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Isothiocyanates (ITCs) are naturally occurring sulfur-containing compounds with diverse biological effects. This study investigated the effects of sulforaphane (SFN, an aliphatic ITC) and benzyl isothiocyanate (BITC, an aromatic ITC) on human acute myeloid leukemia SKM-1 cells, focusing on cell proliferation, cell death, and drug resistance. Both drug-sensitive SKM-1 cells and their drug-resistant SKM/VCR variant, which overexpresses the drug transporter P-glycoprotein, were used. SFN and BITC reduced cell viability in a dose-dependent manner, with BITC showing greater potency. IC50 values ranged from 7.0–8.0 µM for SFN and 4.0–5.0 µM for BITC in both cell types, with only slight differences between the variants. Both ITCs induced autophagy as evidenced by increased LC3-II production and caused a significant increase in the sub-G0/G1 cell population, especially with BITC. Apoptosis was more pronounced after BITC treatment, whereas SFN had a weaker effect. These results suggest that autophagy may act as a defense mechanism in response to ITC-induced apoptosis in human AML cells. [ABSTRACT FROM AUTHOR]

Abstract This study investigates the intricate factors influencing meat quality, including breed, rearing conditions, and processing, with a primary focus on oxidative stress in Holstein Friesian and Simmental cattle within conventional and intensive production systems. A notable difference in oxidative stress was found between animals subjected to intensive-farming versus conventional practices, with Holstein cattle showing a more pronounced antioxidant gene response than Simmental. The analysis revealed that intensive rearing conditions resulted in increased DNA repair activity and expression of stress-response proteins like heat shock proteins, suggestive of greater cellular damage and an adaptive stress response. Muscle tissue analyses, revealed a clear distinction in gene expression associated with meat quality between the breeds and the type of farming system. A negative correlation emerged between oxidative stress levels and genes related to muscle development, which affects meat quality. Intensive farming conditions altered the expressions of apoptotic proteins, impacting meat quality at the molecular level. These results underscore the profound effect rearing conditions have on meat quality, driven by stress-related molecular responses. This highlights the need for further research into the influence of husbandry practices on animal welfare and meat quality, with the intention of developing strategies to mitigate the negative consequences of intensive-farming.

This study investigates the intricate factors influencing meat quality, including breed, rearing conditions, and processing, with a primary focus on oxidative stress in Holstein Friesian and Simmental cattle within conventional and intensive production systems. A notable difference in oxidative stress was found between animals subjected to intensive-farming versus conventional practices, with Holstein cattle showing a more pronounced antioxidant gene response than Simmental. The analysis revealed that intensive rearing conditions resulted in increased DNA repair activity and expression of stress-response proteins like heat shock proteins, suggestive of greater cellular damage and an adaptive stress response. Muscle tissue analyses, revealed a clear distinction in gene expression associated with meat quality between the breeds and the type of farming system. A negative correlation emerged between oxidative stress levels and genes related to muscle development, which affects meat quality. Intensive farming conditions altered the expressions of apoptotic proteins, impacting meat quality at the molecular level. These results underscore the profound effect rearing conditions have on meat quality, driven by stress-related molecular responses. This highlights the need for further research into the influence of husbandry practices on animal welfare and meat quality, with the intention of developing strategies to mitigate the negative consequences of intensive-farming. [ABSTRACT FROM AUTHOR]

Background: Ginseng polysaccharide (GPS) is an ingredient of ginseng with documented anti-tumor properties. However, its effect on colon cancer and the underlying molecular mechanisms have not been investigated clearly. Methods: Cell viability of HT29 and CT26 cells treated with different concentrations of GPS was assessed using the Cell Counting Kit-8 (CCK-8) assay. Western blot assay was used to detect the expression of apoptotic proteins, while the mRNA levels were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Transwell migration assays were used to examine the migration and invasion of cells. Results: The results revealed that GPS effectively suppressed the proliferation of HT29 and CT26 cells. We demonstrated an upregulation of apoptotic proteins in GPS-treated cells, including Bax, cleaved Caspase-3, and p-p53. GPS treatment also increased the mRNA levels of cytochrome C and Bax. Furthermore, the results showed that GPS treatment concurrently promoted the activation of nucleotide-binding domain leucine-rich family pyrin-containing 3 (NLRP3) inflammasome. Transwell migration assays showed that GPS inhibited the migratory and invasive abilities of colon cancer cells. As expected, inhibition of NLRP3 expression using INF39 attenuated the inhibitory effect of GPS on migration and invasion. Upon NLRP3 inhibition, GPS-induced apoptosis was dramatically alleviated, accompanied by a reduction in the expression of apoptotic proteins. Conclusion: In conclusion, this research provides compelling evidence that the GPS-induced NLRP3 signaling pathway plays a pivotal role in apoptosis of colon cells, suggesting potential clinical implications for the therapeutic intervention of colon cancer. Thus, GPS might be a promising anti-tumor drug for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Bromelain is a mixture of protease enzyme extract from the fruit or stem of the pineapple plant. It has a wide range of biological actions, and it is most commonly used as an anti-inflammatory agent. This study was designed to investigate the antidepressant effect of bromelain on chronic unpredictable stress (CUS)-induced depression in rat models by targeting various molecular mechanisms. Result We studied the in silico analysis of the antidepressant potential of bromelain by docking with various proteins involved in the pathophysiology of depression. As a result of in silico studies, bromelain showed good binding energy with IL1β, 5-HT, BDNF, CREB, and TrkB. The mRNA expression of BDNF, TrkB, AKT, ERK, and IL-1β was studied by qRT-PCR. Gene expression studies showed a significant decrease in BDNF, TrkB, AKT, and ERK in chronic unpredictable stress, whereas there was a significant increase in the case of the bromelain- and fluoxetine-treated group. Since neuroinflammation is also one of the major concerns in the pathophysiology of depression, pro-inflammatory cytokines were also studied along with apoptotic markers using ELISA. ELISA results showed a significant increase in inflammatory cytokines in CUS, and it was significantly decreased in the case of the bromelain- and fluoxetine-treated group. Similarly, there was an increased concentration of pro-apoptotic protein in the CUS group, whereas it was decreased in the bromelain and fluoxetine groups. Conclusions From the results, it is clear that bromelain exerts an antidepressive effect by preventing neuroinflammation and neurodegeneration and by enhancing neurogenesis and neuroplasticity. Graphical abstract

