Metformin in combination with chemotherapy increases apoptosis in gastric cancer cells and counteracts senescence induced by chemotherapy.

Gastric cancer (GC) is the fourth leading cause of cancer death in the world, and there is a demand for new therapeutic agents to treat GC. Metformin has been demonstrated to be an antineoplastic agent in some types of cancer; however, it has not been sufficiently valued in treating GC because the effect of metformin in combination with chemotherapy regimens has not yet been evaluated. The present study aimed to evaluate the mechanisms underlying cell death induced by metformin alone or when combined with chemotherapy. The cytogenetic characteristics of the NCI-N87 cell line were determined by fluorescence in situ hybridization (FISH). To determine viability, the cells were treated with metformin, epirubicin, cisplatin, docetaxel and 5-fluorouracil (individually and at different concentrations). Subsequently, the cells were treated with metformin alone, and in combination with the chemotherapeutic drugs and the epirubicin + cisplatin + 5-fluorouracil, docetaxel + cisplatin + 5-fluorouracil, and cisplatin + 5-fluorouracil regimens. Cell viability, proliferation and mitochondrial membrane potential (ΔΨm) were analyzed by spectrophotometry. Apoptosis, caspase activity and cell cycle progression were assessed by flow cytometry. Finally, light microscopy was used to evaluate senescence and clonogenicity. The results revealed that metformin, alone and when combined with chemotherapy, increased the proportion of apoptotic cells, promoted the loss of ΔΨm, and induced apoptosis through caspase activity in GC cells. Moreover, metformin decreased cell proliferation. In addition, metformin alone did not induce senescence and it counteracted the effects of chemotherapy-induced senescence in GC cells. Additionally, metformin, alone and when combined with chemotherapy, decreased the clonogenic capacity of NCI-N87 GC cells. In conclusion, metformin may increase the effects of chemotherapy on NCI-N87 cell death and could represent an option to improve the treatment of GC.

Oxidative stress-induced gene expression changes in prostate epithelial cells in vitro reveal a robust signature of normal prostatic senescence and aging.

Oxidative stress has long been postulated to play an essential role in aging mechanisms, and numerous forms of molecular damage associated with oxidative stress have been well documented. However, the extent to which changes in gene expression in direct response to oxidative stress are related to actual cellular aging, senescence, and age-related functional decline remains unclear. Here, we ask whether H2O2-induced oxidative stress and resulting gene expression alterations in prostate epithelial cells in vitro reveal gene regulatory changes typically observed in naturally aging prostate tissue and age-related prostate disease. While a broad range of significant changes observed in the expression of non-coding transcripts implicated in senescence-related responses, we also note an overrepresentation of gene-splicing events among differentially expressed protein-coding genes induced by H2O2. Additionally, the collective expression of these H2O2-induced DEGs is linked to age-related pathological dysfunction, with their protein products exhibiting a dense network of protein-protein interactions. In contrast, co-expression analysis of available gene expression data reveals a naturally occurring highly coordinated expression of H2O2-induced DEGs in normally aging prostate tissue. Furthermore, we find that oxidative stress-induced DEGs statistically overrepresent well-known senescence-related signatures. Our results show that oxidative stress-induced gene expression in prostate epithelial cells in vitro reveals gene regulatory changes typically observed in naturally aging prostate tissue and age-related prostate disease.

LncRNA PTENP1/miR-21/PTEN Axis Modulates EMT and Drug Resistance in Cancer: Dynamic Boolean Modeling for Cell Fates in DNA Damage Response.

It is well established that microRNA-21 (miR-21) targets phosphatase and tensin homolog (PTEN), facilitating epithelial-to-mesenchymal transition (EMT) and drug resistance in cancer. Recent evidence indicates that PTEN activates its pseudogene-derived long non-coding RNA, PTENP1, which in turn inhibits miR-21. However, the dynamics of PTEN, miR-21, and PTENP1 in the DNA damage response (DDR) remain unclear. Thus, we propose a dynamic Boolean network model by integrating the published literature from various cancers. Our model shows good agreement with the experimental findings from breast cancer, hepatocellular carcinoma (HCC), and oral squamous cell carcinoma (OSCC), elucidating how DDR activation transitions from the intra-S phase to the G2 checkpoint, leading to a cascade of cellular responses such as cell cycle arrest, senescence, autophagy, apoptosis, drug resistance, and EMT. Model validation underscores the roles of PTENP1, miR-21, and PTEN in modulating EMT and drug resistance. Furthermore, our analysis reveals nine novel feedback loops, eight positive and one negative, mediated by PTEN and implicated in DDR cell fate determination, including pathways related to drug resistance and EMT. Our work presents a comprehensive framework for investigating cellular responses following DDR, underscoring the therapeutic potential of targeting PTEN, miR-21, and PTENP1 in cancer treatment.

