Redefining the treponemal history through pre-Columbian genomes from Brazil.

The origins of treponemal diseases have long remained unknown, especially considering the sudden onset of the first syphilis epidemic in the late 15th century in Europe and its hypothesized arrival from the Americas with Columbus' expeditions1,2. Recently, ancient DNA evidence has revealed various treponemal infections circulating in early modern Europe and colonial-era Mexico3-6. However, there has been to our knowledge no genomic evidence of treponematosis recovered from either the Americas or the Old World that can be reliably dated to the time before the first trans-Atlantic contacts. Here, we present treponemal genomes from nearly 2,000-year-old human remains from Brazil. We reconstruct four ancient genomes of a prehistoric treponemal pathogen, most closely related to the bejel-causing agent Treponema pallidum endemicum. Contradicting the modern day geographical niche of bejel in the arid regions of the world, the results call into question the previous palaeopathological characterization of treponeme subspecies and showcase their adaptive potential. A high-coverage genome is used to improve molecular clock date estimations, placing the divergence of modern T. pallidum subspecies firmly in pre-Columbian times. Overall, our study demonstrates the opportunities within archaeogenetics to uncover key events in pathogen evolution and emergence, paving the way to new hypotheses on the origin and spread of treponematoses.

Red blood cell distribution width as a surrogate biomarker of damage and disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: Red blood cell distribution width (RDW) is a measure of variability in mean corpuscular volume. Alterations in RDW can be observed in a variety of human disorders, including inflammatory, cardiovascular, and hepatic or renal diseases. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect virtually any organ in the body. In this work, our objective was to analyse how a complete characterisation of disease characteristics in a large series of patients with SLE is related to RDW values. METHODS: 284 patients with SLE and 181 age- and sex-matched healthy controls were recruited. Complete blood count including RDW was assessed. Multivariable analysis was performed to analyse the relationship between RDW and SLE disease characteristics, including composite scores of disease activity and damage. RESULTS: After multivariable adjustment, RDW was higher in patients with SLE compared to controls (beta coefficient 0.8 [95% confidence interval: 0.3-1] %, p=0.003). Several disease characteristics, such as the presence of extractable nuclear antibodies and antiphospholipid syndrome, and the use of prednisone and azathioprine, were significantly associated with higher levels of RDW after adjustment for confounders. Of note, cumulative disease damage and disease activity scores were associated with higher RDW values after controlling for covariates. CONCLUSIONS: RDW may serve as a surrogate biomarker of accrual disease damage and activity in patients with SLE.

Early use of teduglutide in paediatric patients with intestinal failure is associated with a greater response rate: a multicenter study.

Teduglutide is a glucagon-like-peptide-2 analogue that reduces the need for parenteral support in patients with short bowel syndrome (SBS). Nevertheless, data about long-term therapy with teduglutide in children are still scarce. Our objective was to describe the real-life experience with teduglutide in children with SBS over the last 5 years in Spain. This was a national multicentre and prospective study of paediatric patients with intestinal failure (IF) treated with teduglutide for at least 3 months. The data included demographic characteristics, medical background, anthropometric data, laboratory assessments, adverse events, and parenteral nutrition (PN) requirements. Treatment response was defined as a > 20% reduction in the PN requirement. The data were collected from the Research Electronic Data Capture (REDCap) database. Thirty-one patients from seven centres were included; the median age at the beginning of the treatment was 2.3 (interquartile range (IQR) 1.4-4.4) years; and 65% of the patients were males. The most frequent cause of IF was SBS (94%). The most common cause of SBS was necrotizing enterocolitis (35%). The median residual bowel length was 29 (IQR 12-40) cm. The median duration of teduglutide therapy was 19 (IQR 12-36) months, with 23 patients (74%) treated for > 1 year and 9 treated for > 3 years. The response to treatment was analysed in 30 patients. Twenty-four patients (80%) had a reduction in their weekly PN energy > 20% and 23 patients (77%) had a reduction in their weekly PN volume > 20%. Among the responders, 9 patients (29%) were weaned off PN, with a median treatment duration of 6 (IQR 4.5-22) months. The only statistically significant finding demonstrated an association between a > 20% reduction in the weekly PN volume and a younger age at the start of treatment (p = 0.028).   Conclusions: Teduglutide seems to be an effective and safe treatment for paediatric patients with IF. Some patients require a prolonged duration of treatment to achieve enteral autonomy. Starting treatment with teduglutide at a young age is associated with a higher response rate. What is Known: •  Glucagon-like peptide-2 (GLP-2) plays a crucial role in the regulation of intestinal adaptation in short bowel syndrome (SBS). Teduglutide is a GLP-2 analog that reduces the need for parenteral support in patients with SBS. • Data about long-term therapy with teduglutide in children in real life are still scarce. What is New: • Most pediatric patients with SBS respond in a satisfactory manner to teduglutide treatment. The occurrence of long-term adverse effects is exceptional. • Starting treatment with the drug at a young age is associated with a greater response rate.

