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Glioblastoma (GBM) is the most malignant brain tumor, characterized by cell heterogeneity comprising stem cells (GSCs) responsible for aggressiveness. The calpain/calpastatin (calp/cast) proteolytic system is involved in critical physiological processes and cancer progression. In this work we showed the expression profile of hcast 3-25 (a Type III calpastatin variant devoid of inhibitory units) and the members of the system in several patient-derived GSCs exploring the relationship between hcast 3-25 and activation/activity of calpains. Each GSC shows a peculiar calp/cast mRNA and protein expression pattern, and hcast 3-25 is the least expressed. Differentiation promotes upregulation of all the calp/cast system components except hcast 3-25 mRNA, which increased or decreased depending on individual GSC culture. Transfection of hcast 3-25-V5 into two selected GSCs indicated that hcast 3-25 effectively associates with calpains, supporting the digestion of selected calpain targets. Hcast 3-25 possibly affects the stem state promoting a differentiated, less aggressive phenotype.

Background: Tirzepatide (TZP) is a once-weekly glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic-polypeptide (GIP) receptor co-agonist approved for T2D. TZP provides promising evidence in improving glucose control and weight loss in T2D and obesity across preclinical and human studies, including data from the SURPASS program. Aims: The goal of this paper was to review the evidence on TZP in terms of glucose control, body weight, and the progression of chronic diabetes-related complications and comorbidities. Results: The mean change in HbA1c ranged from −1.6% to −2.06% over placebo, from −0.29% to −0.92% over each GLP-1RAs, and from −0.7% to −1.09% over basal insulins. In SURPASS-6, TZP was more effective than insulin lispro U100 added to basal insulin in reducing HbA1c levels at the study end (−2.1% vs. −1.1%, respectively). Compared to placebo, TZP induces a significant weight loss: 7.5 (5 mg/week); 11 (10 mg/week); and 12 kg (15 mg/week). Compared to GLP-1RAs, TZP reduces body weight from −1.68 kg to −7.16 kg depending on the dose (5 to 15 mg, respectively). Compared to basal insulin alone rigorously titrated, TZP added onto basal-insulin results in the best strategy for the composite endpoint of improvement of glucose control and weight loss. In SURPASS-6, TZP compared to insulin lispro U100 in add-on to insulin glargine U100 reduced body weight by 9 kg in mean (versus weight gain in basal-bolus users: +3.2 kg). TZP has pleiotropic effects potentially dampening the individual cardiovascular risk, including a reduction in systolic arterial pressure by 4 to 6 mmHg and total cholesterol by 4–6% compared to baseline. A post hoc analysis of SURPASS-4 revealed that TZP, compared to glargine U100, delayed the rate of glomerular filtration decline (−1.4 mL/min vs. −3.6 mL/min, respectively), reduced the rate of urinary albumin excretion (−6.8% vs. +36.9%, respectively), and was associated with a lower occurrence of the composite renal endpoint (HR 0.58 [0.43; 0.80]). Conclusions: Consistent evidence indicates that TZP dramatically changes the clinical course of T2D in different clinical scenarios. The efficacy and safety of TZP on chronic diabetes-related comorbidities and complications seem promising, but ongoing trials will clarify the real benefits.

In light of national and regional EU agendas favouring water privatization under forms of neoliberal technocracy, water movements have emerged to contest this paradigm by reframing water as a common good and demanding remunicipalisation (reclaiming public control over water services). As a result, unique cases of water remunicipalisation have aligned their politics with a commons discourse, as in the case of Naples, Italy. However, implementing a commons discourse within an experimental urban setting, embedded in a context of neoliberal technocracy and socio-cultural dynamics is imbued with tensions. Combining literature on commons with that of feminist political ecology, this paper unravels the micro-politics and macro-politics that create tensions in experiments of constructing and institutionalising an urban water commons. The focus of this paper is on ‘lived experiences’ of activists in an ecological (water) struggle, as an entry point to study the (de)construction of the institutionalisation of a commons-oriented water project. Results point to four factors that leave the Naples’ water commons project at risk: enclosing knowledge(s), imbalanced gendered experiences, enclosing practices of participation, and lastly the antagonistic politics at a national and regional scale that continue to isolate the case of Naples as anomaly. By focusing on the neglected facets of embodiment in constructing and institutionalising commons projects, we draw attention to the importance of including embodied knowledge(s), experiences, and practices in the construction, institutionalisation, and ultimately the study, of water commons.