Background: Bromelain is a mixture of protease enzyme extract from the fruit or stem of the pineapple plant. It has a wide range of biological actions, and it is most commonly used as an anti-inflammatory agent. This study was designed to investigate the antidepressant effect of bromelain on chronic unpredictable stress (CUS)-induced depression in rat models by targeting various molecular mechanisms. Result: We studied the in silico analysis of the antidepressant potential of bromelain by docking with various proteins involved in the pathophysiology of depression. As a result of in silico studies, bromelain showed good binding energy with IL1β, 5-HT, BDNF, CREB, and TrkB. The mRNA expression of BDNF, TrkB, AKT, ERK, and IL-1β was studied by qRT-PCR. Gene expression studies showed a significant decrease in BDNF, TrkB, AKT, and ERK in chronic unpredictable stress, whereas there was a significant increase in the case of the bromelain- and fluoxetine-treated group. Since neuroinflammation is also one of the major concerns in the pathophysiology of depression, pro-inflammatory cytokines were also studied along with apoptotic markers using ELISA. ELISA results showed a significant increase in inflammatory cytokines in CUS, and it was significantly decreased in the case of the bromelain- and fluoxetine-treated group. Similarly, there was an increased concentration of pro-apoptotic protein in the CUS group, whereas it was decreased in the bromelain and fluoxetine groups. Conclusions: From the results, it is clear that bromelain exerts an antidepressive effect by preventing neuroinflammation and neurodegeneration and by enhancing neurogenesis and neuroplasticity. [ABSTRACT FROM AUTHOR]

Additional therapeutics are required to minimize the toxicity of aflatoxin B1 (AFB1) in animals due to the drawbacks of mycotoxin binders. The cytochrome P450 enzyme system is necessary for the metabolic activation of AFB1 before it produces the cytotoxic AFB1-exo-8, 9-epoxide (AFBO). It is already proven that enrofloxacin (ENR) has been shown to substantially decrease the activity of the cytochrome P450 enzymes. To understand how ENR affects AFB1-induced cytotoxicity, it is important to highlight this context. In this present study, molecular docking was performed between ENR with CYP3A4 protein, apoptotic proteins (Bax, caspase 3, caspase 8, fas L, MAPK1), and catalase. To assess the effect of ENR on AFB1-induced cytotoxicity by MTT assay and trypan blue dye exclusion techniques, the mammalian simulative Vero cell lines were used in different treatment groups as AFB1 alone, ENR alone, AFB1+ENR, and AFB1+silymarin (known cell protective agent). This was done to further evaluate the in silico analysis. ENR interacted more positively with all of the proteins (CYP3A4, Bax, catalase, caspase 3, caspase 8, MAPK1, and fas L), according to the findings of molecular docking studies. On the other hand, cytotoxicity caused by AFB1 is successfully prevented by ENR at a dose of 25 µg/mL. The results of the present study suggest that ENR primarily protects against cytotoxicity induced by AFB1 in Vero cells as the evidence of in silico studies revealed that ENR may protect AFB1-induced cytotoxicity by interacting with the CYP3A4 enzyme which is primarily required for activation AFB1.

Additional therapeutics are required to minimize the toxicity of aflatoxin B1 (AFB1) in animals due to the drawbacks of mycotoxin binders. The cytochrome P450 enzyme system is necessary for the metabolic activation of AFB1 before it produces the cytotoxic AFB1-exo-8, 9-epoxide (AFBO). It is already proven that enrofloxacin (ENR) has been shown to substantially decrease the activity of the cytochrome P450 enzymes. To understand how ENR affects AFB1-induced cytotoxicity, it is important to highlight this context. In this present study, molecular docking was performed between ENR with CYP3A4 protein, apoptotic proteins (Bax, caspase 3, caspase 8, fas L, MAPK1), and catalase. To assess the effect of ENR on AFB1-induced cytotoxicity by MTT assay and trypan blue dye exclusion techniques, the mammalian simulative Vero cell lines were used in different treatment groups as AFB1 alone, ENR alone, AFB1+ENR, and AFB1+silymarin (known cell protective agent). This was done to further evaluate the in silico analysis. ENR interacted more positively with all of the proteins (CYP3A4, Bax, catalase, caspase 3, caspase 8, MAPK1, and fas L), according to the findings of molecular docking studies. On the other hand, cytotoxicity caused by AFB1 is successfully prevented by ENR at a dose of 25 µg/mL. The results of the present study suggest that ENR primarily protects against cytotoxicity induced by AFB1 in Vero cells as the evidence of in silico studies revealed that ENR may protect AFB1-induced cytotoxicity by interacting with the CYP3A4 enzyme which is primarily required for activation AFB1. [ABSTRACT FROM AUTHOR]

This study deals with the readily reaction of the enaminone derivative 3 with different reagents to give the corresponding pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyrimidine, pyrazole, pyrazolopyridazine, dienamide, and pyranone derivatives. In-vitro cytotoxic screening was performed for all analogs against several human cancer cell lines. Compound 21 showed significant anti-breast cancer activity and a safety profile against the normal human cell lines (BJ-1). Furthermore, compound 21 was chosen as a representative example to study its potential apoptotic mechanism in the MCF-7 cancer cell line. It enhanced DNA fragmentation alongside its characteristic effect on tubulin polymerization. In addition, compound 21 up-regulated the pro-apoptotic Bax protein, decreased the Bcl-2 anti-apoptotic protein, and increased p53 and Caspase-7 levels confirming its mitochondrial intrinsic apoptotic activation. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the early follicular apoptosis in canine ovarian follicles by examining the expression of anti-apoptotic BCL-2 and pro-apoptotic BAX proteins throughout the estrous cycle associated with oocyte maturation. Follicular cells from preantral and antral follicles of varying sizes were isolated and grouped based on follicle type and estrous phase. Antral follicles underwent flow cytometry analysis, whereas preantral follicles were subjected to Western blotting. The meiotic capacity of oocytes from these different follicle types was evaluated through in vitro maturation. Statistical analysis included ANOVA and Duncan's test. Results showed fluctuations in BCL-2 and BAX levels across different follicular stages and estrous phases. BCL-2 levels increased (P <0.05) with follicular development in antral follicles, particularly during estrus, while BAX exhibited variations peaking (P <0.05) during estrus. The BCL-2/BAX ratio in antral follicles was higher (P <0.05) in estrus and diestrus compared to anestrus and proestrus. Additionally, BCL-2 and BAX proteins were detected in preantral follicles, with varying expression levels (P <0.05) across estrous phases. The BCL-2/BAX ratio in preantral follicles was highest (P <0.05) during anestrus and estrus and decreased (P <0.05) in proestrus and diestrus. Oocytes from preantral follicles did not reach the MII stage, regardless of the levels of BCL-2/BAX. Conversely, oocytes obtained from large follicles during estrus showed the highest (P <0.05) maturation percentages, which were associated with the highest BCL-2/BAX ratio. These findings provide insights into the dynamic patterns of BCL-2 /BAX in canine follicles across the estrous cycle, shedding light on their potential roles in oocyte development. • BCL-2 and BAX levels vary across follicular and estrous phases in canines. • No preantral oocytes mature in vitro regardless of the BCL-2 or BAX levels • Large follicle oocytes showed the highest maturation rates and the highest BCL-2/BAX. [ABSTRACT FROM AUTHOR]

