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1.
Chem Biol Interact ; 369: 110278, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36423730

RESUMO

In recent years, studies have reported the role of stress-regulatory hormones, including epinephrine, in regulating the progression of a few cancers. However, the tumor-promoting action of epinephrine is not yet investigated in T cell malignancy, a rare and complicated neoplastic disorder. More so, very little is known regarding the implication of epinephrine in the glucose metabolic rewiring in tumor cells. The present investigation showed that epinephrine enhanced the proliferation of T lymphoma cells through up- and down-regulating the expression of PCNA, cyclin D, and p53, respectively. In addition, epinephrine inhibited apoptosis in T lymphoma cells possibly by increasing the level of BCL2 (an anti-apoptotic protein) and decreasing PARP level (a pro-apoptotic protein). Intriguingly, epinephrine is reported to stimulate glycolysis in T lymphoma cells by increasing the expression of crucial glycolysis regulatory molecules, namely HKII and PKM2, in a HIF-1α-dependent manner. Moreover, augmented production of ROS has been observed in T lymphoma cells, which might be a central player in epinephrine-mediated T cell lymphoma growth. Taken together, our study demonstrates that epinephrine might have a significant role in the progression of T cell lymphoma.


Assuntos
Apoptose , Linfoma de Células T , Humanos , Proliferação de Células , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Glucose/metabolismo , Glicólise , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
2.
Apoptosis ; 27(7-8): 606-618, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35725975

RESUMO

Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.


Assuntos
Cisplatino , Linfoma de Células T , Apoptose , Linhagem Celular Tumoral , Cisplatino/farmacologia , Glucose/metabolismo , Glicólise , Humanos , Linfoma de Células T/metabolismo , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Citrato de Sildenafila/farmacologia
3.
Chronobiol Int ; 38(12): 1714-1725, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34192991

RESUMO

Social interaction, a non-photic cue, plays a role in the synchronization of circadian rhythm under constant environmental conditions. However, little is known about the effect of sex-specific interaction and sex-specific odor on the free-running circadian clock of mice. Hence, in the present study, we investigated the effect of social interaction and odor presentation of same and opposite-sex conspecifics on the free-running rhythm of mice. In this investigation, stranger and dummy mice (saturated with either male- or female-associated odor) were separately exposed to the same and opposite-sex conspecifics of male and female runners and receivers, respectively for 30 min at CT15 for 10-12 d. The results showed that the daily exposure of runners with same and opposite-sex strangers entrained the free-running locomotor activity rhythm in a gender-specific manner. However, daily exposure of same and opposite-sex conspecific odors masked the circadian rhythm of receiver animals by increasing the activity. Further, social interaction and odor presentation caused lengthened and shortened period length, respectively. These results suggest that periodic social interactions can produce entrainment and conspecific odor can produce only masking on free-running circadian locomotor activity rhythm in mice.


Assuntos
Relógios Circadianos , Odorantes , Animais , Ritmo Circadiano , Feminino , Masculino , Camundongos , Atividade Motora , Interação Social
4.
Chronobiol Int ; 38(2): 212-223, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33435752

RESUMO

Social cues are potent non-photic modulators of the circadian clock and play a vital role in resetting the endogenous clock. Several lines of evidence strongly suggest a functional link between olfactory cues and the circadian clock. However, there is a paucity of information on the effects of social interaction with the conspecifics of the opposite sex on the circadian clock. Hence, we studied the effect of social cues of sexually mature naïve opposite sex of the conspecific on the phase resetting of the circadian clock at various circadian times (CT) and molecular changes at the suprachiasmatic nuclei (SCN) and odor responsive structure in the brain of mice. Sexually naïve adult male and female free-running mice (designated as 'runners') were exposed to the conspecifics of the opposite-sex ('strangers') for 30 min at CT3, CT9, CT15, and CT21. Both male and female 'runners' exhibited a phase advance at CT3, delay at CT21, and no response at CT9. However, at CT15 only the male 'runners' exhibited phase advance but not the female 'runners'. Control mice did not elicit any significant phase shifts at all CTs. Social interactions with conspecifics of the opposite-sex up-regulated c-fos/C-FOS, omp in the olfactory bulb, per-1/PER-1 in the SCN, C-FOS, and PER-1 in the piriform cortex of both male and female runners at CT3. However, at CT15 up-regulation of variables only occurred in male but not in female runners. Together, the present investigation has shown the gender difference in circadian clock responses for social cues with conspecific of the opposite-sex in mice.