Ascorbic acid (AsA) is mainly known as an antioxidant. However, if the peculiar features of the AsA system in the different stages of seed development and germinationare taken into consideration, it can be concluded that the function of AsA goes far beyond its antioxidant properties. The possible involvement of AsA in the regulation of hormone synthesis and in the epigenetic control of gene expression opens new directions to further research. In recent years, seed priming with AsA has been successfully used as a strategy to improve germination and plant productivity. Beneficial effects of seed AsA priming could be observed in several crop species, but the underlying molecular mechanism(s) are still unclear. The available evidence suggests that AsA priming induces a wide range of coordinated responses allowing primed seeds to overcome adverse environmental conditions.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have changed considerably the management of type 2 diabetes (T2D). However, recently published data from retrospective cohort studies suggest that chronic exposure to GLP-1RAs in T2D may increase the risk of papillary and medullary thyroid cancer. In this perspective, the role of the incretin system in thyroid carcinogenesis has been reviewed and critically commented on, aiming to understand if the time has arrived to be concerned about the risk. Although evidence suggested, speculative hypotheses should be verified, and further studies are urgently needed to clarify the issue.

Background. One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D). Methods. PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks. Results. The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of −0.14% [95%CI −0.25; −0.03], p = 0.01, and I2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of −0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (−5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]). Conclusion. Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients’ education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.

In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and Type 2 diabetes. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization. Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages. As expected, RNA sequencing highlighted a pro-inflammatory profile but also metabolic signatures including glycolysis and hypoxia as well as a strong unfolded protein response. Glycolysis upregulation was confirmed in SFA-treated macrophages by measuring glycolytic gene expression, glucose uptake, lactate production and extracellular acidification rate. Like in LPS-stimulated macrophages, glycolysis activation in SFA-treated macrophages was dependent on HIF-1α activation and fueled the production of pro-inflammatory cytokines. SFAs and LPS both induced IRE1α endoribonuclease activity, as demonstrated by XBP1 mRNA splicing, but with different kinetics matching HIF-1α activation and the glycolytic gene expression. Interestingly, the knockdown of IRE1α and/or the pharmacological inhibition of its RNase activity prevented HIF-1α activation and significantly decreased glycolysis upregulation. Surprisingly, XBP1s appeared to be dispensable, as demonstrated by the lack of inhibiting effect of XBP1s knockdown on glycolytic genes expression, glucose uptake, lactate production and HIF-1α activation. These experiments demonstrate for the first time a key role of IRE1α in HIF-1α-mediated glycolysis upregulation in macrophages stimulated with pro-inflammatory triggers like LPS or SFAs through XBP1s-independent mechanism. IRE1 could mediate this novel function by targeting other transcripts (mRNA or pre-miRNA) through a mechanism called regulated IRE1-dependent decay or RIDD. Deciphering the underlying mechanisms of this novel IRE1 function might lead to novel therapeutic targets to curtail sterile obesity- or infection-linked inflammation.

High-pressure and temperature extraction (HPTE) can effectively recover bioactive compounds from olive pomace (OP). HPTE extract obtained by extracting OP with ethanol and water (50:50 v/v) at 180 °C for 90 min demonstrated a pronounced ability to preserve intracellular calcium homeostasis, shielding neurons from the harmful effects induced by N-methyl-d-aspartate (NMDA) receptor (NMDAR) overactivation, such as aberrant calpain activation. In this study, the extraction temperature was changed from 37 to 180 °C, and the extracts were evaluated for their antioxidant potency and ability to preserve crucial intracellular Ca2+-homeostasis necessary for neuronal survival. Additionally, to verify the temperature-induced activity of the extract, further extractions on the exhausted olive pomace were conducted, aiming to identify variations in the quality and quantity of extracted phenolic molecules through HPLC analysis. The results revealed a significant increase in bioactive compounds as a function of temperature variation, reaching 6.31 ± 0.09 mgCAE/mL extract for the extraction performed at 180 °C. Subsequent extraction of the exhausted residues yielded extracts that remained active in preventing calcium-induced cell death. Moreover, despite increased antiradical power, extracts re-treated at 180 °C did not display cell protection activity. Our results indicate that the molecules able to maintain physiological Ca2+-homeostasis in murine cortical neurons in conditions of cytotoxic stimulation of NMDAR are wholly recovered from olive pomace only following extraction performed at 180 °C.

Sarcopenia is an age-related clinical complaint characterized by the progressive deterioration of skeletal muscle mass and strength over time. Type 2 diabetes (T2D) is associated with faster and more relevant skeletal muscle impairment. Both conditions influence each other, leading to negative consequences on glycemic control, cardiovascular risk, general health status, risk of falls, frailty, overall quality of life, and mortality. PubMed/Medline, Scopus, Web of Science, and Google Scholar were searched for research articles, scientific reports, observational studies, clinical trials, narrative and systematic reviews, and meta-analyses to review the evidence on the pathophysiology of di-abetes-induced sarcopenia, its relevance in terms of glucose control and diabetes-related outcomes, and diagnostic and therapeutic challenges. The review comprehensively addresses key elements for the clinical definition and diagnostic criteria of sarcopenia, the pathophysiological correlation be-tween T2D, sarcopenia, and related outcomes, a critical review of the role of antihyperglycemic treatment on skeletal muscle health, and perspectives on the role of specific treatment targeting myokine signaling pathways involved in glucose control and the regulation of skeletal muscle metabolism and trophism. Prompt diagnosis and adequate management, including lifestyle inter-vention, health diet programs, micronutrient supplementation, physical exercise, and pharmaco-logical treatment, are needed to prevent or delay skeletal muscle deterioration in T2D.

Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson’s and Huntington’s diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy.

Ever since the identification of vitamin C (ascorbic acid, AsA) as an essential molecule that humans cannot synthesize on their own, finding adequate dietary sources of AsA became a priority in nutrition research. Plants are the main producers of AsA for humans and other non-synthesizing animals. It was immediately clear that some plant species have more AsA than others. Further studies evidenced that AsA content varies in different plant organs, in different developmental stages/environmental conditions and even within different cell compartments. With the progressive discovery of the genes of the main (Smirnoff-Wheeler) and alternative pathways coding for the enzymes involved in AsA biosynthesis in plants, the simple overexpression of those genes appeared a suitable strategy for boosting AsA content in any plant species or organ. Unfortunately, overexpression experiments mostly resulted in limited, if any, AsA increase, apparently due to a tight regulation of the biosynthetic machinery. Attempts to identify regulatory steps in the pathways that could be manipulated to obtain unlimited AsA production were also less successful than expected, confirming the difficulties in “unleashing” AsA synthesis. A different approach to increase AsA content has been the overexpression of genes coding for enzymes catalyzing the recycling of the oxidized forms of vitamin C, namely monodehydroascorbate and dehydroascorbate reductases. Such approach proved mostly effective in making the overexpressors apparently more resistant to some forms of environmental stress, but once more did not solve the issue of producing massive AsA amounts for human diet. However, it should also be considered that a hypothetical unlimited increase in AsA content is likely to interfere with plant development, which is in many ways regulated by AsA availability itself. The present review article aims at summarizing the many attempts made so far to improve AsA production/content in plants, evidencing the most promising ones, and at providing information about the possible unexpected consequences of a pure biotechnological approach not keeping into account the peculiar features of the AsA system in plants.

In this paper, mathematical models aiming at describing the fluid flow of non-Newtonian fluids inside ducts with both convergent and cylindrical sections have been formulated. The theory has been implemented for the description of industrially interesting fluids such as moisture-cured silicones and thermoplastics, which are well described by the Carreau and Cross-Williams-Landel-Ferry (Cross-WLF) rheological models, respectively. The viscous flow in a die has been considered, comparing the results with Computational Fluid Dynamics (CFD) solutions extracted through the Finite Element Method (FEM) software Comsol Multiphysics. The agreement with numerical data is very good, showing the potential for next experimental applications in predicting some very important and useful quantities, such as the extrusion force, which is critical for a wide range of 3D printing processes. The novelty relies in the general applicability of the theoretical models to viscous flows, no matter what its rheological behaviour is.

Background: The most recent modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta®), has been shown to improve clinical outcomes in most patients with cystic fibrosis (PwCF). Unfortunately, the clinical benefits are sometimes variable; thus, improving our knowledge of the possible causes of this variability can help reduce it. Methods: Circulating mononuclear cells (CMCs) and plasma were collected from 16 PwCF (including those on Trikafta® therapy) and 4 non-CF subjects. Cystic fibrosis transmembrane conductance regulator (CFTR) activity and matrix metalloprotease 9 (MMP9) expression were monitored before and after therapy, together with some clinical parameters. The relationship between MMP9 expression and the modulation of the extracellular-regulated 1/2 (ERK1/2) and nuclear factor-kB (NF-kB) pathways was also analyzed. Results: MMP9, markedly expressed in the CMCs and plasma of all the patients included in the study, was downregulated in the clinically responsive PwCF. In the non-responder, the MMP9 levels remained high. The modulation of MMP9 following treatment with Trikafta® may be controlled by the NF-kB pathway. Conclusions: These data strongly suggest that MMP9 downregulation is a potential biomarker of therapy efficacy and that it could be useful in understanding the molecular events underlying the variable clinical responses of patients to Trikafta®. This knowledge could be helpful for future studies of personalized medicine and thereby ensure improvements in individual responses to therapies.

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460.