The expression of the membrane ABCB1 transporter in neoplastic cells is one of the most common causes of reduced sensitivity to chemotherapy. In our previous study, we investigated the effect of a single culture of ABCB1-negative (S) and ABCB1-positive variants of L1210 cells (R and T) in the presence of sulforaphane (SFN). We demonstrated that SFN induces the onset of autophagy more markedly in S cells than in R or T cells. In the current study, we focused on the effect of the repeated culture of S, R and T cells in SFN-containing media. The repeated cultures increased the onset of autophagy compared to the simple culture, mainly in S cells and to a lesser extent in R and T cells, as indicated by changes in the cellular content of 16 and 18 kDa fragments of LC3B protein or changes in the specific staining of cells with monodansylcadaverine. We conclude that SFN affects ABCB1-negative S cells more than ABCB1-positive R and T cells during repeated culturing. Changes in cell sensitivity to SFN appear to be related to the expression of genes for cell-cycle checkpoints, such as cyclins and cyclin-dependent kinases. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion (MI/R) injury, a complicated pathophysiological process, is regulated by lots of signaling pathways. Here in our present study, we identified TANK-binding kinase 1 (TBK1), an IKK-related serine/threonine kinase, as a protective regulator in MI/R injury. Our results indicated that TBK1 was decreased in MI/R injury in mice. However, after overexpressing TBK1 through an intramyocardial injection of TBK1 adenovirus, TBK1 overexpression improved cardiac function detected by echocardiography, decreased infarct size detected by Evans Blue and TTC staining, reduced cardiomyocyte apoptosis measured by TUNEL staining and alleviated disruption of mitochondria and cardiac muscle fibers detected by TEM in response to MI/R injury. Consistently, TBK1 overexpression ameliorated mitochondrial oxygen consumption rate (OCR) in neonatal rat cardiomyocytes (NRCMs) in response to hypoxia/reoxygenation (H/R) injury. Mechanistically, TBK1 overexpression upregulated Bcl-2 (an anti-apoptotic protein) but downregulated Bax (a pro-apoptotic protein) in vivo and in vitro. Collectively, our findings uncovered a pivotal function of TBK1 in MI/R injury through regulating the levels of apoptotic proteins for the first time, which might represent a promising target in treating MI/R patients in the future. • TBK1 overexpression improved the cardiac function, infarct size and cardiomyocyte apoptosis impaired by I/R injury. • TBK1 overexpression improved mitochondrial respiration OCR impaired by H/R injury. • TBK1 alleviated MI/R injury through regulating the levels of apoptotic proteins. [ABSTRACT FROM AUTHOR]

Purpose: To study the radio-sanitization effect of paclitaxel liposomes on breast cancer cells, SK-BR-3. Methods: Breast cancer cell line SK-BR-3 was cultured and made into a cell suspension. Four groups of cells were used: control and radiotherapy groups, paclitaxel group, and paclitaxel liposome + radiotherapy group (combination group). The growth inhibitory effects of the different treatments on SKBR- 3 cells were determined with CCK-8 method. Apoptosis in each group was evaluated with flow cytometry, while Western blotting was employed to assay Bcl-2, Caspase-3 and Bax protein levels. Results: There were marked inhibitory effect on growth of SK-BR-3 cells in drug, radiotherapy and combination groups, relative to control, while apoptosis was greater in combination group than in drug and radiotherapy groups (p < 0.05). The Bcl-2 protein level was higher in radiotherapy, drug and combination groups than in control group, while Caspase-3 and Bax proteins were markedly higher than control values (p < 0.05). Conclusion: Paclitaxel liposomes exert radio-sensitization effect on SK-BR-3 by regulating the levels of apoptotic proteins. This provides a basis for research and development of new drugs. [ABSTRACT FROM AUTHOR]

Myricetin, one of the most extensively studied polyphenols, is present abundantly in various fruits and vegetables and exhibits diverse pharmacological properties. The multifaceted biological action of myricetin against tumor heterogeneity makes it an impressive anticancer agent whose efficacy has been confirmed by an overwhelming number of studies. Myricetin shows its therapeutic potential by targeting and modulating the expression of various molecular target which are involved in inflammation, cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Myricetin deters tumor progression by inducing apoptosis via both intrinsic and extrinsic pathway, activating/inactivating several signaling pathways, and reactivating various tumor suppressor genes. This comprehensive review represents the effect of myricetin on various hallmarks of cancer with insight into the molecular mechanism employed by myricetin to mitigate cell proliferation, angiogenesis, metastasis, and induce apoptosis. In addition, enhanced bioavailability of myricetin through conjugation and its increased efficacy as an anticancer agent when used in combination are also highlighted. [ABSTRACT FROM AUTHOR]

Cancer treatment frequently carries side effects, therefore, the search for new selective and effective molecules is indispensable. Hymenaea courbaril L. has been used in traditional medicine in South America to treat several diseases, including prostate cancer. Leaves’ extracts from different polarities were evaluated using the 3-(4,5-methyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) cell viability assay to determine the cytotoxicity in prostate p53-null cells, followed by bio-guided fractionations to obtain the most cytotoxic fraction considering the selectivity index. The most cytotoxic fraction was analyzed by GC/MS to identify the active compounds. The majority compound, caryophyllene oxide, induced early and late apoptosis, depolarized the mitochondrial membrane, leading to several morphological changes and shifts in apoptotic proteins, and caspases were evidenced. Depolarization of the mitochondrial membrane releases the pro-apoptotic protein Bax from Bcl-xL. The apoptosis process is caspase-7 activation-dependent. Caryophyllene oxide is a safe anti-proliferative agent against PC-3 cells, inducing apoptosis with low toxicity towards normal cells.