Impact of Aging on the Morphology of the Adrenal Gland in Rats / Impacto del Envejecimiento en la Morfología de la Glándula Suprarrenal en Ratas

SUMMARY: Aging is an inevitable biological process that affects the function of all organs, including the adrenal gland, which is essential for producing steroid hormones that regulate metabolism, stress response, and immune activation. Understanding how aging affects the morphology of this gland is crucial to developing interventions to mitigate its adverse effects. Thus, this study aimed to describe the morphoquantitative alterations of the adrenal gland in senescent Sprague Dawley rats compared to adult rats. Twelve male rats were divided into 6 adult rats aged 6 months (group A) and 6 senescent rats aged 36 months (group S). Histopathological studies, quantification of collagen fibers types I and III, and stereological analysis were performed to determine the volume density (Vv), surface area (Sv), and number (Nv) of the nuclei of the zona fasciculata cells. Adrenal gland tissue from group S presented dysplasia, metaplasia, intracellular fat accumulation, fibrosis, blood vessel dilation, and increased presence of apoptotic cells. Capsule thickening and increased collagen type I were also observed. There was a significant decrease in Vv, Sv, and Nv of zona fasciculata nuclei in group S compared to group A. The results indicate that aging induces significant morphoquantitative changes in the adrenal gland, which could contribute to the decrease in glucocorticoid production and alterations in aldosterone and cortisol secretion observed in senescence. Understanding these alterations is crucial to developing interventions that mitigate the adverse effects of aging on the endocrine system.

El envejecimiento es un proceso biológico inevitable que afecta la función de todos los órganos, incluida la glándula suprarrenal, fundamental para la producción de hormonas esteroides que regulan el metabolismo, la respuesta al estrés y la activación inmunológica. Comprender cómo el envejecimiento afecta la morfología de esta glándula es crucial para desarrollar intervenciones que mitiguen sus efectos adversos. Así, el objetivo de este estudio fue describir las alteraciones morfocuantitativas de la glándula suprarrenal en ratas Sprague Dawley senescentes comparadas con ratas adultas. Se utilizaron 12 ratas macho, divididas en dos grupos: 6 ratas adultas de 6 meses de edad (grupo A) y 6 ratas senescentes de 36 meses de edad (grupo S). Se realizaron estudios histopatológicos, cuantificación de fibras de colágeno tipos I y III y análisis estereológicos para determinar la densidad de volumen (Vv), de superficie (Sv) y de número (Nv) de los núcleos de las células de la zona fasciculada. El tejido de la glándula suprarrenal del grupo S presentó displasia, metaplasia, acumulación de grasa intracelular, fibrosis, dilatación de vasos sanguíneos y mayor presencia de células apoptósicas. También se observó un engrosamiento de la cápsula y un incremento del colágeno tipo I. Hubo una disminución significativa en Vv, Sv y Nv de los núcleos de la zona fasciculada en el grupo S en comparación con el grupo A. Los resultados indican que el envejecimiento induce cambios morfocuantitativos significativos en la glándula suprarrenal, lo que podría contribuir a la disminución en la producción de glucocorticoides y alteraciones en la secreción de aldosterona y cortisol observadas en la senescencia. Comprender estas alteraciones es crucial para desarrollar intervenciones que mitiguen los efectos adversos del envejecimiento en el sistema endocrino.

Addition of Polyphenols to Drugs: The Potential of Controlling "Inflammaging" and Fibrosis in Human Senescent Lung Fibroblasts In Vitro.

