Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response.

Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1's role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

Screening the NCI diversity set V for anti-MRSA activity: cefoxitin synergy and LC-MS/MS confirmation of folate/thymidine biosynthesis inhibition.

IMPORTANCE: New antibacterial agents are urgently needed to counter increasingly resistant bacteria. One approach to this problem is library screening for new antibacterial agents. Library screening efforts can be improved by increasing the information content of the screening effort. In this study, we screened the National Cancer Institute diversity set V against methicillin-resistant Staphylococcus aureus (MRSA) with several enhancements. One of these is to screen the library before and after microsomal metabolism as means to identify potential active metabolites. A second enhancement is to screen the library in the absence and presence of sub-minimum inhibitory concentration levels of another antibiotic, such as cefoxitin in this study. This identified four agents with synergistic activity with cefoxitin out of 16 agents with good MRSA activity alone. Finally, active agents from this effort were counter-screened in the presence of thymidine, which quickly identified three folate/thymidine biosynthesis inhibitors, and also screened for bactericidal vs bacteriostatic activity.

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment.

Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

Lipid metabolism reprogramming in renal cell carcinoma.

Metabolic reprogramming is recognized as a hallmark of cancer. Lipids are the essential biomolecules required for membrane biosynthesis, energy storage, and cell signaling. Altered lipid metabolism allows tumor cells to survive in the nutrient-deprived environment. However, lipid metabolism remodeling in renal cell carcinoma (RCC) has not received the same attention as in other cancers. RCC, the most common type of kidney cancer, is associated with almost 15,000 death in the USA annually. Being refractory to conventional chemotherapy agents and limited available targeted therapy options has made the treatment of metastatic RCC very challenging. In this article, we review recent findings that support the importance of synthesis and metabolism of cholesterol, free fatty acids (FFAs), and polyunsaturated fatty acids (PUFAs) in the carcinogenesis and biology of RCC. Delineating the detailed mechanisms underlying lipid reprogramming can help to better understand the pathophysiology of RCC and to design novel therapeutic strategies targeting this malignancy.

The Contribution of NMDA Receptors in Antinociceptive Effect of Pregabalin: Comparison of Two Models of Pain Assessment.

BACKGROUND: Pregabalin has shown remarkable antinociceptive effects in neuropathic pain; however, its efficacy against acute and visceral pain remained controversial. OBJECTIVES: The present study aimed at investigating the involvement of N-methyl-D-aspartate (NMDA) receptors in the antinociceptive effect of pregabalin in both acute and visceral pain using and comparing hot plate test and writhing test in male mice. METHODS: NMDA (15 and 30 mg/kg), as an agonist or MK801 (0.02 and 0.05 mg/kg) as an NMDA receptor (NMDAR) antagonist, were injected intraperitoneally either alone or 15 minutes before a dose of pregabalin that produced almost 30% antinociception (100 mg/kg in hot plate test and 5 mg/kg in writhing tests). Then, the percentage of maximal possible effect (MPE%) at the 30th and 60th minutes in hot plate test and effect percentage (E%) in writhing test were measured and compared as antinociceptive indexes. RESULTS: In hot plate test, pretreatment with MK801 (0.05 mg/kg) significantly increased antinociceptive effect of 100 mg/kg pregabalin, but pretreatment with NMDA did not result in any effect. Pretreatment with MK801 in writhing test significantly increased the antinociceptive effect of 5 mg/kg pregabalin (In contrast to 30 mg/kg NMDA that significantly decreased it.). NMDA induced antinociception reduction or MK801 increased antinociception in writhing test were significantly higher than what was observed in hot plate test. CONCLUSIONS: Our results suggested that pregabalin antinociception in acute and visceral pain is mediated through NMDA receptors. Although this effect depends on the dose of NMDAR ligand, it is more pronounced in the behavioral response in the writhing test.

The effects of co-administration of pregabalin and vitamin E on neuropathic pain induced by partial sciatic nerve ligation in male rats.

