Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to ...investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.
We present an integrated sedimentological, paleontological and oxygen isotope stratigraphic study of a Pleistocene marine to coastal section at the Enza river, allowing to highlight the role of ...tectonics at the mountain front of the Northern Apennines and that of climate at the onset of the Mid Pleistocene Transition. Two main evolutive steps, separated by a pronounced angular unconformity, characterize the deposition of the studied marine sedimentary succession ranging between 1.73 and 1.071 Ma. The lower part of the section shows a continuous outer shelf sedimentation, whereas the post unconformity sedimentation shows cyclothemes, documenting a progressive shallowing of the bathymetry. These are linked to enhanced eustatic oscillations leading to increasing amplitude of the transgressive-regressive cycles. The new δ18O data allowed correlating the last 14 m underneath the unconformity to the MIS 49 to 45, improving our understanding of the time duration of the sedimentary gap, estimated around 140 ka. This is primarily associated with the growth of the Quattro Castella thrust ramp anticline, when a deeper mid-crustal thrust co-occurred, causing an increased deformation and tilting rate. The consequent change in morphotectonic setting strongly impacted the environment and ecosystem of this Early Pleistocene shelf. Starting at about 1.25 Ma, the section records an increasing riverine detritus, competing with the shore-parallel shelfal sediment dynamics. In a frame of increasing slope of the Northern Apennines topography, this enhanced fluvial activity might correlate with the increasing amplitude of climate oscillations during the Mid Pleistocene Transition, as recognized in other Mediterranean settings. This is recorded by a cyclothemic deposition, linked to eustatic oscillations.
•New oxygen isotopic data facilitates dating a prominent unconformity on the Enza section to the interval 1385–1245 ka.•The Pleistocene paleoenvironment of the Enza section was a shallowing shelf at the mountain front of the Apennines.•The divergent pattern of growing stratigraphy is linked to thrusts activity, a waning surficial and a waxing deep.•The Mid Pleistocene Transition over the shelf deposits, controlled timing of the unconformity and subsequent T/R cycles.
There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy.
102 stage II ...high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the x03C7;2 test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS.
Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI ≥25 (HR: 3.69, p = 0.002).
Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer.
Borderline ovarian tumor (BOT) accounts for 15-20% of all epithelial ovarian tumors. Concerns have arisen about the clinical and prognostic implications of BOT with exophytic growth patterns. We ...retrospectively reviewed all cases of BOT patients surgically treated from 2015 to 2020. Patients were divided into an endophytic pattern (with intracystic tumor growth and intact ovarian capsule) and an exophytic pattern (with tumor growth outside the ovarian capsule) group. Among the 254 patients recruited, 229 met the inclusion criteria, and of these, 169 (73.8%) belonged to the endophytic group. The endophytic group showed more commonly an early FIGO stage than the exophytic group (100.0% vs. 66.7%,
< 0.001). Furthermore, tumor cells in peritoneal washing (20.0% vs. 0.6%,
< 0.001), elevated Ca125 levels (51.7% vs. 31.4%,
= 0.003), peritoneal implants (0 vs. 18.3%,
< 0.001), and invasive peritoneal implants (0 vs. 5%,
= 0.003) were more frequently observed in the exophytic group. The survival analysis showed 15 (6.6%) total recurrences, 9 (5.3%) in the endophytic and 6 (10.0%) patients in the exophytic group (
= 0.213). At multivariable analysis, age (
= 0.001), FIGO stage (
= 0.002), fertility-sparing surgery (
= 0.001), invasive implants (
= 0.042), and tumor spillage (
= 0.031) appeared significantly associated with recurrence. Endophytic and exophytic patterns in borderline ovarian tumors show superimposable recurrence rates and disease-free survival.
Methane Derived Authigenic Carbonate (MDAC) concretions have been recently exposed in the Pleistocene Argille Azzurre Fm. outcropping along the Enza riverbanks, Northern Apennines foothills, Italy. ...The relations between the sediment deposition, the coeval tectonic deformation and the MDAC concretions have been investigated to unravel the mechanism of methane migration through the sediments and the processes leading to MDAC occurrence. The biogenic methane responsible for the formation of MDAC chimneys and slabs has been generated in the organic-rich Pliocene sediments located in the Po Plain subsurface. The gas migrated up-dip towards the Northern Apennines foothills. The MDAC cements are mainly composed of dolomite, whose precipitation requires thousand years and the absence of SO4 in the pore fluids. According with the sedimentation rates of the MDAC-hosting Pleistocene succession, the Sulphate Methane Transition Zone migrated upwards faster than time required for dolomite precipitation. Therefore, the connate water migrating together with the methane could have acted as second DIC source, allowing the MDAC formation also in the methane-rich zone.
•Methane Derived Authigenic Carbonates in the Northern Apennines foothills.•Migration of biogenic methane and connate water from Pliocene age source rocks.•Precipitation of dolomite cements requires low sulphates and thousands years.•Sulphate–Methane transition migrates upwards faster than the dolomite precipitation.•Contribution of connate water as secondary DIC source during the MDAC formation.