Background/aim: Tetrazolium-based cell proliferation assays using MDA-MB-231 and HeLa cells revealed that 3,4-dihydro-lactucin (3,4-DHL), a compound isolated from Microbispora rosea AL22, possesses anticancer properties. Apoptotic cell death was observed in 3,4-DHL-treated cells. Lactucopicrin, a related compound, reportedly exerts anticancer activity against different cancer types. However, data on the anticancer mechanism of lactucins are limited. This study aimed to investigate apoptosis induction in MDA-MB-231 cells treated with 3,4-DHL., Materials and Methods: Morphological changes, changes in mitochondrial membrane potential, and apoptosis induction in MDA-MB-231 cells treated with 3,4-DHL were investigated. Furthermore, molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of anti-apoptotic proteins were performed to determine the effector mechanism of 3,4-DHL., Results: 3,4-DHL induced cytotoxicity at a half-maximal inhibitory concentration of 37.62 μg/ml, along with various morphological alterations in apoptotic and viable cells. Furthermore, 3,4-DHL-treated cells showed mitochondrial membrane potential depolarization, intense annexin V-fluorescein isothiocyanate staining, and increased caspase 3 and 8 activities. Molecular-docking studies demonstrated that 3,4-DHL should bind to the active site of various anti-apoptotic proteins, forming stable complexes., Conclusion: Our findings revealed that 3,4-DHL has great potential to be used as an apoptosis-inducing agent in cancer therapy. However, further in-vivo confirmation is required in evaluation of 3,4-DHL as an anticancer agent in cancer chemotherapy., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Canine transmissible venereal tumors (CTVTs) generally have different cytomorphologic subtypes and phases of progression. Some tumors have variable biologic behavior including a progressive increase in tumor aggressiveness and variable responses to chemotherapy. This behavior is partially due to high p‐glycoprotein expression by tumor cells, which leads to the expulsion of chemotherapeutic drugs. Other possible causes include changes in pro‐ and anti‐apoptotic genes from the BCL‐2 family and DNA repair systems, which are associated with the p53 gene family. Objectives: We aimed to determine the relative expression of the multi‐drug resistance 1 (MDR1), p53, b‐cell lymphoma 2 (BCL2), and bcl 2‐associated X (BAX) genes in CTVT before and after therapy and establish a relationship with treatment responses, cytomorphologic patterns, and tumor progression identified with histopathology. Methods: RT‐qPCR was performed on 21 CTVT tumor samples before and after initiating chemotherapy to determine specific gene expression. Normal canine testicular tissue was used as a negative control for all experiments. Results: MDR1 expression was decreased before and after initiating vincristine therapy in CTVT tumor tissues compared with normal canine testicular tissue; p53 and BAX were overexpressed at both time points compared with normal tissue, and no statistical differences were seen between the different morphologic types. However, BAX expression was decreased in the group with quick therapeutic responses but was still overexpressed compared with normal testicular tissue. In the group with the slowest chemotherapeutic responses, BCL2 was overexpressed. Conclusion: The findings of this study showed a relative increase in MDR1 gene expression in response to chemotherapy and higher expression in plasmacytoid CTVTs compared with the other cytomorphologic patterns. BCL2 overexpression was related to a favorable prognosis, and p53, BAX, and BCL2 were expressed independent of the cytomorphologic CTVT type. All of the genes were expressed independent of tumor progression, as noted on histopathology. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NACT) followed by radical surgical hysterectomy and pelvic lymph node dissection is considered an effective method to treat patients with bulky stage IB–IIA cervical cancer, but not all patients benefit from NACT. Apoptotic proteins play important roles in the progression of chemotherapy, and second mitochondria-derived activator of caspase (Smac) may have a cooperative relationship with Omi/HtrA2, leading to carcinogenesis and chemotherapy resistance. Chemosensitivity is an important prognostic factor for cervical cancer patients. The aim of this study was to evaluate the significance of Smac, survivin, X-linked inhibitor-of-apoptosis protein (XIAP), and Omi/HtrA2 expression in predicting the response to neoadjuvant chemotherapy and the prognostic significance of te expression of these proteins in cervical cancer patients. Our findings showed that low expression levels of survivin and high expression levels of Omi/HtrA2 in chemotherapy-responsive cervical carcinoma patients significantly increased chemosensitivity. [ABSTRACT FROM AUTHOR]

Objective: To explore the immunomodulatory effect of genipin on T cell in sepsis mice and its potential mechanism. Methods: After cecal ligation and puncture (CLP) in mice, 1 mg/kg, 2.5 mg/kg, 5 mg/kg genipin and phosphate buffer (PBS) were injected into tail vein at 0 h and 24 h, respectively. Mortality of mice was observed and recorded for 7 consecutive days. The mice were divided into Sham group (n=8), Genipin group (n=8), CLP group (n=8), CLP and Genipin group (n=14). Sham group was injected with PBS and Sham operation was performed. Genipin group was injected with 2.5 mg/kg genipin and sham operation was performed. CLP group was injected with PBS and operated. CLP and Genipin group was injected with 2.5 mg/kg Genipin and operated. The spleens were collected 26 hours after CLP. The total splenic lymphocyte count, CD4+, CD8+, cytokines and apoptotic proteins FADD, caspase-3 and caspase-8 were detected. Results: The survival rate of genipin mice treated with 2.5 mg/kg was higher than that of other mice. The total splenic lymphocyte count, CD4+, CD8+, interleukin (IL)-2, interferon (IFN)-γ levels in CLP group were lower than those in Sham group and Genipin group, the above indexes in CLP group were higher than those in CLP group (P<0.05). The expression of apoptotic proteins FADD, caspase- 3, caspase-8, IL-4 and IL-10 levels in CLP group were higher than those in Sham group, Genipin group, the above indexes in CLP group were lower than those in CLP group (P<0.05). Conclusions: Genipin can improve the immune suppression in late sepsis by inhibiting T cell apoptosis, and it can improve the survival rate of septic mice. [ABSTRACT FROM AUTHOR]

Survivin is one of the major members of Inhibitory Apoptotic Proteins (IAP) family. The functional anti-apoptotic and regulatory role of Survivin in the cell cycle had made it as an interesting candidate for tumor studies. Acute lymphoblastic leukemia is one of the most common malignancies of children that accounts for 30% of all the childhood malignancies. The purpose of this study was to investigate the prognostic importance of Survivin level in B-cell acute lymphoblastic leukemia patients of Iran in four different steps of disease in order to follow up its impact on various treatment ways, the development of the disease, and the response to treatment in the patients. The expression level of Survivin was evaluated in 85 patients with B-cell acute lymphoblastic leukemia and 85 healthy controls using Quantitative Real-Time Polymerase Chain Reaction. Also, western blot analysis was done to confirm the results. Based on our findings, the expression of Survivin showed a significant up-regulation in patients compared to controls. Therefore, a correlation between Survivin expression and the development pattern of B-cell acute lymphoblastic leukemia with a strong diagnostic efficiency (AUC-ROC, 0.8562) was observed. Therefore, it can be introduced as a potential marker for prognosis B-cell Acute Lymphoblastic Leukemia in the future. [ABSTRACT FROM AUTHOR]

The protozoan parasite Leishmania possesses an intrinsic ability to modulate a multitude of pathways in the host, toward aiding its own proliferation. In response, the host reprograms its cellular, immunological, and metabolic machinery to evade the parasite's lethal impact. Besides inducing various antioxidant signaling pathways to counter the elevated stress response proteins like heme oxygenase-1 (HO-1), Leishmania also attempts to delay host cell apoptosis by promoting anti-apoptotic proteins like Bcl-2. The downstream modulation of apoptotic proteins is regulated by effector pathways, including the PI3K/Akt survival pathway, the mitogen-activated protein kinases (MAPKs) signaling pathway, and STAT phosphorylation. In addition, Leishmania assists in its infection in a time-dependent manner by modulating the level of various proteins of autophagic machinery. Immune effector cells, such as mast cells and neutrophils, entrap and kill the pathogen by secreting various granular proteins. In contrast, the host macrophages exert their leishmanicidal effect by secreting various cytokines, such as IL-2, IL-12, etc. An interplay of various signaling pathways occurs in an organized network that is highly specific to both pathogen and host species. This Review analyzes the modulation of expression of proteins, including the cytokines, providing a realistic approach toward understanding the pathophysiology of disease and predicting some prominent markers for disease intervention and vaccine support strategies.

[Display omitted] Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most eminent forms of pulmonary involvement in Scleroderma. In this study we investigate the interaction between cytokines and apoptotic proteins in treatment naive Scleroderma (SSc) patients with and without pulmonary involvement. Newly diagnosed treatment naïve Scleroderma (SSc) patients (n = 100) and healthy controls (n = 100) were enrolled. Patients were classified as ILD-SSc, PAH-SSc and non-pulmonary SSc (np-SSc). Study variables like mRSS score, autoantibody profile, serum cytokines, serum TGF-β (1,2,3) and apoptotic proteins were assessed for these patients. Scleroderma patients showed elevated levels of serum cytokines, but significantly lower IL-22 and TGF- β1 when compared to healthy controls (p < 0.05). Apoptotic proteins were significantly elevated among Scleroderma patients, but the patient groups also showed significant lower caspase 1/3/9 levels when compared to healthy controls (p < 0.05). ILD-SSc patients reported higher mRSS score (p = 0.0436) when compared with PAH-SSc and np-SSc. In ILD-SSc patients, finger tightening (p = 0.0481) and calcinosis/lesions (p = 0.0481) were significant clinical presentations whereas, digital ulcers were significantly prominent in np-SSc patients (p = 0.0132). Elevated TGF-β3 levels (p = 0.02) in SSC-ILD and reduced IL-4 levels (p = 0.02) in SSC-PAH were significant cytokines as compared to np-SSc. Significant correlations were obtained among serum cytokines and apoptotic proteins in Scleroderma patients with and without pulmonary involvement. (p < 0.05) Our study highlights the correlation between mRSS score, cytokines and apoptotic proteins in SSc patients with pulmonary involvement. A longitudinal follow up in these patients with assessment of these immunological parameters may be helpful in monitoring the disease. [ABSTRACT FROM AUTHOR]

Impaired regeneration and consequent muscle wasting is a major feature of muscle degenerative diseases. Nutritional interventions as adjuvant strategy for preventing such conditions are recently gaining increasing attention. Ingestion of n3-polyunsaturated fatty acids has been suggested to have a positive impact on muscle diseases. We recently demonstrated that the dietary n3-fatty acid, alpha-linolenic acid (ALA), exerts potent beneficial effects in preserving skeletal muscle regeneration in models of muscle dystrophy. To better elucidate the underlying mechanism we investigate here on the expression level of the anti- and pro-apototic proteins, as well as caspase-3 activity, in C2C12 myoblasts challenged with pathological levels of TNF. The results demonstrated that ALA protective effect on C2C12 myoblasts was associated to an increased Bcl-2/Bax ratio. Indeed, the effect of ALA was directed to rescue Bcl-2 expression and decrease Bax expression both affected in an opposite way by TNF treatment. This effect was associated with a decrease in caspase-3 activity by ALA. TNF is a major pro-inflammatory cytokine that is expressed in damaged skeletal muscle, therefore, counteract inflammatory signals in the muscle microenvironment represents a critical strategy to ameliorate skeletal muscle pathologies

This research designed to explore the antitumor activity of puerarin against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were assessed by MTS and flow cytometry. Caspase-3, -8, and -9 activities were assessed with the colorimetric caspase protease assay. Apoptotic proteins like PARP, cyclin D1, Bcl-2 family, XIAP, and cIAP I were researched by western blot. The PI3K inhibitor LY294002 was used to investigate the possible mechanism relating the PI3K/Akt signaling pathway. Puerarin in vitro inhibited proliferation and induced apoptosis of Z138 cells. Expressions of PI3K and p-Akt were downregulated by puerarin. Puerarin negatively regulated NF-κB activity by inhibiting NF-κB phosphorylation with nuclear translocation inhibition. This kind of effects was correlated with the suppression of expression of cyclin D1, BAX, Bcl-2, XIAP etc. This function was modulated by the PI3K inhibitor. Our results demonstrated that puerarin can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway. Puerarin may have therapeutic applications in the treatment of MCL. [ABSTRACT FROM AUTHOR]