Assuntos
Relógios Circadianos , Animais , Ritmo Circadiano , Feminino , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores Sexuais , Interação Social , Núcleo Supraquiasmático/metabolismo
5.
Environ Toxicol ; 36(4): 628-641, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33274819

RESUMO

Nimbolide is a tetranortriterpenoid derived from the leaves and flowers of Azadirachta indica (Neem). It exhibits anticancer activity against a variety of cancers by modulating various crucial features, including cell proliferation, apoptosis, and invasion and metastasis. More importantly, the cytotoxic effect of nimbolide has also been observed against T cell lymphoma, but the underlying mechanisms are still unexplored. So far, no study has been conducted to observe the effect of nimbolide on cancer cell metabolism. Therefore, the present investigation was designed to explore the molecular mechanisms of the antitumor potential of nimbolide against T cell lymphoma, a neoplastic disorder of thymic origin. In addition, we also unraveled the anti-glycolytic activity of nimbolide against T lymphoma cells with possible molecular mechanisms. Our results showed the cytotoxic action of nimbolide against three different cell lines of T cell lymphoma, namely Dalton's lymphoma, HuT-78, and J6. Nimbolide-induced apoptosis in T lymphoma cells by altering the level of reactive oxygen species, p53, Bcl2, Bax, and cytochrome c, with subsequent cleavage of caspase 3. Remarkably, nimbolide inhibited the expression of hypoxia-inducible factor-1α, glucose transporter 3, hexokinase II, and pyruvate dehydrogenase kinase 1, which led to the suppression of glycolysis with concomitant activation of oxidative phosphorylation. Hence, the results of the present investigation demonstrate that nimbolide exerts tumoricidal activity against T lymphoma cells via augmentation of apoptosis and reversal of altered cell metabolism. Thus, the present study provides a new insight for the therapeutic utilization of nimbolide against T cell lymphoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucose/metabolismo , Limoninas/farmacologia , Caspase 3/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Espécies Reativas de Oxigênio/metabolismo
6.
Apoptosis ; 25(1-2): 135-150, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31867678

RESUMO

Lysophosphatidic acid (LPA) is a bioactive lipid, which plays an indispensable role in various physiological and pathological processes. Moreover, an elevated level of LPA has been observed in malignancies of different origins and implicated in their progression via modulation of proliferation, apoptosis, invasion and metastasis. Interestingly, few recent reports suggest a pivotal role of LPA-modulated metabolism in oncogenesis of ovarian cancer. However, little is understood regarding the role of LPA in the development and progression of T cell malignancies, which are considered as one of the most challenging neoplasms for clinical management. Additionally, mechanisms underlying the LPA-dependent modulation of glucose metabolism in T cell lymphoma are also not known. Therefore, the present study was undertaken to explore the role of LPA-altered apoptosis and glucose metabolism on the survival of T lymphoma cells. Observations of this investigation suggest that LPA supports survival of T lymphoma cells via altering apoptosis and glucose metabolism through changing the level of reactive species, namely nitric oxide and reactive oxygen species along with expression of various survival and glucose metabolism regulatory molecules, including hypoxia-inducible factor 1-alpha, p53, Bcl2, and glucose transporter 3, hexokinase II, pyruvate kinase muscle isozyme 2, monocarboxylate transporter 1, pyruvate dehydrogenase kinase 1. Taken together' the results of the present investigation decipher the novel mechanisms of LPA-mediated survival of T lymphoma cells via modulation of apoptosis and glucose metabolism.


Assuntos
Glucose/metabolismo , Linfoma de Células T/metabolismo , Lisofosfolipídeos/metabolismo , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Linfoma de Células T/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo
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