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Simple Summary: The present research investigates the counterintuitive effects of sublethal chemotherapy doses in non-small-cell lung cancer (NSCLC), focusing on their role in enhancing cancer cell malignancy and the role of Aldo-keto reductase family 1 member B10 (AKR1B10) in this process. This study is designed to understand how sublethal doses of chemotherapy drugs like taxol and doxorubicin lead to increased cancer cell migration, invasion, metastasis, and the consequent upregulation of AKR1B10. Our findings uncover the fact that AKR1B10 plays a crucial role in NSCLC progression and chemoresistance, with its increased expression being linked to enhanced malignancy. The results are significant for the research community as they provide insight into the currently paradoxical molecular mechanisms of chemotherapy-induced resistance in lung cancer. This could lead to the potential development of more effective treatment strategies that consider the impact of chemotherapy dosing on cancer cell behavior, potentially improving patient outcomes by preventing the unintentional enhancement of cancer aggressiveness. Chemotherapy remains a cornerstone in lung cancer treatment, yet emerging evidence suggests that sublethal low doses may inadvertently enhance the malignancy. This study investigates the paradoxical effects of sublethal low-dose chemotherapy on non-small-cell lung cancer (NSCLC) cells, emphasizing the role of Aldo-keto reductase family 1 member B10 (AKR1B10). We found that sublethal doses of chemotherapy unexpectedly increased cancer cell migration approximately 2-fold and invasion approximately threefold, potentially promoting metastasis. Our analysis revealed a significant upregulation of AKR1B10 in response to taxol and doxorubicin treatment, correlating with poor survival rates in lung cancer patients. Furthermore, silencing AKR1B10 resulted in a 1–2-fold reduction in cell proliferation and a 2–3-fold reduction in colony formation and migration while increasing chemotherapy sensitivity. In contrast, the overexpression of AKR1B10 stimulated growth rate by approximately 2-fold via ERK pathway activation, underscoring its potential as a target for therapeutic intervention. The reversal of these effects upon the application of an ERK-specific inhibitor further validates the significance of the ERK pathway in AKR1B10-mediated chemoresistance. In conclusion, our findings significantly contribute to the understanding of chemotherapy-induced adaptations in lung cancer cells. The elevated AKR1B10 expression following sublethal chemotherapy presents a novel molecular mechanism contributing to the development of chemoresistance. It highlights the need for strategic approaches in chemotherapy administration to circumvent the inadvertent enhancement of cancer aggressiveness. This study positions AKR1B10 as a potential therapeutic target, offering a new avenue to improve lung cancer treatment outcomes by mitigating the adverse effects of sublethal chemotherapy. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) affects glucose uptake in adipocytes and may play an important role in adipose physiology. One of the principal functions of adipose tissue is the provision of energy substrate through lipolysis. In the present study, we investigated the effects of ET-1 on lipolysis in 3T3-L1 adipocytes. When glycerol release in the culture medium was measured as an index of lipolysis, the results showed that ET-1 caused a significant increase that was time and dose dependent. With a concentration of 10 nM ET-1, stimulation of glycerol release plateaued after 4 h of exposure. This effect was inhibited by the ETA receptor antagonist BQ-610 (10 [micro]M) but not by the E[T.sub.B] receptor antagonist BQ-788 (10 [micro]M). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the cAMP-dependent protein kinase A-mediated, phospholipase [A.sub.2] (PL[A.sub.2])mediated, protein kinase C (PKC)-mediated, phosphatidylinositol 3 (PI 3)-kinase-mediated, and the mitogen-activated protein kinase (MAPK)-mediated pathways. Inhibition of adenylyl cyclase activation by SQ-22536 (100 [micro]M) did not block ET-l-induced lipolysis. Pretreatment of adipocytes with the PL[A.sub.2] inhibitor dexamethasone (100 nM), the PKC inhibitor H-7 (6 [micro]M), or the PI 3-kinase inhibitor wortmannin (100 nM) also had no effect. ET-l-induced lipolysis was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation using PD-98059 (75 [micro]M), whereas a p38 MAPK inhibitor (SB-203580; 20 [micro]M) had no effect. Results of Western blot further demonstrated that ET-1 induced ERK phosphorylation. These data show that ET-1 induces lipolysis in 3T3-L1 adipocytes via a pathway that is different from the conventional cAMP-dependent pathway used by isoproterenol and that involves ERK activation. glycerol; adipocytes; mitogen-activated protein kinase

Abstract: Resistin, a hormone secreted by adipocytes, is suggested to be an important link between obesity and diabetes. The aim of this study was to evaluate the regulatory effect of estrogen on adipocyte resistin gene expression in ovariectomized (OVX) rats and in isolated rat adipocytes in vitro. Subcutaneous injection of estradiol benzoate reduced resistin mRNA levels in adipocytes isolated from the inguinal, parametrial, perirenal, retroperitoneal, or periovarian fat deposits of OVX rats, while an in vitro study showed that estradiol treatment decreased resistin mRNA levels in cultured rat periovarian fat adipocytes. Results of Western blotting analysis also showed that estrogen decreased adipose resistin contents in vivo and in vitro. These data suggest that estrogen is a pivotal negative regulator of resistin gene expression. [Copyright &y& Elsevier]

