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Purpose: Intra-articular corticosteroid (CS) injections for knee osteoarthritis (OA) management are endorsed by several scientific societies, while the use of hyaluronic acid (HA) and platelet-rich plasma (PRP) is more controversial. Aim of the study was to quantify and compare the clinical effectiveness of CS injections with respect to HA and PRP in patients with knee OA. Methods: The search was conducted on PubMed, Cochrane, and Web of Science following the PRISMA guidelines. Randomized controlled trials (RCTs) on the comparison of CS injections and HA or PRP injections for the treatment of knee OA were included. The minimal clinically important difference (MCID) was used to interpret the clinical relevance of the improvements at different follow-ups up to 12 months. The study quality was assessed using the Cochrane RoB-2 tool and the GRADE guidelines. Results: Thirty-five RCTs were included (3348 patients). The meta-analysis comparing CS and HA revealed no difference in terms of WOMAC improvement, while HA showed superior VAS pain improvement at long-term follow-up (P = 0.011), without reaching the MCID. PRP offered a superior WOMAC improvement compared to CS at short- (P = 0.002), mid- (P < 0.001, exceeding the MCID), and long-term (P < 0.001, exceeding the MCID) follow-ups. PRP offered a superior VAS improvement at mid- (P < 0.001, exceeding the MCID) and long-term (P = 0.023) follow-ups. Conclusion: CS injections for knee OA offer similar results to HA and PRP only at short term, while there is an overall superiority of PRP at longer follow-ups. This difference is not only statistically significant but also clinically relevant in favour of PRP.

Prolamins are hydrophobic proteins extracted using water-ethanol mixtures, useful for texturing meat and cheese alternatives at low temperatures due to their self-aggregating properties. This study explored the rheological and structural properties of the corn prolamin zein under varying temperature and pH conditions and compared its rheological behavior to the barley prolamin hordein. Zein showed plasticization when heated, with plasticization temperatures ranging from 41.3 °C at pH 4 to 46.7 °C at pH 6. Texture maps indicated that zein formed brittle gels within the linear viscoelastic range and tougher structures at crossover, unlike hordein, which was more elastic and lacked a clear plasticization behavior (softening) during heating. These differences were linked to zein's hydrophobicity. Coarse-grained molecular dynamics simulations showed zein self-aligning into anisotropic protein structures during heating, with its radius of gyration increasing from Rg = 21 Å to Rg = 34 Å by heating. This study provided insights into the structuring of prolamins and highlighted the need to understand plasticization mechanisms to improve zein's functionality in food applications.

Abstract Purpose The purpose of this study was to quantify and compare the clinical relevance of the different intra‐articular corticosteroids (CS) effects in vivo for osteoarthritis (OA) treatment. Methods The search was conducted on PubMed, Cochrane, and Web of Science in October 2023. The PRISMA guidelines were used. Inclusion criteria: animal or human randomized controlled trials (RCTs), English language and no time limitation, on the comparison of different intra‐articular CS for OA treatment. The articles' quality was assessed using the Cochrane RoB2 and GRADE guidelines for human RCTs, and SYRCLE's tool for animal RCTs. Results Eighteen RCTs were selected (16 human and 2 animal studies), including 1577 patients (1837 joints) and 31 animals (51 joints). The CS used were triamcinolone (14 human and 2 animal studies), methylprednisolone (7 human and 1 animal study), betamethasone (3 human studies) and dexamethasone (1 human study). All studies addressed knee OA except for three human and one animal study. A meta‐analysis was performed on the comparison of methylprednisolone and triamcinolone in humans with knee OA analysing VAS pain at very short‐ (≤2 weeks), short‐ (>2 and ≤4 weeks), mid‐ (>4 and ≤8 weeks), long‐ (>8 and ≤ 12 weeks), and very long‐term (>12 and ≤24 weeks). Triamcinolone showed better post‐injection values compared to methylprednisolone at very short‐term (p = 0.028). No difference in terms of VAS improvement was observed at any follow‐up. Conclusions The available preclinical and clinical literature provides limited evidence on the comparison of different CS, hindering the possibility of determining the best CS approach in terms of molecule and dose for the intra‐articular injection of OA joints. Level of Evidence Level I.