The combination of a polyphenol, quercetin, with dasatinib initiated clinical trials to evaluate the safety and efficacy of senolytics in idiopathic pulmonary fibrosis, a lung disease associated with the presence of senescent cells. Another approach to senotherapeutics consists of controlling inflammation related to cellular senescence or "inflammaging", which participates, among other processes, in establishing pulmonary fibrosis. We evaluate whether polyphenols such as caffeic acid, chlorogenic acid, epicatechin, gallic acid, quercetin, or resveratrol combined with different senotherapeutics such as metformin or rapamycin, and antifibrotic drugs such as nintedanib or pirfenidone, could present beneficial actions in an in vitro model of senescent MRC-5 lung fibroblasts. A senescent-associated secretory phenotype (SASP) was evaluated by the measurement of interleukin (IL)-6, IL-8, and IL-1ß. The senescent-associated ß-galactosidase (SA-ß-gal) activity and cellular proliferation were assessed. Fibrosis was evaluated using a Picrosirius red assay and the gene expression of fibrosis-related genes. Epithelial-mesenchymal transition (EMT) was assayed in the A549 cell line exposed to Transforming Growth Factor (TGF)-ß in vitro. The combination that demonstrated the best results was metformin and caffeic acid, by inhibiting IL-6 and IL-8 in senescent MRC-5 cells. Metformin and caffeic acid also restore cellular proliferation and reduce SA-ß-gal activity during senescence induction. The collagen production by senescent MRC-5 cells was inhibited by epicatechin alone or combined with drugs. Epicatechin and nintedanib were able to control EMT in A549 cells. In conclusion, caffeic acid and epicatechin can potentially increase the effectiveness of senotherapeutic drugs in controlling lung diseases whose pathophysiological component is the presence of senescent cells and fibrosis.

Recent Insights into Salicylic Acid Accumulation: Emerging Molecular Players and Novel Perspectives on Plant Development and Nutrition.

Salicylic acid (SA) is a central phytohormone that orchestrates genetic and physiological responses involving defense mechanisms against pathogens. This review presents cutting-edge research on emerging molecular players identified within the past five years contributing to SA accumulation. Furthermore, we delve into two relatively underexplored domains: the dynamic production of SA throughout the plant life cycle, with a specific focus on senescence, and the intricate interplay between SA, nutrition, and its multifaceted implications on plant development and defense response. This synthesis aims to provide a contemporary and comprehensive understanding of the diverse roles of SA in plant biology.

Effect of simulated extreme rainfall on the vegetative phenology of perennial and annual herbaceous plants from a Brazilian dry forest.

Detecting changes in the phenological responses of herbaceous species as a function of predicted climate change is important for forecasting future scenarios for the functioning of dry tropical forests, especially when predicting an increase in the frequency and intensity of extreme droughts. Because of the sensitivity of plants to water availability, our study hypothesizes that if years become drier or wetter, herbaceous plants will synchronously change the onset, duration, and intensity of their vegetative phenophases. We used a historical series of 60 years of precipitation observations for the Caatinga vegetation to define daily average of precipitation for rainy (Twet), median (Tcontrol), and dry (Tdry) years. We simulated past average daily rainfall (Twet, Tcontrol, and Tdry) while growing two herbaceous perennials and two herbaceous annuals. We monitored plant growth and measured the activity (absence or presence) and intensity of vegetative phenophases. We used circular statistical analysis to assess differences between treatments. Our results revealed that leaf production was seasonal but relatively uniform for perennial species and highly seasonal (wet season) for annual species. Simulated dry years induced lower leaf emergence concentrated over a few months in annual species, but this effect was more strongly significant in one of the two perennial species. Both annual and perennial species can experience delayed and less intense leaf abscission during the rainy season in years with below-average precipitation. In contrast, large voluminous rains in years with above-average precipitation can accelerate and intensify the process of leaf renewal. If future precipitation reductions occur, the changes in phenological response indicate that the cover of annual and perennial herbaceous species in this study will likely decrease, altering the landscape and functioning of dry tropical forests. However, the potential trade-offs observed may help populations of these species to persist during years of severe drought in the Caatinga.

The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.

Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.

The role of interleukin-10 in mitigating endoplasmic reticulum stress in aged mice through exercise.