Evolutionary Processes in the Emergence and Recent Spread of the Syphilis Agent, Treponema pallidum.

The incidence of syphilis has risen worldwide in the last decade in spite of being an easily treated infection. The causative agent of this sexually transmitted disease is the bacterium Treponema pallidum subspecies pallidum (TPA), very closely related to subsp. pertenue (TPE) and endemicum (TEN), responsible for the human treponematoses yaws and bejel, respectively. Although much focus has been placed on the question of the spatial and temporary origins of TPA, the processes driving the evolution and epidemiological spread of TPA since its divergence from TPE and TEN are not well understood. Here, we investigate the effects of recombination and selection as forces of genetic diversity and differentiation acting during the evolution of T. pallidum subspecies. Using a custom-tailored procedure, named phylogenetic incongruence method, with 75 complete genome sequences, we found strong evidence for recombination among the T. pallidum subspecies, involving 12 genes and 21 events. In most cases, only one recombination event per gene was detected and all but one event corresponded to intersubspecies transfers, from TPE/TEN to TPA. We found a clear signal of natural selection acting on the recombinant genes, which is more intense in their recombinant regions. The phylogenetic location of the recombination events detected and the functional role of the genes with signals of positive selection suggest that these evolutionary processes had a key role in the evolution and recent expansion of the syphilis bacteria and significant implications for the selection of vaccine candidates and the design of a broadly protective syphilis vaccine.

CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns.

BACKGROUND: The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established. METHODS: Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used. RESULTS: We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation. CONCLUSIONS: Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract.

Circulating GDF15 concentrations in girls with low birth weight: effects of prolonged metformin treatment.

BACKGROUND: Low birth weight (LBW) followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) plays an important role in the regulation of energy homeostasis, reducing food intake and body weight. We assessed whether GDF15 concentrations are raised by long-term metformin treatment in LBW/catch-up girls with precocious pubarche (PP, pubic hair <8 years), and whether they relate to changes in endocrine-metabolic variables, body composition, and abdominal fat partitioning. METHODS: Circulating GDF15 was determined in 30 LBW/catch-up girls with PP randomly assigned to receive metformin for 4 years (n = 15; 425 mg/d for 2 years, then 850 mg/d for 2 years) or to remain untreated (n = 15). Endocrine-metabolic variables, body composition (by absorptiometry), and abdominal fat partitioning (by MRI) were assessed at the start and yearly during follow-up. RESULTS: Circulating GDF15 concentrations increased significantly in LBW-PP girls only after 3 and 4 years on metformin. GDF15 levels associated negatively with insulin, HOMA-IR, androgens, body fat, and visceral fat. CONCLUSION: Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with reduced prenatal growth. GDF15 could be among the mediators of such effects, especially over the long term. IMPACT: Low birth weight followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) is a peptide hormone that reduces food intake and lowers body weight; metformin is an exogenous GDF15 secretagogue. Serum GDF15 concentrations increase after 3 and 4 years on metformin and associate negatively with insulin, androgens, body fat, and visceral fat. Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with low birth weight. GDF15 could mediate these effects, especially over the long term.

Circulating progranulin in human infants: relation to prenatal growth and early postnatal nutrition.