Timoma é um tumor que surge a partir de células do timo, um órgão presente em todos os mamíferos e responsável pela maturação de linfócitos T, que regride de tamanho ao longo da vida, até que na idade adulta é gradualmente substituído por tecido adiposo. Tais tumores são mais comuns em animais idosos e os sinais clínicos associados a esse tipo de neoplasia são muitas vezes não específicos até que atinjam grandes proporções. Um diagnóstico preliminar de timoma é muitas vezes feito com base na localização do tumor e citologia aspirativa. Comparado a outros tipos de tumor que podem ocorrer nessa região, os timomas costumam ter bom prognóstico com o tratamento. O presente artigo relata o caso de uma cadela da raça Labrador Retriever de onze anos de idade, diagnosticada com timoma de origem epitelial, que como tratamento elegeu-se a timectomia através de toracotomia intercostal com ressecção de costela. O timoma foi identificado através de exames de imagem como radiografia torácica e tomografia computadorizada, pela citologia aspirativa e confirmado diagnóstico por meio de exame histopatológico. A paciente teve evolução favorável no pós-operatório e, até o momento, apresenta-se em ótimo estado geral.

Este relato de caso tem por objetivo descrever como a Eletroquimioterapia assim como outras ações conjuntas tais como neoadjuvância, ressecções cirúrgicas e a quimioterapia, atuaram no tratamento de um cão com 13 anos de idade diagnosticado com Mastocitoma de Grau III, alto grau de malignidade. A escolha da melhor terapia assim como o momento certo de cada processo foi baseado no exame de citologia aspirativa por agulha fina (CAAF) e confirmado pela especificação histológica tanto da lesão quanto dos linfonodos regionais. Conhecido como tumor de células redondas, o mastocitoma faz parte do grupo de neoplasias constituídas de mastócitos, de origem cutânea ou visceral. São mais comuns em cães, representando de 7% a 21% dos tumores de pele, destes de 11% a 21% possuem variações cutâneas malignas. Assim como neste relato, cerca de 45% dos casos ocorrem em membros pélvicos, região de períneo e genitália. Registros apontam para casos em cães com média de 8 anos de idade, mas já existem relatos em que o tumor atingiu caninos mais jovens, a partir dos 6 anos.

Abstract Purpose The aim of the present in vivo analysis was to evaluate the osseointegration process of titanium implants with three different surfaces (machined, sandblasted and acid-etched, and laser-treated) after 15 and 30 days of healing period. Materials and methods Thirty-six implants with different surfaces were placed in the iliac crest of four Bergamasca sheep. The implant surfaces tested were sandblasted and acid-etched (group A), laser-treated (group B), and fully machined (group C). Two animals were sacrificed after 15 days while the other two after 30 days. Histological and histomorphometric analyses were performed. Results After 30 days, the bone tissue layer onto implant groups A and B appeared almost continuous with small marrow spaces interruption, while on the machined surface (group C), larger spaces with marrow tissue alternated with the bony trabeculae onto the titanium surface. Implants in groups A and B showed significantly higher implant contact percentage (BIC%) value than group C (P < 0.05). Moreover, it was observed a BIC% increase in both groups A and B between 15 and 30 days while in the machined group (group C), the BIC% decreased. Conclusion Results from the present in vivo analysis revealed that both sandblasted/acid-etched and laser-treated titanium implants, compared to the machined ones, have higher values of osseointegration in less healing time.

The thyroid gland requires iodine to synthesize thyroid hormones, and iodine deficiency results in the inadequate production of thyroxine and related thyroid, metabolic, developmental, and reproductive disorders. Iodine requirements are higher in infants, children, and during pregnancy and lactation than in adult men and non-pregnant women. Iodine is available in a wide range of foods and water and is susceptible to almost complete gastric and duodenal absorption as an iodide ion. A healthy diet usually provides a daily iodine consumption not exceeding 50% of the recommended intake. Iodine supplementation is usually necessary to prevent iodine deficiency disorders (IDDs), especially in endemic areas. The community-based strategy of iodine fortification in salt has eradicated IDDs, such as endemic goiter and cretinism, in countries providing adequate measures of iodine prophylaxis over several decades in the 20th century. Iodized salt is the cornerstone of iodine prophylaxis in endemic areas, and the continuous monitoring of community iodine intake and its related clinical outcomes is essential. Despite the relevant improvement in clinical outcomes, subclinical iodine deficiency persists even in Western Europe, especially among girls and women, being an issue in certain physiological conditions, such as pregnancy and lactation, and in people consuming unbalanced vegetable-based or salt-restricted diets. Detailed strategies to implement iodine intake (supplementation) could be considered for specific population groups when iodized salt alone is insufficient to provide adequate requirements.