Purpose: The objective of this study was to analyze and compare the stresses in two different bone-implant interface conditions in anisotropic three-dimensional finite element models (FEMs) of an osseointegrated implant of either commercially pure titanium or yttrium-partially stabilized zirconia (Y-PSZ) in combination with different superstructures (gold alloy or Y-PSZ crown) in the posterior maxilla., Materials and Methods: Three-dimensional FEMs were created of a first molar section of the maxilla into which was embedded an implant, connected to an abutment and superstructure, using commercial software. Two versions of the FEM were constructed; these allowed varying assignment of properties (either a bonded and or a contact interface), so that all experimental variables could be investigated in eight groups. Compact and cancellous bone were modeled as fully orthotropic and transversely isotropic, respectively. Oblique (200-N vertical and 40-N horizontal) occlusal loading was applied at the central and distal fossae of the crown., Results: Maximum von Mises and compressive stresses in the compact bone in the two interfaces were lower in the zirconia implant groups than in the titanium implant groups. A similar pattern of stress distribution in cancellous bone was observed, not only on the palatal side of the platform but also in the apical area of both types of implants., Conclusion: The biomechanical parameters of the new zirconia implant generated a performance similar to that of the titanium implant in terms of displacement, stresses on the implant, and the bone-implant interface; therefore, it may be a viable alternative, especially for esthetic regions.

Purpose: The purpose of this study was to analyze and compare the implant-bone interface stresses in anisotropic three-dimensional finite element models of an osseointegrated implant with platform switching and a conventional matching-diameter implant platform and abutment in the posterior maxilla., Materials and Methods: Three-dimensional finite element models were created of a first molar section of the maxilla and embedded with a single endosseous implant (4.1 3 10 mm). One model simulated a 4.1-mm-diameter abutment connection and the other was a narrower 3.4-mm-diameter abutment connection, ie, simulating a platform-switching configuration. A gold alloy crown with 2-mm occlusal thickness was applied over the titanium abutment. Material properties of compact and cancellous bone were modeled as fully orthotropic and transversely isotropic, respectively. Oblique (200-N vertical and 40-N horizontal) occlusal loads were applied and perfect bonding was assumed at all interfaces., Results: Maximum von Mises, compressive, and tensile stresses in compact bone were lower in the platform-switching model than in the conventional model. However, the maximum von Mises stress in cancellous bone was higher in the platform-switching model than in the conventional model., Conclusion: The platform-switching technique reduced the stress concentration in the area of compact bone and shifted it to the area of cancellous bone during oblique loading.

Objective: In order to characterize the regulation of resistin gene expression, we explore the effect of tumornecrosis factor-alpha (TNF-alpha) on resistin mRNA expression and its underlying mechanism in 3T3-L1 adipocytes., Methods and Procedures: Differentiated 3T3-L1 adipocytes were treated for 24 h with 0-10 ng/ml of TNF-alpha or with 2.5 ng/ml of TNF-alpha for 0-24 h, and then resistin mRNA levels were measured by northern blotting. To further explore the involvement of nitric oxide (NO) in TNF-alpha-regulated resistin expression, the effect of the NO donor, sodium nitroprusside (SNP), on resistin mRNA levels in adipocytes and the effect of the nitric oxide synthase (NOS) inhibitors, N(G)-nitro-L-arginine methyl ester (L-NAME), and S,S'-1,3-phenylene-bis(1,2-ethanediyl)-bis-isothiourea.2HBr (PBITU), on the TNF-alpha effect in adipocytes were examined. The effects of TNF-alpha on inducible NOS (iNOS) protein expression in adipocytes were also measured by western blotting., Results: Our results showed that TNF-alpha caused a dose-dependent reduction in resistin mRNA levels. This effect seemed to be associated with the TNF-alpha-induced expression of iNOS. The results showed that TNF-alpha induced iNOS expression and release of NO after 24-h treatment of differentiated 3T3-L1 adipocytes. Pretreatment with L-NAME and PBITU significantly reversed the TNF-alpha-induced downregulation of resistin expression, while treatment with SNP mimicked the inhibitory effect of TNF-alpha on resistin expression. In addition, pretreatment with protein tyrosine kinase (PTK) inhibitors, genistein and AG-1288, prevented TNF-alpha-induced iNOS expression and subsequent resistin downregulation., Discussion: Our data suggest that TNF-alpha suppresses resistin expression by inducing iNOS expression, thus causing overproduction of NO, which downregulates resistin gene expression.