BACKGROUND: Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. We longitudinally assessed PGRN concentrations in infants born appropriate (AGA) or small for gestational age (SGA), the latter being at risk for obesity and type 2 diabetes, especially if they experience an excessive postnatal catch-up in weight and are formula-fed (FF). METHODS: The study population consisted of 183 infants who were exclusively breast-fed [(BF), AGA, n = 66; SGA, n = 40], or FF (AGA, n = 31; SGA, n = 46) over the first 4 months. Assessments included auxology, fasting glucose, insulin, IGF-1, high-molecular-weight adiponectin, PGRN and body composition (by DXA), at birth, and at age 4 and 12 months. RESULTS: PGRN levels were low at birth and unaffected by prenatal growth. PGRN increased at 4 and 12 months, although to a lesser extent in SGA infants, and was unrelated to the mode of feeding. PGRN correlated with markers of adiposity, inflammation and insulin resistance in both AGA and SGA infants, especially in those FF. CONCLUSIONS: The attenuated increase of PGRN levels in SGA infants over the first year of life, along with the association to markers of unhealthy metabolic profile, might point to a role of PGRN in future disease risks. IMPACT: Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. In healthy infants, PGRN concentrations are low at birth and experience a significant and progressive increase up to age 12 months, which is less marked in infants born small for gestational age (SGA) and is unrelated to the mode of feeding. Circulating PGRN is related to markers of adiposity, inflammation, and insulin sensitivity, especially in formula-fed SGA infants. PGRN may play a role in the metabolic adaptations of SGA infants during early life, potentially contributing to the risk for obesity and type 2 diabetes in this population.

Team Cohesion Profiles: Influence on the Development of Mental Skills and Stress Management.

High-level sports competitions involve facing highly challenging situations. Athletes must maintain strong team cohesion with peers, have specific mental abilities, and high-stress control to overcome adversity and report high sports performance. This research aimed to identify team cohesion profiles and examine whether participants differed significantly in their mental abilities and stress management. The sample consisted of 146 promising and talented athletes from the Sports Talent Development of the Provincial Council of Guipúzcoa (Spain) (Mage = 20.08; SD = 4.68), who completed the questionnaire on Psychological Characteristics Related to Sports Performance (CPRD). Cluster analyzes revealed three profiles; (a) profile with low team cohesion; (b) profile with average team cohesion; (c) profile with high team cohesion. Results showed significant differences in mental abilities (i.e., positive self-talk), and marginally significant differences in self-confidence, between the profiles. The best scores were reported in profile (b). In conclusion, the combination of low individualism, high social cohesion, and medium team spirit seems to be the most recommendable for promoting mental abilities and self-confidence in athletes' samples. As practical implications, the programs that train the mental abilities of athletes and control management should consider the importance of team cohesion to obtain improvements in the results of the competitions.

The role of maternal age, growth, and environment in shaping offspring performance in an aerial conifer seed bank.

PREMISE: Maternal effects have been demonstrated to affect offspring performance in many organisms, and in plants, seeds are important mediators of these effects. Some woody plant species maintain long-lasting canopy seed banks as an adaptation to wildfires. Importantly, these seeds stored in serotinous cones are produced by the mother plant under varying ontogenetic and physiological conditions. METHODS: We sampled the canopy seed bank of a highly serotinous population of Pinus pinaster to test whether maternal age and growth and the environmental conditions during each crop year affected seed mass and ultimately germination and early survival. After determining retrospectively the year of each seed cohort, we followed germination and early survival in a semi-natural common garden. RESULTS: Seed mass was related to maternal age and growth at the time of seed production; i.e., slow-growing, older mothers had smaller seeds, and fast-growing, young mothers had larger seeds, which could be interpreted either as a proxy of senescence or as a maternal strategy. Seed mass had a positive effect on germination success, but aside from differences in seed mass, maternal age had a negative effect and diameter had a positive effect on germination timing and subsequent survival. CONCLUSIONS: The results highlight the importance of maternal conditions combined with seed mass in shaping seedling establishment. Our findings open new insights in the offspring performance deriving from long-term canopy seed banks, which may have high relevance for plant adaptation.

Amylin serum levels are upregulated in patients with systemic lupus erythematosus.