Gait impairments negatively affect the quality of life of people with Parkinson's disease (PwPD). Aerobic exercise (AE) is an alternative to alleviate these impairments and its combination with transcranial direct current stimulation (tDCS) has demonstrated synergistic effects. However, the effect of multitarget tDCS application (i.e., motor, and prefrontal cortices simultaneously) combined with physical exercise on gait impairments is still little known. Thus, the proposed randomized clinical trial will verify the acute effects of AE combined with tDCS applied on motor and prefrontal cortices separately and simultaneously on gait (spatial-temporal and cortical activity parameters) in PwPD. Twenty-four PwPD in Hoehn & Yahr stages I-III will be recruited for this crossover study. PwPD will practice AE on treadmill simultaneously with the application of anodal tDCS during four intervention sessions on different days (∼ one week of interval). Active tDCS will be applied to the primary motor cortex, prefrontal cortex, and both areas simultaneously (multitarget), with an intensity of 2 mA for 20 min. For sham, the stimulation will remain at 2 mA for 10 s. The AE will last a total of 30 min, consisting of warm-up, main part (20 min with application of tDCS), and recovery. Exercise intensity will be controlled by heart rate. Spatial-temporal and cortical activity parameters will be acquired before and after each session during overground walking, walking with obstacle avoidance, and walking with a cognitive dual task at self-preferred velocity. An accelerometer will be positioned on the fifth lumbar vertebra to obtain the spatial-temporal parameters (i.e., step length, duration, velocity, and swing phase duration). Prefrontal cortex activity will be recorded from a portable functional near-infrared spectroscopy system and oxygenated and deoxygenated hemoglobin concentrations will be analyzed. Two-way ANOVAs with repeated measures for stimulation and moment will be performed. The findings of the study may contribute to improving gait in PwPD. Trial registration: Brazilian Clinical Trials Registry (RBR-738zkp7).

Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the standard of care for hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer in combination with endocrine therapy. However, the real-world efficacy and safety of standard versus reduced doses in elderly patients remain unclear. This study aims to compare the clinical outcomes of standard versus reduced doses of CDK4/6 inhibitors in elderly patients with metastatic breast cancer. Methods: This multicenter retrospective cohort study included 158 patients aged ≥70 years diagnosed with HR+/HER2-negative metastatic breast cancer who received either standard or reduced doses of CDK4/6 inhibitors (Ademaciclib, Ribociclib, Palbociclib) as first-line therapy. Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. PFS and OS were estimated using the Kaplan–Meier method, and comparisons between groups were performed using a log-rank test. Results: Of the total population, 108 patients (68.4%) received the standard dose, and 50 patients (31.6%) received a reduced dose. The standard-dose group had significantly longer median PFS compared to the reduced-dose group (21.3 vs. 15.2 months, p = 0.014), while the median OS did not differ significantly (37.2 vs. 37.2 months, p = 0.103). Subgroup analyses revealed no significant differences in PFS or OS between standard and reduced doses for Ademaciclib and Ribociclib, while Palbociclib at standard dose showed superior PFS (21.9 vs. 12.7 months, p = 0.029) and OS (50.5 vs. 28.6 months, p = 0.026). The incidence of Grade 2–4 AEs was higher in the standard-dose group (74.2% vs. 56.8%, p = 0.044). Conclusions: Dose reduction of CDK4/6 inhibitors, particularly Ademaciclib and Ribociclib, is a viable option in elderly patients, maintaining comparable OS outcomes to standard dosing while reducing the risk of adverse events. Palbociclib at standard dose may offer superior outcomes. These findings support personalized dosing strategies to optimize efficacy and tolerability in frail or elderly patients. [ABSTRACT FROM AUTHOR]

Mutations in the CHKB gene cause muscular dystrophy. Here, the authors show that in mouse models of the disease changes in lipid metabolism are associated with decreased PPAR signaling, and show PPAR agonists can rescue expression of injury markers in myocytes in vitro.

IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.

(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In the present work, we structurally evaluated the impact of RdRp mutations found at baseline in 39 patients treated with remdesivir and associated with a different degree of antiviral response in vivo. (2) Methods: A refined bioinformatics approach was applied to assign SARS-CoV-2 clade and lineage, and to define RdRp mutational profiles. In line with such a method, the same mutations were built and analyzed by combining docking and thermodynamics evaluations with both molecular dynamics and representative pharmacophore models. (3) Results: Clinical studies revealed that patients bearing the most prevalent triple mutant P323L+671S+M899I, which was present in 41% of patients, or the more complex mutational profile P323L+G671S+L838I+D738Y+K91E, which was found with a prevalence of 2.6%, showed a delayed reduced response to remdesivir, as confirmed by the increase in SARS-CoV-2 viral load and by a reduced theoretical binding affinity versus RdRp (ΔGbindWT = −122.70 kcal/mol; ΔGbindP323L+671S+M899I = −84.78 kcal/mol; ΔGbindP323L+G671S+L838I+D738Y+K91E = −96.74 kcal/mol). Combined computational approaches helped to rationalize such clinical observations, offering a mechanistic understanding of the allosteric effects of mutants on the global motions of the viral RNA synthesis machine and in the changes of the interactions patterns of remdesivir during its binding.

Simple Summary: This study explores the effectiveness and safety of a common breast cancer treatment in elderly patients, a group often overlooked in clinical trials. Specifically, it focuses on using CDK4/6 inhibitors with hormone therapy for treating metastatic HR+/HER2- breast cancer in patients aged 70 and older. This research aims to understand how well this treatment works and how tolerable it is for this vulnerable population, which faces unique challenges due to age and other health conditions. The results of this study may provide valuable insights for clinicians, enabling more informed treatment decisions which optimize therapeutic outcomes and enhance the quality of life for elderly patients with breast cancer. Background: Metastatic HR+/HER2- breast cancer is commonly treated with CDK4/6 inhibitors in combination with endocrine therapy. However, the efficacy and safety of this approach in elderly patients (≥70 years) remain unclear, particularly in the context of real-world clinical practice. This study aims to evaluate the clinical outcomes and tolerability of CDK4/6 inhibitor treatments in this fragile population, which is often under-represented in randomized clinical trials. Patients and methods: This retrospective multicenter study included elderly patients with metastatic HR+/HER2-negative breast cancer receiving first-line CDK4/6 inhibitors. The primary endpoint was progression-free survival (PFS). The secondary endpoints focused on the overall survival (OS), safety, and tolerability, considering variables such as tumor subtype, age, comorbidities, and treatment specifics. Results: The median PFS and OS were slightly lower than those reported in clinical trials, reflecting the inclusion of a more fragile population. The luminal B subtype was linked to a poorer PFS, while other factors like age, BMI, and ECOG status did not significantly affect the outcomes. A safety analysis indicated a higher incidence of grade 3 or higher toxicities, especially in frail patients, leading to dose reductions. Despite these challenges, CDK4/6 inhibitors were generally well-tolerated, allowing most patients to continue therapy. Conclusions: CDK4/6 inhibitors with endocrine therapy are effective in elderly patients with metastatic HR+/HER2- breast cancer, though careful management is crucial to balance efficacy and minimize adverse events. [ABSTRACT FROM AUTHOR]

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.

Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.

Purpose: The purpose of this study was to quantify and compare the clinical relevance of the different intra‐articular corticosteroids (CS) effects in vivo for osteoarthritis (OA) treatment. Methods: The search was conducted on PubMed, Cochrane, and Web of Science in October 2023. The PRISMA guidelines were used. Inclusion criteria: animal or human randomized controlled trials (RCTs), English language and no time limitation, on the comparison of different intra‐articular CS for OA treatment. The articles' quality was assessed using the Cochrane RoB2 and GRADE guidelines for human RCTs, and SYRCLE's tool for animal RCTs. Results: Eighteen RCTs were selected (16 human and 2 animal studies), including 1577 patients (1837 joints) and 31 animals (51 joints). The CS used were triamcinolone (14 human and 2 animal studies), methylprednisolone (7 human and 1 animal study), betamethasone (3 human studies) and dexamethasone (1 human study). All studies addressed knee OA except for three human and one animal study. A meta‐analysis was performed on the comparison of methylprednisolone and triamcinolone in humans with knee OA analysing VAS pain at very short‐ (≤2 weeks), short‐ (>2 and ≤4 weeks), mid‐ (>4 and ≤8 weeks), long‐ (>8 and ≤ 12 weeks), and very long‐term (>12 and ≤24 weeks). Triamcinolone showed better post‐injection values compared to methylprednisolone at very short‐term (p = 0.028). No difference in terms of VAS improvement was observed at any follow‐up. Conclusions: The available preclinical and clinical literature provides limited evidence on the comparison of different CS, hindering the possibility of determining the best CS approach in terms of molecule and dose for the intra‐articular injection of OA joints. Level of Evidence: Level I. [ABSTRACT FROM AUTHOR]

Abstract Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In light of the urgent need to identify novel approaches to be used in the emergency phase, we have embarked on an exploratory campaign aimed at repurposing natural substances and clinically available drugs as potential anti-SARS-CoV2-2 agents by targeting viral proteins. Here we report on a strategy based on the virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike's protein receptor binding domain (RBD). By combining an in silico approach and molecular in vitro testing we have been able to identify several triterpenoid/steroidal agents that inhibit interaction of the Spike RBD with the carboxypeptidase domain of the Angiotensin Converting Enzyme (ACE2). In detail, we provide evidence that potential binding sites exist in the RBD of the SARS CoV-2 Spike protein and that occupancy of these pockets reduces the ability of the RBD to bind to the ACE2 consensus in vitro. Naturally occurring and clinically available triterpenoids such as glycyrrhetinic and oleanolic acids, as well as primary and secondary bile acids and their amidated derivatives such as glyco-ursodeoxycholic acid and semi-synthetic derivatives such as obeticholic acid reduces the RBD/ACE2 binding. In aggregate, these results might help to define novel approaches to COVID-19 based on SARS-CoV-2 entry inhibitors.

Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.

In mammalian cells, telomerase transcribes telomeres in large G-rich non-coding RNA, known as telomeric repeat-containing RNA (TERRA), which folds into noncanonical nucleic acid secondary structures called G-quadruplexes (G4s). Since TERRA G4 has been shown to be involved in telomere length and translation regulation, it could provide valuable insight into fundamental biological processes, such as cancer growth, and TERRA G4 binders could represent an innovative strategy for cancer treatment. In this work, the three best candidates identified in our previous virtual screening campaign on bimolecular DNA/RNA G4s were investigated on the monomolecular Tel DNA and TERRA G4s by means of molecular modelling simulations and in vitro and in cell analysis. The results obtained in this work highlighted the stabilizing power of all the three candidates on TERRA G4. In particular, the two compounds characterized by a chromene scaffold were selective TERRA G4 binders, while the compound with a naphthyridine core acted as a dual Tel/TERRA G4-binder. A biophysical investigation by circular dichroism confirmed the relative stabilization efficiency of the compounds towards TERRA and Tel G4s. The TERRA G4 stabilizing hits showed good antiproliferative activity against colorectal and lung adenocarcinoma cell lines. Lead optimization to increase TERRA G4 stabilization may provide new powerful tools against cancer.

Binding of viral envelope glycoproteins (Env) to the host cell CD4 receptor mediates HIV-1 entry. Here, the authors develop compounds that inhibit the CD4-induced conformational changes in Env and show that the gp120 β20-β21 element is a key regulator for Env transitions.

Abstract Background Numerous studies have investigated the role of the dietary factors in the prevention of cognitive decline but the short-term effects of foods choice on cognitive performances in the elderly are poorly explored. Our aim was to investigate the choice of foods among elderly Italian individuals and the association with cognitive function. Methods In this longitudinal study, the participants were 214 individuals aged ≥65 years with a score >20 at the Mini Mental State Examination. The cognitive sub-test of ADAScale was used to detect cognitive decline progression over 12 months. Food choices was measured by a combination of a 24-h recall and a seven-day diet record and Principal Components Analysis. Results The Principal Components Analysis identified four food and four nutrient patterns. MMSE and ADAS-cog score after 1 year were found to be associated with legumes pattern (B = 0.25, p = 0.007; 95% CI 0.07/0.44; and B = −0.10, p = 0.006; CI −0.79/−0.30, respectively). A dietary pattern including plant proteins was independently associated with an improved ADAS-cog after 1 year (B = 0.584, p = 0.04; OR 1.79, CI 0.04–0.42). Conclusions The Principal Components Analysis is useful to investigate the choice of foods and nutrients in the elderly. We demonstrated an association between legumes pattern with cognitive performances.