OBJECTIVE: This study was performed to evaluate the effect of pregabalin co-administration with vitamin E in Partial Sciatic Nerve Ligation (PSNL)-induced neuropathic pain in rats. METHODS: Male Wistar rats were randomly allocated as control, sham, and PSNL groups (n = 8). PSNL was induced by tight ligation of the sciatic nerve with a copper wire. On day 14th, the PSNL and sham operated rats received either pregabalin (1, 3, and 30 mg/kg), vitamin E (100 and 200 mg/kg), or their combination intraperitoneally. An antinociceptive effect was evaluated as latency times and Maximum possible Effect Percent (%MPE) using tail-flick test. Locomotor activity was evaluated by open-field test before PSNL surgery and then twice at the 14th days (before and after drug injection). Ligated nerves were removed on the 28th days after surgery for histological examinations. RESULTS: The time course of latency times and %MPE showed significant decrease in PSNL but not in sham and control groups. Pregabalin (3 and 30 mg/kg) and vitamin E (100 and 200 mg/kg) caused significant increases in latency time in PSNL (but not sham) group compared to control group. Vitamin E 200 mg/kg increased significantly %MPE in PSNL group compared to sham group. In addition, the %MPE following combination treatment of pregabalin (30 mg/kg) and vitamin E (100 mg/kg) was significantly higher than both vitamin E and control group. Also combination of pregabalin with 100 mg/kg of vitamin E reversed Wallerian degeneration of sciatic nerve and the inflammatory responses to almost similar to sham group. Pregabalin and vitamin E did not affect locomotor activity. CONCLUSION: Our results showed antinociceptive effects of both vitamin E and pregabalin alone or in combination in PSNL rats and also neuroprotective properties without affecting locomotor activity.

The Role of NMDARs Ligands on Antinociceptive Effects of Pregabalin in the Tail Flick Test.

BACKGROUND: Pregabalin as a new anticonvulsant has been used in different pain treatments. OBJECTIVES: The aim of this study was to investigate the role of N-methyl-D-aspartate (NMDA) ligands in antinociceptive effect of pregabalin in mice using tail flick. MATERIALS AND METHODS: NMDA (15 and 30 mg/kg) as an agonist or MK801 (0.02 and 0.05 mg/kg) as an antagonist were injected intraperitoneally either alone or 15 minutes before antinociceptive dose of pregabalin (100 mg/kg). Then the latency times and %MPE were measured in the tail flick assay during 75 minutes. RESULTS: NMDA and MK801 had no effects alone. NMDA pretreatment significantly decreased the latency times of pregabalin till 75(th) minutes. In NMDA pretreated groups, %MPE30 unlike %MPE75 decreased significantly compared to those of pregabalin. MK801 delayed the latency times in pretreated groups, but %MPE30 and %MPE75 did not change significantly compared to pregabalin alone. CONCLUSIONS: Our findings support the role of NMDARs in pregabalin antinociception, because the NMDAR agonist, unlike the antagonist, decreased the antinociceptive effect of pregabalin, even if tail flick is not an adequate pain assessment method in this regard.

Anti-leishmanial effect of itraconazole niosome on in vitro susceptibility of Leishmania tropica.

The novel niosomal system aimed to deliver the active drug entity to the target site. The objective of this study was to prepare and evaluate the effect of itraconazole niosome on the in vitro susceptibility of Leishmania tropica as compared to itraconazole alone or tartar emetic. The overall growth rate of promastigotes treated with various concentrations of itraconazole niosome was significantly lower than that of itraconazole alone (IC50=0.24 µg/ml vs. IC50=0.43 µg/ml, P<0.01). In contrast, the mean multiplication rate of amastigotes inside the macrophages and also the mean number of amastigotes in each macrophage treated with itraconazole niosome (34.9 and 3.0) were significantly lower (P<0.01) than those treated with itraconazole alone (62.0 and 3.8) or tartar emetic (63.9 and 4.2), respectively. These findings indicated that niosomes could be developed as a novel drug delivery for itraconazole in the in vitro model. Further studies are required to evaluate the effect of itraconazole niosome on volunteer human subjects.

Evaluation of Antinociceptive Effect of Pregabalin in Mice and its Combination with Tramadol using Tail Flick Test.

The development of combination therapy is a coherent approach in severe pain treatment. The present study investigated the antinociceptive effect of pregabalin alone and in combination with tramadol in acute pain modeling. Therefore, three groups of male mice received either pregabalin (1 to 400 mg/Kg), tramadol (10 to 80 mg/Kg) or their combination intraperitoneally. Then latency time, maximum possible effect (%MPE) and area under curve (AUC) were calculated in tail flick test. The antinociceptive indexes were significantly increasedin10, 100 and 200 mg/kg ofpregabalin while tramadol showed dose-dependentantinociception (effective dose 50% was 54 to 79 mg/Kg). The antinociceptive effect of 100 mg/Kg of pregabalin (%MPE = 35±4%) was similar to that of 50 mg/Kg of tramadol. The combination of non-analgesic doses (10 mg/Kg) of tramadol and pregabalin did not increase %MPE and AUC, but the co-administration of 30 mg/Kg of tramadol with pregabalin (10 mg/Kg) increased all antinociceptive indexes significantly compared to the controls and with each drug alone. In conclusion, pregabalin showed a comparable antinociceptive effect to tramadol. The increase in analgesic effect was observed after the combination of low analgesic doses of tramadol with pregabalin, while the combination of non-analgesic doses of each drug reversed the interaction to antagonism. Therefore to increase the analgesic effect in pain management, more attention should be paid to respecting right proportion of drug combination. Further studies that specify the mechanism(s) and statement of interaction are needed to expand these findings to clinical applications.

Possible association between human blood types and opioid addiction.

Drug addiction is a complex disorder that has been shown to have a genetic component like several other diseases. Finding any factor that is associated with higher risk of addiction tendency may influence the strategies of prevention and treatment of drug abuse and also provide an avenue of further research in genetics, immunology, and other related fields. This case-control study aimed at finding the frequency rate of ABO blood groups and Rhesus (Rh) factor among opioid dependents. Therefore, 249 opioid dependents referred to the Drug Quit center at Bam, Iran (case group) were compared with 360 blood donors referred to the Blood Transfusion Center (control group) in regard to the frequency of blood groups and Rh factor. The two groups were matched for demographic features. The odds ratio for AB blood group in addicts was 3.98 compared to non-addicts (p < .001) and the odds ratio of negative Rh in addicts compared to non-addicts was 4.27 (p < .001). According to the findings, in this population the frequency of negative Rh and AB blood group were significantly less than the predictive values. The relationship between opioid use and blood group type requires a cohort study eliminating all extraneous factors in order to be proved.

Evaluation of moisturizing effect of methanolic extract of five medicinal plants incorporated into cream bases using impedance and extensiometry methods.

BACKGROUND: Skin moisturizing is an important issue due to its impact on skin function. Adverse reactions to herbal extracts have been rarely reported and can be used in moisturizers. This study was conduct to evaluate moisturizing effect of a methanolic extract of five medicinal plants incorporated into cream bases. METHODS: Methanolic extract of five medicinal plants including olive, burdock, licorice, mallow and marsh horsetail was prepared. The extracts were dissolved in distilled water completely and freeze-dried to a dry powder. These extracts were added separately to the cream based formulation that has been suggested to be appropriate for adding herbal extracts. Moisturizing effects of these creams with herbal extracts were assessed using the impedance method on 12 rats equally divided into six groups (one control and five cases), as well as the extensiometry method on 25 mice divided into five groups (in each group one cream with herbal extract and control cream were tested concurrently). Obtained results were compared with the control cream based. RESULTS: The maximum moisturizing effect was observed with the marsh horsetail. Other creams with herbal extracts, except the one with the licorice, also exerted significantly higher moisturizing effect compared to the controls (P<0.05). Regarding the force for skin tearing, the differences were statistically significant in all groups when compared to the control group (P<0.05) and the highest difference was seen in the marsh horsetail group (2.0832 ± 0.6811 kgN). CONCLUSIONS: The highest moisturizing activity was observed using marsh horsetail extract that can be explained by flavonoids content of marsh horsetail.

The study of substructures of addiction phenomena in high school students using problem finding workshops.

BACKGROUND: Addiction is one of the complicated problems in Iranian young population. The social and cultural dimensions of this social disease are less considered. So considering socio-cultural and environmental resources, this study investigated the substructures of addiction according to the viewpoints of high-school students of Kerman, Iran in 2007-2008. METHODS: This qualitative study accomplished in ten high schools through a one-day problem finding workshop and continued until data saturation. The resulted terms and phrases were analyzed by content analysis. To assure about the validity and reliability, the outputs reviewed by workshops participants, and classification and codification of the data were executed separately by two experts. FINDINGS: A total of 212 students, 45.3% girls and 54.7% boys, participated in the study. The students introduced the followings as the addiction substantial fundaments: lack of knowledge, positive attitude and interpretation of addiction as a value, family or friends' habit, economy status, psycho-personality problems and availability. Rules infirmity or non-implementation of the current rules enforcement, geographical status and addiction as a conspiracy were also observed in students' statements. CONCLUSION: The positive attitudes and historical roots of addiction along with the process of changing the values caused the growth of drug addiction in young population which could neutralize the security measures, legislations policy and even the knowledge. Therefore, intensification of personal protective factors and culturalization addressed for improving inner layers of values are recommended.