OBJECTIVES: Amylin is a pancreatic hormone that participates in glucose homeostasis. We aimed to investigate how serum amylin levels are expressed in patients with systemic lupus erythematosus (SLE) compared to matched controls, and their possible relationship to disease-related characteristics, such as activity or damage. METHODS: 144 SLE patients and 96 non-diabetic sex- (female 96% vs. 91%, p=0.43) and age-matched controls (49±11 vs. 51±8 years, p=0.09) were included. Amylin, insulin and C-peptide serum levels, as well as insulin resistance indexes were assessed in both groups. Multivariable regression analysis was performed to compare amylin between groups and to explore its interrelations with SLE features. The analyses were adjusted for glucocorticoids intake and for insulin resistance classic risk factors. RESULTS: Patients with SLE exhibited significant higher serum levels of amylin when compared to controls after multivariable analysis (beta coef. 1.56 [95%CI 1.01-2.11], p=0.000). Moreover, SLE patients not on prednisone (beat coef. 1.54 [95%CI 0.98-2.10] ng/ml, p=0.000) and those on prednisone (beta coef. 1.51 [95%CI 0.96-2.07] ng/ml, p=0.000) disclosed higher amylin serum levels compared to controls in the fully multivariable analysis. Hyperamylinaemia in SLE patients remained significant even adjusting for differences in the insulin resistance and beta cell production rates between patients and controls. The damage produced by the disease and its severity were independently and positively associated with amylin serum levels. CONCLUSIOINS: Amylin is upregulated in SLE patients compared to controls, regardless of the insulin resistance that SLE may present. The damage produced by the disease and its severity independently explains this upregulation.

Validation of the motivation scale towards Health-Oriented physical activity (EMAPS) in Spanish Population.

The aim of the present study was to examine the psychometric properties of the motivation scale towards health-oriented physical activity (EMAPS) in the Spanish Population. A sample of 808 participants (Mage = 33.90; SD = 12.91; 366 men and 440 women), participated to ensure the structural, methodological, and external correlates of EMAPS scale validation. Results of the structural stage of analyses confirmed 6 dimensions of EMAPS (i.e., intrinsic motivation, integrated regulation, identified regulation, introjected regulation, external regulation and amotivation). In conclusion, results provided evidence for the reliability and validity of the Spanish version of the EMAPS scores. Thus, this instrument may serve to provide a measure of the motivation towards health-oriented physical activity purposes in the Spanish population.

The Cdc14 Phosphatase Controls Resolution of Recombination Intermediates and Crossover Formation during Meiosis.

Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. The coordinated resolution of meiotic recombination intermediates is required for crossover formation, ultimately necessary for the accurate completion of both rounds of chromosome segregation. Numerous master kinases orchestrate the correct assembly and activity of the repair machinery. Although much less is known, the reversal of phosphorylation events in meiosis must also be key to coordinate the timing and functionality of repair enzymes. Cdc14 is a crucial phosphatase required for the dephosphorylation of multiple CDK1 targets in many eukaryotes. Mutations that inactivate this phosphatase lead to meiotic failure, but until now it was unknown if Cdc14 plays a direct role in meiotic recombination. Here, we show that the elimination of Cdc14 leads to severe defects in the processing and resolution of recombination intermediates, causing a drastic depletion in crossovers when other repair pathways are compromised. We also show that Cdc14 is required for the correct activity and localization of the Holliday Junction resolvase Yen1/GEN1. We reveal that Cdc14 regulates Yen1 activity from meiosis I onwards, and this function is essential for crossover resolution in the absence of other repair pathways. We also demonstrate that Cdc14 and Yen1 are required to safeguard sister chromatid segregation during the second meiotic division, a late action that is independent of the earlier role in crossover formation. Thus, this work uncovers previously undescribed functions of the evolutionary conserved Cdc14 phosphatase in the regulation of meiotic recombination.

Circulating growth-and-differentiation factor-15 in early life: relation to prenatal and postnatal growth and adiposity measurements.

BACKGROUND: Growth-and-differentiation-factor-15 (GDF15) is a regulator of energy homeostasis. To determine the relationship between circulating GDF15 and parameters of metabolic health, we assessed longitudinally GDF15 concentrations in infants born either appropriate- (AGA) or small-for-gestational-age (SGA), the latter population known to be at risk for metabolic alterations, particularly after a rapid postnatal catch-up in weight. METHODS: The study cohort consisted of 103 infants (70 AGA and 33 SGA). Assessments included body length, weight, and ponderal index (PI); fasting glucose, insulin, IGF-I, high-molecular-weight adiponectin, GDF15; and body composition (by absorptiometry) at birth, and at age 4, 12 and 24 months. RESULTS: GDF15 levels at birth were significantly higher than those at each subsequent time point and were similar in AGA and SGA subjects. GDF15 concentrations dropped at age 4 months, more substantially in SGA infants, and continued to decline in both subgroups reaching adult concentrations by age 24 months. GDF15 levels correlated inversely with the changes in PI, IGF-I and body fat throughout follow-up. CONCLUSIONS: Early life is associated with supra-adult concentrations of GDF15. The lower levels of GDF15 in SGA subjects may be an adaptive mechanism to promote catch-up in weight and might increase the risk for obesity later in life.