Cardiolipin (CL) is a hallmark phospholipid localized within the inner mitochondrial membrane. Upon several mitochondrial stress conditions, CL is translocated to specialized platforms, where it may ...play a role in signaling events to promote mitophagy and apoptosis. Recent studies characterized the molecular composition of MAM-associated lipid microdomains and their implications in regulating the autophagic process. In this study we analyzed the presence of CL within MAMs following autophagic stimulus and the possible implication of raft-like microdomains enriched in CL as a signaling platform in autophagosome formation. Human 2FTGH fibroblasts and SKNB-E-2 cells were stimulated under nutrient deprivation with HBSS. MAM fraction was obtained by an ultracentrifugation procedure and analyzed by HPTLC immunostaining. CL interactions with mitofusin2 (MFN2), calnexin (CANX) and AMBRA1 were analyzed by scanning confocal microscopy and coimmunoprecipitation. The analysis revealed that CL accumulates in MAMs fractions following autophagic stimulus, where it interacts with MFN2 and CANX. It associates with AMBRA1, which in turn interacts with BECN1 and WIPI1. This study demonstrates that CL is present in MAM fractions following autophagy triggering and interacts with the multimolecular complex (AMBRA1/BECN1/WIPI1) involved in autophagosome formation. It may have both structural and functional implications in the pathophysiology of neurodegenerative disease(s).
Different strategies have been proposed for the treatment of locally advanced cervical cancer (LACC), with different impacts on patient's quality of life (QoL). This study aimed to analyze urinary, ...bowel, and sexual dysfunctions in a series of LACC patients who underwent chemotherapy, radiotherapy, radical surgery, or a combination of these treatments.
Patients with LACC who underwent neoadjuvant radio-chemotherapy (NART/CT;
= 35), neoadjuvant chemotherapy (NACT;
= 17), exclusive radio-chemotherapy (ERT/CT;
= 28), or upfront surgery (UPS;
= 10) from November 2010 to September 2019 were identified from five oncological referral centers. A customized questionnaire was used for the valuation of urinary, gastrointestinal, and sexual dysfunctions.
A total of 90 patients were included. Increased urinary frequency (>8 times/day) was higher in ERT/CT compared with NACT/RT (57.1% vs. 28.6%;
= 0.02) and NACT (57.1% vs. 17.6%;
= 0.01). The use of sanitary pads for urinary leakage was higher in ERT/CT compared with NACT/RT (42.9% vs. 14.3%;
= 0.01) and NACT (42.9% vs. 11.8%;
= 0.03). The rate of reduced evacuations (<3 times a week) was less in UPS compared with NACT/RT (50% vs. 97.1%;
< 0.01), NACT (50% vs. 88.2,
< 0.01), and ERT/CT (50% vs. 96.4%;
< 0.01). A total of 52 women were not sexually active after therapy, and pain was the principal reason for the avoidance of sexual activity.
The rate and severity of urinary, gastrointestinal, and sexual dysfunction were similar in the four groups of treatment. Nevertheless, ERT/CT was associated with worse sexual and urinary outcomes.
ER lipid raft-associated protein 1 (ERLIN1) and 2 (ERLIN2) are 40 kDa transmembrane glycoproteins belonging to the family of prohibitins, containing a PHB domain. They are generally localized in the ...endoplasmic reticulum (ER), where ERLIN1 forms a heteroligomeric complex with its closely related ERLIN2. Well-defined functions of ERLINS are promotion of ER-associated protein degradation, mediation of inositol 1,4,5-trisphosphate (IP3) receptors, processing and regulation of lipid metabolism. Until now, ERLINs have been exclusively considered protein markers of ER lipid raft-like microdomains. However, under pathophysiological conditions, they have been described within mitochondria-associated endoplasmic reticulum membranes (MAMs), tethering sites between ER and mitochondria, characterized by the presence of specialized raft-like subdomains enriched in cholesterol and gangliosides, which play a key role in the membrane scrambling and function. In this context, it is emerging that ER lipid raft-like microdomains proteins, i.e., ERLINs, may drive mitochondria-ER crosstalk under both physiological and pathological conditions by association with MAMs, regulating the two main processes underlined, survival and death. In this review, we describe the role of ERLINs in determining cell fate by controlling the “interchange” between apoptosis and autophagy pathways, considering that their alteration has a significant impact on the pathogenesis of several human diseases.
LDL receptor–related proteins 6 (LRP6) is a type I transmembrane receptor (C-terminus in cytosol), which appears to be essential in numerous biological processes, since it is an essential co-receptor ...of Wnt ligands for canonical β-catenin dependent signal transduction. It was shown that tissue plasminogen activator (tPA), physically interacting with LRP6, induces protein phosphorylation, which may have large implication in the regulation of neural processes. In this investigation we analyzed whether LRP6 is associated with lipid rafts following tPA triggering in neuroblastoma cells and the role of raft integrity in LRP6 cell signaling. Sucrose gradient separation revealed that phosphorylated LRP6 was mainly, but not exclusively present in lipid rafts; this enrichment became more evident after triggering with tPA. In these microdomains LRP6 is strictly associated with ganglioside GM1, a paradigmatic component of these plasma membrane compartments, as revealed by coimmunoprecipitation experiments. As expected, tPA triggering induced LRP6 phosphorylation, which was independent of LRP1, as revealed by knockdown experiments by siRNA, but strictly dependent on raft integrity. Moreover, tPA induced β-catenin phosphorylation was also significantly prevented by previous pretreatment with methyl-β-cyclodextrin. Our results demonstrate that LRP6 mediated signal transduction pathway triggered by tPA acts through lipid rafts in neuroblastoma cells. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents. Indeed, these data, pointing to the key role of lipid rafts in tPA triggered signaling involving β-catenin, may have pharmacological implications, suggesting that cyclodextrins, and potentially other drugs, such as statins, may represent an useful tool.
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