ABSTRACT In the present study, the purpose was to investigate the effect of p-coumaric acid on the mRNA-expression levels of inflammatory cytokines, transcription factor, MAP kinases, and apoptotic proteins by real time reverse transcription polymerase chain reaction in the cardiac tissue of sodium arsenite exposed rats. Sodium arsenite administration (5 mg/kg/b.wt, once daily for 30 days) upregulated the mRNA-expression levels of inflammatory cytokines (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and tumor growth factor-beta), transcription factor (NF-Kb-Rel A), protein kinases (Janus kinase and p38), caspase 3, and proapoptotic protein Bax in the cardiac tissue of rats, but the antiapoptotic protein Bcl-2 mRNA expression was found be downregulated. However, p-coumaric acid (75, 100 mg/kg/b. wt. oral) pretreatment daily before the sodium arsenite exposure protected the changes in the above mRNA-expression profiles observed in the cardiac tissues. In conclusion, this study confirmed that p-coumaric acid could be a promising dietary agent for protecting against the sodium arsenite-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Structural alterations in the limbic system, neuronal cell loss, and low levels of neurotrophins have been implicated in the pathogenesis of depression. While it is generally accepted that increasing monoamine levels in the brain can effectively alleviate depression, the precise neurobiological mechanisms involved are unclear. In the present study, we examined the effects of two antidepressants, duloxetine and mirtazapine, on the expression of apoptotic and neurotrophic proteins in the cerebral cortex and hippocampus of mice. Duloxetine (10 mg/kg) and mirtazapine (3 mg/kg) were chronically administered for 21 days, and qRT-PCR analysis was carried for the following: neurotrophins (BDNF, NGF, FGF-2, and NT-3); anti-apoptotic proteins (Bcl-2 and Bcl-xL) and pro-apoptotic proteins (Bax, Bad, and p53). Both duloxetine and mirtazapine produced antidepressant activity in the forced swimming test and induced increased cortical and hippocampal mRNA expression of BDNF. Duloxetine also increased Bcl-2, Bcl-xL, FGF-2, and NT-3 expression in the cerebral cortex, and FGF-2 expression in the hippocampus. Moreover, duloxetine reduced Bax and p53 expression in the hippocampus, and Bad expression in the cerebral cortex. Mirtazapine decreased Bcl-xL and Bax expression in the hippocampus, and Bad and p53 expression in both the hippocampus and cerebral cortex. Mirtazapine also increased the expression of neurotrophins, NGF and NT-3, in the cerebral cortex. These results suggest that duloxetine and mirtazapine could elicit their therapeutic effect by modulating the activity of apoptotic and neurotrophic pathways, thus enhancing plasticity and cell survival in depressive patients. [Copyright &y& Elsevier]

Purpose: Outcome for patients with Wilms tumor (WT) with favorable histology is good. Deletions of chromosomes 1p and 16q impart a poorer outcome. Value of apoptotic protein expression is not clear.Methods: Expression of four immunohistochemically detectable apoptosis-regulating proteins (bcl-2, bcl-x, bax and p53) were analyzed in 30 specimens of WT and compared to recurrence and recurrence-free survival (RFS).Results: The 30 patients included ranged from 4 to 72 months in age (mean 31). The mean available follow-up was 35.3 months (range 1-54). Six patients developed recurrence. The 5-year RFS for blastema-predominant tumors was 40% as compared to 91% for triphasic histology which was significant (p = 0.048). The 5-year RFS in patients with bcl-2 negative tumors was 63% as compared to 100% for bcl-2 positive tumors, the difference being significant (p = 0.019). The 5-year RFS in patients with p-53 positive tumors was 27% as compared to 91% for p-53 negative tumors; however, this difference in the RFS was not statistically significant (p = 0.143). bax and bcl-x expression were not related to the RFS.Conclusions: Tumors that are bcl-2 negative have a relatively higher recurrence rate and a poorer RFS. They may benefit from a more intensive follow-up regime for early detection of recurrence. [ABSTRACT FROM AUTHOR]

The present study aims to investigate the mechanism of phosphorylation of apoptotic proteins and tests the hypothesis that the hypoxia-induced increased tyrosine phosphorylation of apoptotic proteins Bcl-2 and Bcl-xl is Ca2+-influx-dependent. Piglets were divided in normoxic (Nx, n = 5), hypoxic (Hx, n = 5) and hypoxic-pretreated with clonidine (Clo + Hx, n = 4) groups. Hypoxic animals were exposed to an FiO2 of 0.06 for 1 h. Clonidine (12.5 μg/kg, IV) was administered to piglets 30 min prior to hypoxia. Hypoxia was confirmed by ATP and phosphocreatinine (PCr) levels. Cytosol was isolated and separated by 12% SDS–PAGE and probed with tyrosine phosphorylated (p) -Bax, Bad, Bcl-2 and Bcl-xl antibodies and bands were detected. The ATP levels (μmol/g brain) in the Nx, Hx, Clo + Hx were 4.3 ± 1.0 ( P < 0.05 vs. Hx, Clo-Hx), 0.9 ± 0.8 and 1.5 ± 0.3, respectively. The PCr levels in the Nx, Hx, Clo + Hx were 2.7 ± 0.7 ( P < 0.05 vs. Hx, Clo-Hx), 0.9 ± 0.2 and 0.9 ± 0.9, respectively. Ca2+-influx (pmoles/mg protein) was 4.96 ± 0.94 in Nx, 11.11 ± 2.38 in Hx, and 6.23 ± 2.07 in Clo + Hx ( P < 0.05 Nx vs. Hx and Hx vs. Clo + Hx). p-Bcl-2 density was 21.1 ± 1.1 Nx, 58.9 ± 9.6 Hx and 29.5 ± 6.4 Clo + Hx ( P < 0.05 vs. Hx). p-Bcl-xl density was 29.6 ± 1.5 Nx, 50.6 ± 7.4 Hx and 32.1 ± 0.1 Clo + Hx ( P < 0.05 vs. Hx). p-Bax density was 38.6 ± 16.2 Nx, 46.1 ± 5.5 Hx and 41.6 ± 1.9 Clo + Hx groups ( P = NS). p-Bad was 66.7 ± 12.8 Nx, 71.2 ± 6.8 Hx and 78.7 ± 22.5 Clo + Hx groups ( P = NS). Results showed that clonidine administration prior to hypoxia prevents the hypoxia-induced increased nuclear Ca2+-influx and increased phosphorylation of Bcl-2 and Bcl-xl while phosphorylation of Bad and Bax was not altered. We conclude that post-translational modification of anti-apoptotic proteins Bcl-2 and Bcl-xl during hypoxia is nuclear Ca2+-influx-dependent. We propose that blockade of nuclear Ca2+-influx that prevents phosphorylation of antiapoptotic proteins may become a neuroprotective strategy. [ABSTRACT FROM AUTHOR]

Regular exercise is thought to provide protection against age-related cognitive decline and possibly reduce risk of dementias. The mechanisms for the exercise protective effects are not known although changes in inflammatory cytokine levels may be involved. We conducted a systematic review of the literature to assess 1) the effects of exercise on cytokines in the brain, 2) the methodological rigour of studies which have examined these exercise effects and 3) the potential role of regular exercise in reducing the pro-inflammatory cytokine milieu that may contribute to dementia.We also reviewed the effects of exercise on concurrent pro and anti-apoptotic protein expression in the brain as related to cytokine changes. Five databases were searched until January 2010 with an initial 630 articles identified; 61 articles were retrieved of which 10 met study inclusion criteria. Investigations of both acute and chronic (training) exercise were assessed for methodological quality using a modified PEDro scale. Two studies were carried out with human participants and eight with mouse or rat models; studies differed markedly in design and methodological rigour, the types, intensities and durations of exercise, the cytokine and apoptotic proteins measured, and the regions of the brain (or proxy compartments) sampled. Despite variations in design, specific cytokine outcomes, and exercise type, the 10 studies provide limited evidence that acute strenuous exercise increases and exercise training decreases pro-inflammatory cytokines centrally. Two animal studies relate training associated decreases in pro-inflammatory cytokines with improved cognitive function using behavioural assessments such as the Morris maze. Recommendations for the design of future research on exercise, central cytokines, and cognition are offered. [ABSTRACT FROM AUTHOR]

Abstract: Camptothecin analogs and guanylate cyclase activator YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] have been shown to induce apoptosis in cancer cells. However, the combined effect of camptothecin analogs and YC-1 on the viability of epithelial ovarian cancer cells remains uncertain. We assessed the combined effect of YC-1 on the camptothecin toxicity in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Camptothecin and YC-1 induced apoptosis in OVCAR-3 and SK-OV-3 cells in a dose- and time-dependent manner. Both compounds induced nuclear damage, decreased Bid and Bcl-2 protein levels, enhanced cytochrome c release, activated caspase-3 and upregulated tumor suppressor p53. Camptothecin decreased Bax protein levels, whereas YC-1 increased Bax levels. YC-1 enhanced the camptothecin-induced changes in the apoptotic protein levels and increased apoptotic effect of camptothecin on ovarian carcinoma cell lines. The results suggested that YC-1 may enhance a camptothecin toxicity against ovarian carcinoma cell lines by increasing activation of the caspase-8 and Bid pathway as well as activation of the mitochondria-mediated apoptotic pathway, leading to cytochrome c release and subsequent caspase-3 activation. Combination of camptothecin analogs and YC-1 may provide a therapeutic benefit against ovarian adenocarcinoma. [Copyright &y& Elsevier]

We have shown that hypoxia results in increased influx of nuclear Ca and increased expression of nuclear apoptotic proteins. The present study tests the hypothesis that hypoxia alters the distribution of pro-apoptotic proteins Bad and Bax, and the anti-apoptotic proteins Bcl-xl, and Bcl-2 in the nuclear, mitochondrial and cytosolic compartments of the cerebral cortex of newborn piglets and the administration of Clonidine, an inhibitor of high affinity nuclear Ca-ATPase, will prevent the hypoxia-induced increase in apoptotic proteins' expression. Studies were conducted in 19 newborn piglets, 6 normoxic (Nx), 7 hypoxic and 6 Clonidine-treated hypoxic (Hx-Clo). Tissue hypoxia was documented biochemically by measuring cerebral tissue ATP and phosphocreatine (PCr) levels. Bax and Bad protein expression increased in all the three compartments during hypoxia, while there was no significant change in the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. In Clonidine pretreated hypoxic group, the hypoxia-induced increased expression of pro-apoptotic proteins Bad and Bax was prevented in all the three fractions. We conclude that hypoxia results in increased expression of pro-apoptotic proteins in nuclear, mitochondrial and cytosolic compartments and that the increased expression of pro-apoptotic proteins during hypoxia is nuclear Ca-influx-dependent. We propose that during hypoxia the increased ratio of (pro-apoptotic Bad and Bax/anti-apoptotic Bcl-xl and Bcl-2) in all the three compartments, will lead to altered mitochondrial and nuclear membrane permeability as well as caspase-9 activation in the cytosolic compartment. [ABSTRACT FROM AUTHOR]

Abstract: Heart failure is known to be associated with an increase in cardiomyocyte apoptosis; however, neither its occurrence nor the mechanisms involved in hearts failing due to volume overload are completely understood. This study examined some of the signal pathways, which are known to regulate pro- or anti-apoptotic proteins, in heart failure due to volume overload induced by arteriovenous (AV) shunt in male Sprague–Dawley rats. Animals were assessed for cardiac function at 16 weeks of the operation and the left ventricle was used for studying apoptosis and associated signal transduction mechanisms. Hemodynamic and echocardiographic data indicated the presence of severe heart failure in AV shunt rats. A marked elevation in the amount of tumor necrosis factor-α and increased occurrence of apoptosis were detected in the volume overloaded myocardium. Western blot analysis revealed a significant increase in BAX and caspases 3/9 proteins in the failing hearts whereas the levels of phosphorylated Akt and Bcl-2 proteins were decreased. These data suggest that there is a downregulation in the Akt-dependent survival signal involving anti-apoptotic protein, Bcl-2, whereas the signals for the pro-apoptotic protein, BAX, are upregulated and these alterations may play a role in cardiomyocyte apoptosis in heart failure due to volume overload. [Copyright &y& Elsevier]

Abstract: Apoptotic protease activating factor-1 (Apaf-1) is a critical regulator of apoptosis and a crucial part of the apoptosome that is assembled in response to several cellular stresses like hypoxia. We have previously shown that hypoxia results in increased influx of nuclear Ca2+ and increased expression of nuclear apoptotic proteins. The present study investigates that Apaf-1 is expressed during hypoxia in the cerebral cortex of newborn piglets and that administration of clonidine prevents the hypoxia induced increase expression of Apaf-1. Studies were conducted in 19 newborn piglets, 6 normoxic (Nx), 7 hypoxic (Hx FiO2 of 0.05–0.07 for 1h) and 6 clonidine-treated hypoxic (Hx-Clo) piglets. Tissue hypoxia was confirmed biochemically by determining the levels of high energy phosphates ATP and phosphocreatine (PCr). Neuronal nuclei, mitochondrial membranes and cytosolic fractions were isolated and separated by 12% SDS–PAGE and probed with specific antibodies to Apaf-1. The expression of Apaf-1 in neuronal nuclei was 48.86±5.27 in Nx, 108.43±6.37 in Hx and 78.53±7.00 in Hx-Clo. The Apaf-1 expression of in mitochondrial fraction was 72.73±11.76 in Nx, 132.27±16.15 in Hx and 85.17±5.64 in Hx-Clo. Similarly, the expression of Apaf-1 in cytosolic fraction was 86.79±6.97 in Nx, 193.95±15.41 in Hx and 111.07±7.91 in Hx-Clo. In summary, the results show that hypoxia results in increased expression of Apaf-1 proteins in neuronal nuclear, mitochondrial and cytosolic fractions. Administration of a high affinity Ca2+-ATPase, prevented the hypoxia induced increased expression of Apaf-1 protein, suggesting that the hypoxia-induced increased expression of Apaf-1 proteins is nuclear Ca2+-influx mediated. We conclude that cerebral hypoxia-induced increase in Apaf-1 protein will lead to increased activation of procaspase-9 to caspase-9 in the cytosolic compartment leading to a cascade of hypoxic neuronal death. [Copyright &y& Elsevier]

Cancer treatment frequently carries side effects, therefore, the search for new selective and effective molecules is indispensable. Hymenaea courbaril L. has been used in traditional medicine in South America to treat several diseases, including prostate cancer. Leaves' extracts from different polarities were evaluated using the 3-(4,5-methyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) cell viability assay to determine the cytotoxicity in prostate p53-null cells, followed by bio-guided fractionations to obtain the most cytotoxic fraction considering the selectivity index. The most cytotoxic fraction was analyzed by GC/MS to identify the active compounds. The majority compound, caryophyllene oxide, induced early and late apoptosis, depolarized the mitochondrial membrane, leading to several morphological changes and shifts in apoptotic proteins, and caspases were evidenced. Depolarization of the mitochondrial membrane releases the pro-apoptotic protein Bax from Bcl-xL. The apoptosis process is caspase-7 activation-dependent. Caryophyllene oxide is a safe anti-proliferative agent against PC-3 cells, inducing apoptosis with low toxicity towards normal cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Resistance to Taxanesoccurs at molecular and genetic levels. • Taxanes inhibit tubulin depolymerization • Nanocarriers and RNAi techniques decrease the magnitude of resistance to Taxanes. • Secondary metabolites reverse drug resistance by targeting P-gp, β-tubulin and the Akt/NF-κB pathways. One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. I n vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and β-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients. [ABSTRACT FROM AUTHOR]

Muscle disuse and denervation leads to muscle atrophy, but underlying mechanisms can be different. Previously, we have found ceramide (Cer) accumulation and lipid raft disruption after acute hindlimb suspension (HS), a model of muscle disuse. Herein, using biochemical and fluorescent approaches the influence of unilateral denervation itself and in combination with short-term HS on membrane-related parameters of rat soleus muscle was studied. Denervation increased immunoexpression of sphingomyelinase and Cer in plasmalemmal regions, but decreased Cer content in the raft fraction and enhanced lipid raft integrity. Preliminary denervation suppressed (1) HS-induced Cer accumulation in plasmalemmal regions, shown for both nonraft and raft-fractions; (2) HS-mediated decrease in lipid raft integrity. Similar to denervation, inhibition of the sciatic nerve afferents with capsaicin itself increased Cer plasmalemmal immunoexpression, but attenuated the membrane-related effects of HS. Finally, both denervation and capsaicin treatment increased immunoexpression of proapoptotic protein Bax and inhibited HS-driven increase in antiapoptotic protein Bcl-2. Thus, denervation can increase lipid raft formation and attenuate HS-induced alterations probably due to decrease of Cer levels in the raft fraction. The effects of denervation could be at least partially caused by the loss of afferentation. The study points to the importance of motor and afferent inputs in control of Cer distribution and thereby stability of lipid rafts in the junctional and extrajunctional membranes of the muscle. [ABSTRACT FROM AUTHOR]

Introduction : Cancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design. Areas covered : This review article addresses the potential of THIQ as anticancer agents. Various medicinal chemistry strategies employed for the design and development of THIQ analogs as inhibitors or modulators of relevant anticancer targets have been discussed in detail. Moreover, the common strategies employed for the synthesis of the core scaffold are also highlighted. Expert opinion : Evidently, THIQs have tremendous potential in anticancer drug design. Some of these analogs exhibited potent activity against various cancer molecular targets. However, there are some drawbacks, such as selectivity that need addressing. The synthetic ease for constructing the core scaffold complimented with its reactivity makes it ideal for further structure-activity relationship studies. For these reasons, THIQ is a privileged scaffold for the design and development of novel anticancer agents.

Impact Statement: Alternative agents that will increase the effectiveness of cisplatin, which are widely used in the advanced stage and metastatic bladder cancer, are being investigated. In previous studies, Cucurbitacin B (CuB), which is a natural compound from the Cucurbitaceae family has been shown to inhibit the proliferation of tumor cells and create synergistic effects with cisplatin. In this study, we investigated the synergistic effect of CuB with cisplatin for the first time in bladder cancer in vitro and in vivo models. Our findings showed that CuB treatment with cisplatin reduced cell proliferation, and reduced tumor development through activating apoptosis and autophagy via PI3K/AKT/mTOR signaling pathway. Our results showed that CuB may be a new agent that can support conventional treatment in bladder cancer. Our study is important in terms of enlightening new pathways and developing new treatment methods in the treatment of bladder cancer.