Experience With Teduglutide in Pediatric Short Bowel Syndrome: First Real-life Data.

OBJECTIVES: The aim of the study was to describe the experience with teduglutide of several Spanish hospitals in pediatric patients with SBS (SBS). METHODS: Seventeen pediatric patients with intestinal failure associated with SBS were treated with teduglutide. Patients received 0.05 mg ·â€Škg ·â€Šday of subcutaneous teduglutide. Patients' demographics and changes in parenteral nutrition (PN) needs, fecal losses, and citrulline level initially and at 3, 6, and 12 months were collected, as well as any adverse events. RESULTS: Patients were receiving 55 ml ·â€Škg ·â€Šday and 33 kcal ·â€Škg ·â€Šday of parenteral supplementation on average at baseline (2 patients received only hydroelectrolytic solution). A total of 12/17 patients achieved parenteral independence: 3 patients after 3 months of treatment, 4 patients at 6 months, and 5 after 12 months. One patient discontinued treatment 1 year after the beginning as no changes in parenteral support or fecal losses were obtained. All others decreased their intravenous requirements by 50%. One patient suffered an episode of cholecystitis, and another one with a pre-existing cardiac disease, developed a cardiac decompensation. CONCLUSIONS: Teduglutide seems to be a safe and effective treatment in the pediatric SBS population with better results than in the pivotal study as well as in the adult population.

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides.

A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 µM). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 µM, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

Significance of Aspergillus niger aggregate species as contaminants of food products in Spain regarding their occurrence and their ability to produce mycotoxins.

The Aspergillus niger aggregate contains 15 morphologically indistinguishable species which presence is related to ochratoxin A (OTA) and fumonisin B2 (FB2) contamination of foodstuffs. The taxonomy of this group was recently reevaluated and there is a need of new studies regarding the risk that these species might pose to food security. 258 isolates of A. niger aggregate obtained from a variety of products from Spain were classified by molecular methods being A. tubingensis the most frequently occurring (67.5%) followed by A. welwitschiae (19.4%) and A. niger (11.7%). Their potential ability to produce mycotoxins was evaluated by PCR protocols which allow a rapid detection of OTA and FB2 biosynthetic genes in their genomes. OTA production is not widespread in A. niger aggregate since only 17% of A. niger and 6% of A. welwitschiae isolates presented the complete biosynthetic cluster whereas the lack of the cluster was confirmed in all A. tubingensis isolates. On the other hand, A. niger and A. welwitschiae seem to be important FB2 producers with 97% and 29% of the isolates, respectively, presenting the complete cluster. The genes involved in OTA and FB2 were overexpressed in producing isolates and their expression was related to mycotoxin synthesis.

A diphenyldiselenide derivative induces autophagy via JNK in HTB-54 lung cancer cells.

Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase-dependent apoptosis and arrest at the G0 /G1 phase in acute lymphoblastic leucemia CCRF-CEM cells. Consistent with this, PARP cleavage; enhanced caspase-2, -3, -8 and -9 activity; reduced CDK4 expression and increased levels of p53 were detected in these cells upon DPDS 2 treatment. Mutated p53 expressed in CCRF-CEM cells retains its transactivating activity. Therefore, increased levels of p21CIP1 and BAX proteins were also detected. On the other hand, DPDS 6, the compound with the highest selectivity index for cancer cells, resulted in G2 /M cell cycle arrest and caspase-independent cell death in p53 deficient HTB-54 lung cancer cells. Autophagy inhibitors 3-methyladenine, wortmannin and chloroquine inhibited DPDS 6-induced cell death. Consistent with autophagy, increased LC3-II and decreased SQSTM1/p62 levels were detected in HTB-54 cells in response to DPDS 6. Induction of JNK phosphorylation and a reduction in phospho-p38 MAPK were also detected. Moreover, the JNK inhibitor SP600125-protected HTB-54 cells from DPDS 6-induced cell death indicating that JNK activation is involved in DPDS 6-induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential.