Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.

The objective of this study is to evaluate the influence of carbimazole-induced hypothyroidism on testis of adult albino rats and the probable protective effect of α-lipoic acid (ALA). The rats were divided into four groups; Control, α-lipoic acid group, carbimazole, and carbimazole+α-lipoic acid groups. Rats were exposed to ALA (60 mg/kg BW) or carbimazole (1.35 mg/kg BW) or both via gavages for 30 days. Morphometric analysis revealed a significant decrease in tubular diameter, germinal epithelium thickness, and interstitial space as compared to the controls. Also, rats exposed to carbimazole showed a significant decline in testicular weight, sperm motility, and count. Also, deterioration of the testicular architecture. ALA supplementation resulted in a significant improvement in the tubular diameter and germinal epithelium thickness, but no significant improvement regarding interstitial space was observed. Another observation was the significant decline in serum testosterone and FSH in the carbimazole group, indicating reduced steroidogenesis. A significant reduction in reduced glutathione content was detected in the testes of the carbimazole group over the controls, while malonaldehyde (MDA) concentration significantly increased. Conversely, ALA supplementation ameliorated the toxicity induced by hypothyroidism as illustrated by enhanced reproductive organ weights, testosterone, LH, and FSH levels, testicular steroidogenesis, and oxidative stress parameters. Hypothyroidism altered testicular antioxidant balance and negatively affected spermatogenesis. On the other hand, ALA through its antioxidant properties alleviated testicular toxicity in carbimazole-exposed rats. The objective of this study is to evaluate the influence of carbimazole-induced hypothyroidism on testis of adult albino rats and the probable protective effect of α-lipoic acid (ALA). The rats were divided into four groups; Control, α-lipoic acid group, carbimazole, and carbimazole+α-lipoic acid groups. Rats were exposed to ALA (60 mg/kg BW) or carbimazole (1.35 mg/kg BW) or both via gavages for 30 days. Morphometric analysis revealed a significant decrease in tubular diameter, germinal epithelium thickness, and interstitial space as compared to the controls. Also, rats exposed to carbimazole showed a significant decline in testicular weight, sperm motility, and count. Also, deterioration of the testicular architecture. ALA supplementation resulted in a significant improvement in the tubular diameter and germinal epithelium thickness, but no significant improvement regarding interstitial space was observed. Another observation was the significant decline in serum testosterone and FSH in the carbimazole group, indicating reduced steroidogenesis. A significant reduction in reduced glutathione content was detected in the testes of the carbimazole group over the controls, while malonaldehyde (MDA) concentration significantly increased. Conversely, ALA supplementation ameliorated the toxicity induced by hypothyroidism as illustrated by enhanced reproductive organ weights, testosterone, LH, and FSH levels, testicular steroidogenesis, and oxidative stress parameters. Hypothyroidism altered testicular antioxidant balance and negatively affected spermatogenesis. On the other hand, ALA through its antioxidant properties alleviated testicular toxicity in carbimazole-exposed rats.

Tramadol is a centrally acting analgesic drug, used for the management of moderate to severe pain in a variety of diseases. The long-term use of tramadol can induce endocrinopathy. This study aimed to evaluate the effect of tramadol dependence on the adrenal cortex and the effect of its withdrawal. Thirty adult male rats were divided into three experimental groups: the control group, the tramadol-dependent group that received increasing therapeutic doses of tramadol orally for 1 month, and the recovery group that received tramadol in a dose and duration similar to the previous group followed by a withdrawal period for another month. Specimens from the adrenal cortex were processed for histological, immunohistochemical, enzyme assay, and quantitative real-time PCR (RT-qPCR) studies. Tramadol induced a significant increase in malondialdehyde level and a significant decrease in the levels of glutathione peroxidase and superoxide dismutase. A significant decrease in the levels of adrenocorticotrophic hormones, aldosterone, cortisol, corticosterone, and dehydroepiandrosterone sulfate was also detected. Severe histopathological changes in the adrenal cortex were demonstrated in the form of disturbed architecture, swollen cells, and shrunken cells with pyknotic nuclei. Inflammatory cellular infiltration and variable-sized homogenized areas were also detected. A significant increase inP53andBaximmunoreaction was detected and confirmed by RT-qPCR. The ultrastructural examination showed irregular, shrunken adrenocorticocytes with dense nuclei. Dilated smooth endoplasmic reticulum, mitochondria with disrupted cristae, and numerous coalesced lipid droplets were also demonstrated. All these changes started to return to normal after the withdrawal of tramadol. Thus, it was confirmed that the long-term use of tramadol can induce severe adrenal changes with subsequent insufficiency.