Although unfolded protein response (UPR) is essential for cellular protection, its prolonged activation may induce apoptosis, compromising cellular longevity. The aging process increases the endoplasmic reticulum (ER) stress in skeletal muscle. However, whether combined exercise can prevent age-induced ER stress in skeletal muscle remains unknown. Evidence suggests that ER stress may increase inflammation by counteracting the positive effects of interleukin-10 (IL-10), whereas its administration in cells inhibits ER stress and apoptosis. This study verified the effects of aging and combined exercise on physical performance, ER stress markers, and inflammation in the quadriceps of mice. Moreover, we verified the effects of IL-10 on ER stress markers. C57BL/6 mice were distributed into young (Y, 6 mo old), old sedentary (OS, sedentary, 24 mo old), and old trained group (OT, submitted to short-term combined exercise, 24 mo old). To clarify the role of IL-10 in UPR pathways, knockout mice lacking IL-10 were used. The OS mice presented worse physical performance and higher ER stress-related proteins, such as C/EBP homologous protein (CHOP) and phospho-eukaryotic translation initiation factor 2 alpha (p-eIF2α/eIF2α). The exercise protocol increased muscle strength and IL-10 protein levels in OT while inducing the downregulation of CHOP protein levels compared with OS. Furthermore, mice lacking IL-10 increased BiP, CHOP, and p-eIF2α/eIF2α protein levels, indicating this cytokine can regulate the ER stress response in skeletal muscle. Bioinformatics analysis showed that endurance and resistance training downregulated DNA damage inducible transcript 3 (DDIT3) and XBP1 gene expression in the vastus lateralis of older people, reinforcing our findings. Thus, combined exercise is a potential therapeutic intervention for promoting adjustments in ER stress markers in aged skeletal muscle.NEW & NOTEWORTHY Aging elevates endoplasmic reticulum (ER) stress in skeletal muscle, potentially heightening inflammation by opposing interleukin-10 (IL-10) effects. This study found that short-term combined exercise boosted strength and IL-10 protein levels while reducing CHOP protein levels in older mice. In addition, IL-10-deficient mice exhibited increased ER stress markers, highlighting IL-10's role in regulating ER stress in skeletal muscle. Consequently, combined exercise emerges as a therapeutic intervention to elevate IL-10 and adjust ER stress markers in aging.

MASLD does not affect fertility and senolytics fail to prevent MASLD progression in male mice.

Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.

The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration.

It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

Effects of pilates exercises on strength, endurance and muscle power in older adults: Systematic review and meta-analysis.

INTRODUCTION: Pilates exercises have been used by the older adults and have shown potential to improve some components of physical fitness. OBJECTIVE: To verify the effects of Pilates on strength, endurance and muscle power in older adults. METHODS: The searches were performed in the databases: PubMed, EMBASE, CENTRAL, CINAHL, Web of Science, SPORTDiscus, LILACS and PEDro until September 2022, without filters that limited the date of publications or language. The studies included were: randomized clinical trials (RCTs); interventions that used Pilates; interventions with outcomes involving strength, endurance and/or muscle power; participants over 60 years old. RESULTS: 24 RCTs (1190 participants) were selected. There is low quality evidence that Pilates did not significantly improve muscle strength compared to the control group (Standardized Mean Difference (SMD) = 1.18 [95%CI -0.71, 3.08] I2 = 93%), and moderate quality compared to other exercises (SMD = 0.01 [CI95% -0.46, 0.48] I2 = 0%). Very low quality evidence shows that Pilates can improve muscular endurance of upper limbs compared to control group (Mean Difference (MD) = 4.87 [95%CI 2.38, 7.36] I2 = 88%) and lower limbs compared to other exercises (MD = 2.68 [CI95% 0.26, 5.10] I2 = 87%). It was not possible to perform muscle power analysis due to the reduced number of studies. CONCLUSION: Currently, it is not feasible to recommend Pilates exercises as a means to improve strength, endurance and muscle power in the older adults. More RCTs covering this topic are needed given the low quality of evidence available at this time.

Combined physical exercise re-synchronizes expression of Bmal1 and REV-ERBα and up-regulates apoptosis and metabolism in the prostate during aging.

BACKGROUND: Aging increases the prevalence of prostate cancer. The circadian clock coordinates metabolism, cell cycle, and tumor suppressor p53. Although physical exercise has several effects on preventing prostate diseases, its effect on regulating genes and proteins of the circadian rhythm of the prostate needs to be better evaluated. The present study verified expression of REV-ERBα (Nr1d1), Bmal1, apoptosis, tumor suppressors, energetic metabolism markers, and androgen receptors in the prostatic microenvironment in 18-month-old mice submitted to combined physical training. METHODS: C57BL/6 J mice were divided into 2 groups: 6 months-old (n = 10) and 18 months-old, (n = 20). The 18-month-old animals were divided into 2 subgroups: sedentary (n = 10, 18 m Sed) and submitted to combined physical training (n = 10, 18 m TR). Combined physical training protocol was performed by running on the treadmill (40-60 % of incremental load test) and climbing strength training (40-50 % of maximum repetition test), consisting of 5×/week (3 days aerobic and 2 days strength) for 3 weeks. The prostate was prepared for Western blot and RT-qPCR analysis, and the plasm was prepared for the biochemistry analysis. RESULTS: Combined physical exercise during aging led to increased levels of Bmal1 and decreased levels of REV-ERBα in the prostate. These results were accompanied by a reduction in the AMPK/SIRT1/PGC-1α proteins and an increase in the PI3K/AKT and p53/PTEN/caspase 3 pathways, promoting apoptotic potential. CONCLUSION: These findings suggest that strength and aerobic physical exercise may be preventive in the development of preneoplastic molecular alterations and age-related features by re-synchronizes Bmal1 and REV-ERBα in prostatic tissues.

NKG2C+CD57+ natural killer cells with senescent features are induced during cutaneous leishmaniasis and accumulate in patients with lesional healing impairment.

Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of CL.

Delayed senescence and crop performance under stress: always a functional couple?

Exposure to abiotic stresses accelerates leaf senescence in most crop plant species, thereby reducing photosynthesis and other assimilatory processes. In some cases, genotypes with delayed leaf senescence (i.e. 'stay-green') show stress resistance, particularly in cases of water deficit, and this has led to the proposal that senescence delay improves crop performance under some abiotic stresses. In this review, we summarize the evidence for increased resistance to abiotic stress, mostly water deficit, in genotypes with delayed senescence, and specifically focus on the physiological mechanisms and agronomic conditions under which the stay-green trait may ameliorate grain yield under stress.

Evidence of a pan-tissue decline in stemness during human aging.

Despite their biological importance, the role of stem cells in human aging remains to be elucidated. In this work, we applied a machine learning methodology to GTEx transcriptome data and assigned stemness scores to 17,382 healthy samples from 30 human tissues aged between 20 and 79 years. We found that ~60% of the studied tissues exhibit a significant negative correlation between the subject's age and stemness score. The only significant exception was the uterus, where we observed an increased stemness with age. Moreover, we observed that stemness is positively correlated with cell proliferation and negatively correlated with cellular senescence. Finally, we also observed a trend that hematopoietic stem cells derived from older individuals might have higher stemness scores. In conclusion, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration may contribute to human aging.

Protective Effect of Curcumin on D-Galactose-Induced Senescence and Oxidative Stress in LLC-PK1 and HK-2 Cells.

D-galactose has been widely used as an inducer of cellular senescence and pathophysiological processes related to aging because it induces oxidative stress. On the other hand, the consumption of antioxidants such as curcumin can be an effective strategy to prevent phenotypes related to the enhanced production of reactive oxygen species (ROS), such as aging and senescence. This study aimed to evaluate the potential protective effect of curcumin on senescence and oxidative stress and endoplasmic reticulum stress induced by D-galactose treatment in Lilly Laboratories Culture-Porcine Kidney 1 (LLC-PK1) and human kidney 2 (HK-2) proximal tubule cell lines from pig and human, respectively. For senescence induction, cells were treated with 300 mM D-galactose for 120 h and, to evaluate the protective effect of the antioxidant, cells were treated with 5 µM curcumin for 24 h and subsequently treated with curcumin + D-galactose for 120 h. In LLC-PK1 cells, curcumin treatment decreased by 20% the number of cells positive for senescence-associated (SA)-ß-D-galactosidase staining and by 25% the expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and increased by 40% lamin B1 expression. In HK-2 cells, curcumin treatment increased by 60% the expression of proliferating cell nuclear antigen (PCNA, 50% Klotho levels, and 175% catalase activity. In both cell lines, this antioxidant decreased the production of ROS (20% decrease for LLC-PK1 and 10 to 20% for HK-2). These data suggest that curcumin treatment has a moderate protective effect on D-galactose-induced senescence in LLC-PK1 and HK-2 cells.

The neurobiological effects of senescence on dopaminergic system: A comprehensive review.

Over time, the body undergoes a natural, multifactorial, and ongoing process named senescence, which induces changes at the molecular, cellular, and micro-anatomical levels in many body systems. The brain, being a highly complex organ, is particularly affected by this process, potentially impairing its numerous functions. The brain relies on chemical messengers known as neurotransmitters to function properly, with dopamine being one of the most crucial. This catecholamine is responsible for a broad range of critical roles in the central nervous system, including movement, learning, cognition, motivation, emotion, reward, hormonal release, memory consolidation, visual performance, sexual drive, modulation of circadian rhythms, and brain development. In the present review, we thoroughly examine the impact of senescence on the dopaminergic system, with a primary focus on the classic delimitations of the dopaminergic nuclei from A8 to A17. We provide in-depth information about their anatomy and function, particularly addressing how senescence affects each of these nuclei.

Subcellular structure, heterogeneity, and plasticity of senescent cells.

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro-survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions.