. RICTOR protein level was induced by unprimed MSCs CM and was lower in KI67+ proliferating MM cells treated with primed MSCs CM. RICTOR was underexpressed in clinical relapse samples compared with baseline samples of the same patients. Inhibiting RICTOR expression in primary MM cells promoted their growth, and enforced expression of RICTOR in MM cell lines inhibited their growth. Our findings suggest that, after prolonged interactions with MM cells, bone marrow MSCs shift from MM-repressive to MM-permissive. AVAILABILITY OF DATA AND MATERIALS: Our institutional GEP data of MM cells from newly diagnosed patients used to show RICTOR expression have been deposited at Gene Expression Omnibus (GEO: GSE2658, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2658).

CD8+ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8+ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8+ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8+ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8+ T cells at the molecular level.

Stress is adverse experience that require constant adaptation to reduce the emotional and physiological burden, or "allostatic load", of an individual. Despite their everyday occurrence, a subpopulation of individuals is more susceptible to stressors, while others remain resilient with unknown molecular signatures. In this study, we investigated the contribution of the DNA modifications, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), underlying the individual differences in stress susceptibility and resilience. Genome-wide 5mC and 5hmC profiles from 3- and 6-month adult male mice that underwent various durations of social defeat were generated. In 3-month animals, 5mC and 5hmC work in parallel and do not distinguish between stress-susceptible and resilient phenotypes, while in 6-month animals, 5mC and 5hmC show distinct enrichment patterns. Acute stress responses may epigenetically "prime" the animals to either increase or decrease their predisposition to depression susceptibility. In support of this, re-exposure studies reveal that the enduring effects of social defeat affect differential biological processes between susceptible and resilient animals. Finally, the stress-induced 5mC and 5hmC fluctuations across the acute-chronic-longitudinal time course demonstrate that the negative outcomes of chronic stress do not discriminate between susceptible and resilient animals. However, resilience is more associated with neuroprotective processes while susceptibility is linked to neurodegenerative processes. Furthermore, 5mC appears to be responsible for acute stress response, whereas 5hmC may function as a persistent and stable modification in response to stress. Our study broadens the scope of previous research offering a comprehensive analysis of the role of DNA modifications in stress-induced depression.

AKT kinase is a key regulator in cell metabolism and survival, and its activation is strictly modulated. Herein, we identify XAF1 (XIAP-associated factor) as a direct interacting protein of AKT1, which strongly binds the N-terminal region of AKT1 to block its K63-linked poly-ubiquitination and subsequent activation. Consistently, Xaf1 knockout causes AKT activation in mouse muscle and fat tissues and reduces body weight gain and insulin resistance induced by high-fat diet. Pathologically, XAF1 expression is low and anti-correlated with the phosphorylated p-T308-AKT signal in prostate cancer samples, and Xaf1 knockout stimulates the p-T308-AKT signal to accelerate spontaneous prostate tumorigenesis in mice with Pten heterozygous loss. And ectopic expression of wild-type XAF1, but not the cancer-derived P277L mutant, inhibits orthotopic tumorigenesis. We further identify Forkhead box O 1 (FOXO1) as a transcriptional regulator of XAF1, thus forming a negative feedback loop between AKT1 and XAF1. These results reveal an important intrinsic regulatory mechanism of AKT signaling.

Homeostatic maintenance and repair of lymphatic vessels are essential for health. We investigated the dynamics and the molecular mechanisms of lymphatic endothelial cell (LEC) renewal in adult mesenteric quiescent lymphatic vasculature using label-retention, lineage tracing, and cell ablation strategies. Unlike during development, adult LEC turnover and proliferation was confined to the valve regions of collecting vessels, with valve cells displaying the shortest lifespan. Proliferating valve sinus LECs were the main source for maintenance and repair of lymphatic valves. We identified mechanistic target of rapamycin complex 1 (mTORC1) as a mechanoresponsive pathway activated by fluid shear stress in LECs. Depending on the shear stress level, mTORC1 activity drives division of valve cells or dictates their mechanic resilience through increased protein synthesis. Overactivation of lymphatic mTORC1 in vivo promoted supernumerary valve formation. Our work provides insights into the molecular mechanisms of maintenance of healthy lymphatic vascular system.

The present review focuses on the phenomenon of autophagy, a catabolic cellular process, which allows for the recycling of damaged organelles, macromolecules, and misfolded proteins. The different steps able to activate autophagy start with the formation of the autophagosome, mainly controlled by the action of several autophagy-related proteins. It is remarkable that autophagy may exert a double role as a tumour promoter and a tumour suppressor. Herein, we analyse the molecular mechanisms as well as the regulatory pathways of autophagy, mainly addressing their involvement in human astrocytic neoplasms. Moreover, the relationships between autophagy, the tumour immune microenvironment, and glioma stem cells are discussed. Finally, an excursus concerning autophagy-targeting agents is included in the present review in order to obtain additional information for the better treatment and management of therapy-resistant patients.

Sestrins are a small gene family of pleiotropic factors whose actions promote cell adaptation to a range of stress conditions. In this report we disclose the selective role of Sestrin2 (SESN2) in dampening aerobic glycolysis to adapt to limiting glucose conditions. Removal of glucose from hepatocellular carcinoma (HCC) cells inhibits glycolysis associated with the downregulation of the rate-limiting glycolytic enzyme hexokinase 2 (HK2). Moreover, the accompanying upregulation of SESN2 through an NRF2/ATF4-dependent mechanism plays a direct role in HK2 regulation by destabilizing HK2 mRNA. We show SESN2 competes with insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) for binding with the 3'-UTR region of HK2 mRNA. Interactions between IGF2BP3 and HK2 mRNA result in their coalescence into stress granules via liquid-liquid phase separation (LLPS), a process which serves to stabilize HK2 mRNA. Conversely, the enhanced expression and cytoplasmic localization of SESN2 under glucose deprivation conditions favors the downregulation of HK2 levels via decreases in the half-life of HK2 mRNA. The resulting dampening of glucose uptake and glycolytic flux inhibits cell proliferation and protect cells from glucose starvation-induced apoptotic cell death. Collectively, our findings reveal an intrinsic survival mechanism allowing cancer cells to overcome chronic glucose shortages, also providing new mechanistic insights into SESN2 as an RNA-binding protein with a role in reprogramming of cancer cell metabolism.

Hormonal signaling plays key roles in tissue and metabolic homeostasis. Accumulated evidence has revealed a great deal of insulin and estrogen signaling pathways and their interplays in the regulation of mitochondrial, cellular remodeling, and macronutrient metabolism. Insulin signaling regulates nutrient and mitochondrial metabolism by targeting the IRS-PI3K-Akt-FoxOs signaling cascade and PGC1α. Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism through its receptors (ERα, ERβ, and GPER). Insulin and estrogen signaling converge on Sirt1, mTOR, and PI3K in the joint regulation of autophagy and mitochondrial metabolism. Dysregulated insulin and estrogen signaling lead to metabolic diseases. This article reviews the up-to-date evidence that depicts the pathways of insulin signaling and estrogen-ER signaling in the regulation of metabolism. In addition, we discuss the cross-talk between estrogen signaling and insulin signaling via Sirt1, mTOR, and PI3K, as well as new therapeutic options such as agonists of GLP1 receptor, GIP receptor, and β3-AR. Mapping the molecular pathways of insulin signaling, estrogen signaling, and their interplays advances our understanding of metabolism and discovery of new therapeutic options for metabolic disorders.

MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.

Endometriosis is a common reproductive disorder characterized by the presence of endometrial implants outside of the uterus. It affects ~1 in 10 women of reproductive age. Endometriosis in the ovary, also known as endometrioma (OMA), is the most frequent implantation site and the leading cause of reproductive failure in affected women. Ovarian aging is one of the characteristic features of OMA, however its underlying mechanism yet to be determined. Accumulated evidence has shown that pelvic and local microenvironments in women with OMA are manifested, causing detrimental effects on ovarian development and functions. Whilst clinical associations of OMA with poor ovarian reserve, premature ovarian insufficiency, and early menopause have been reported. Moreover, surgical ablation, fenestration, and cystectomy of OMA can further damage the normal ovarian reservoir, and trigger hyperactivation of primordial follicles, subsequently resulting in the undesired deterioration of ovarian functions. Nevertheless, there is no effective treatment to delay or restore ovarian aging. This review comprehensively summarised the pathogenesis and study hypothesis of ovarian aging caused by OMA in order to propose potential therapeutic targets and interventions for future studies.

Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan. FOXOs act as downstream of several signaling pathway and are extensively regulated through post-translational modifications. The transcriptional program activated by FOXOs in various cell types, organisms, and under various conditions has been described and has shed some light on what the critical transcriptional targets are in mediating FOXO function. At the cellular level, these studies have revealed a role for FOXOs in cell metabolism, cellular redox, cell proliferation, DNA repair, autophagy, and many more. The general picture that emerges hereof is that FOXOs act to preserve equilibrium, and they are important for cellular homeostasis. Here, we will first briefly summarize the general knowledge of FOXO regulation and possible functions. We will use genomic stability to illustrate how FOXOs ensure homeostasis. Genomic stability is critical for maintaining genetic integrity, and therefore preventing disease. However, genomic mutations need to occur during lifetime to enable evolution, yet their accumulation is believed to be causative to aging. Therefore, the role of FOXO in genomic stability may underlie its role in lifespan and aging. Finally, we will come up with questions on some of the unknowns in FOXO function, the answer(s) to which we believe will further our understanding of FOXO function and ultimately may help to understand lifespan and its consequences.

Background: ALMS1 is a ubiquitous gene associated with Alström syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis in the lungs, kidneys and liver. TGF-β is one of the main pathways implicated in fibrosis, controlling the cell cycle, apoptosis, cell migration, cell adhesion and epithelial-mesenchymal transition (EMT). Nevertheless, the role of ALMS1 gene in fibrosis generation and other implicated processes such as cell migration or cell adhesion via the TGF- β pathway has not been elucidated yet. Methods: Initially, we evaluated how depletion of ALMS1 affects different processes like apoptosis, cell cycle and mitochondrial activity in HeLa cells. Then, we performed proteomic profiling with TGF-β stimuli in HeLa ALMS1 -/- cells and validated the results by examining different EMT biomarkers using qPCR. The expression of these EMT biomarkers were also studied in hTERT-BJ-5ta ALMS1 -/-. Finally, we evaluated the SMAD3 and SMAD2 phosphorylation and cell migration capacity in both models. Results: Depletion of ALMS1 generated apoptosis resistance to thapsigargin (THAP) and C2-Ceramide (C2-C), and G2/M cell cycle arrest in HeLa cells. For mitochondrial activity, results did not show significant differences between ALMS1 +/+ and ALMS1 -/-. Proteomic results showed inhibition of downstream pathways regulated by TGF-β. The protein-coding genes (PCG) were associated with processes like focal adhesion or cell-substrate adherens junction in HeLa. SNAI1 showed an opposite pattern to what would be expected when activating the EMT in HeLa and BJ-5ta. Finally, in BJ-5ta model a reduced activation of SMAD3 but not SMAD2 were also observed. In HeLa model no alterations in the canonical TGF-β pathway were observed but both cell lines showed a reduction in migration capacity. Conclusion: ALMS1 has a role in controlling the cell cycle and the apoptosis processes. Moreover, the depletion of ALMS1 affects the signal transduction through the TGF-β and other processes like the cell migration and adhesion capacity.

RNA-RBP interaction is important in immune regulation and implicated in various immune disorders. The differentiation of proinflammatory T cell subset T_H17 and its balance with regulatory T cell (T_reg) generation is closely related to autoimmune pathogenesis. The roles of RNA-RBP interaction in regulation of T_H17/T_reg differentiation and autoinflammation remain in need of further investigation. Here we report that lncRNA-GM polarizes T_H17 differentiation but inhibits iT_reg differentiation by reducing activity of Foxo1, a transcriptional factor that is important in inhibiting T_H17 differentiation but promoting T_reg generation. lncRNA-GM-deficient mice were protected from experimental autoimmune encephalomyelitis. Mechanistically, lncRNA-GM directly binds to cytoplasmic Foxo1, thus inhibiting its activity through blocking dephosphorylation of Foxo1 by phosphatase PP2A to promote Il23r transcription. The human homolog of lncRNA-GM (AK026392.1) also polarizes human T_H17 differentiation. Our study provides mechanistic insight into the interaction of lncRNA and transcriptional factor in determining T cell subset differentiation during T cell-mediated autoimmune diseases.