-
Cancer Diagnosis & Prognosis 2023One of the major hallmarks of many cancer cells is dedifferentiated cells (immature cells) with little or no resemblance to normal cells. Besides the poor... (Review)
Review
One of the major hallmarks of many cancer cells is dedifferentiated cells (immature cells) with little or no resemblance to normal cells. Besides the poor differentiation, malignant cells also have important features such as aggressiveness and resistance to different therapeutics. Differentiation potentiators hold great promise for cancer treatment. Dimethyl sulfoxide (DMSO) is a well-characterized pharmaceutical solvent. It is used as a component of numerous cancer therapeutic approaches, including cancer treatment and several approved cancer immune therapeutics such as Car-T cell therapy and the FDA-approved drug Mekinist (trametinib DMSO) for melanoma treatment. It is also biologically recognized as a pharmaceutical solvent and cryoprotectant. In the current literature, there are no mentions of DMSO's possible ability to potentiate therapeutic activity as a component of these cancer treatments. This review aimed to summarize scientific evidence and substantiate the concept that DMSO can contribute positively to the overall efficacy of cancer treatment as an adjuvant that is safe, inexpensive, and an effective differentiation-inducing therapeutic agent.
PubMed: 36632588
DOI: 10.21873/cdp.10172 -
Aging and Disease Aug 2021Neuroinflammation is a biological process by which the central nervous system responds to stimuli/injuries affecting its homeostasis. So far as this reactive response... (Review)
Review
Neuroinflammation is a biological process by which the central nervous system responds to stimuli/injuries affecting its homeostasis. So far as this reactive response becomes exacerbated and uncontrolled, it can lead to neurodegeneration, compromising the cognitive and neuropsychiatric domains. Parallelly, modifications in the hypothalamic signaling of neuroprotective hormones linked also to the inflammatory responses of microglia and astrocytes can exacerbate these processes. To complicate the picture, modulations in the gut microbiota (GM) can induce changes in neuroinflammation, altering cognitive and neuropsychiatric functioning. We conducted a web-based search on PubMed. We described studies regarding the cross-talk among microglia and astrocytes in the neuroinflammation processes, along with the role played by the steroid hormones, and how this can reflect on cognitive decline/neurodegeneration, in particular on Alzheimer's Disease (AD) and its neuropsychiatric manifestations. We propose and support the huge literature showing the potentiality of complementary/alternative therapeutic approaches (nutraceuticals) targeting the sustained inflammatory response, the dysregulation of hypothalamic system and the GM composition. NF-κB and Keap1/Nrf2 are the main molecular targets on which a list of nutraceuticals can modulate the altered processes. Since there are some limitations, we propose a new intervention natural treatment in terms of Oxygen-ozone (O-O) therapy that could be potentially used for AD pathology. Through a meta-analytic approach, we found a significant modulation of O on inflammation-NF-κB/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling, reducing mRNA (p<0.00001 Odd Ratio (OR)=-5.25 95% CI:-7.04/-3.46) and protein (p<0.00001 OR=-4.85 95%CI:-6.89/-2.81) levels, as well as on Keap1/Nrf2 pathway. Through anti-inflammatory, immune, and steroid hormones modulation and anti-microbial activities, O at mild therapeutic concentrations potentiated with nutraceuticals and GM regulators could determine combinatorial effects impacting on cognitive and neurodegenerative domains, neuroinflammation and neuroendocrine signalling, directly or indirectly through the mediation of GM.
PubMed: 34341712
DOI: 10.14336/AD.2021.0122 -
Frontiers in Pharmacology 2020The success of cancer therapy is often compromised by the narrow therapeutic index of many anticancer drugs and the occurrence of drug resistance. The association of... (Review)
Review
The success of cancer therapy is often compromised by the narrow therapeutic index of many anticancer drugs and the occurrence of drug resistance. The association of anticancer therapies with natural compounds is an emerging strategy to improve the pharmaco-toxicological profile of cancer chemotherapy. Sulforaphane, a phytochemical found in cruciferous vegetables, targets multiple pathways involved in cancer development, as recorded in different cancers such as breast, brain, blood, colon, lung, prostate, and so forth. As examples to make the potentialities of the association chemotherapy raise, here we highlight and critically analyze the information available for two associations, each composed by a paradigmatic anticancer drug (cisplatin or doxorubicin) and sulforaphane.
PubMed: 32425794
DOI: 10.3389/fphar.2020.00567 -
Experimental Neurology Nov 2020We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1...
We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects.
Topics: Agmatine; Animals; Antidepressive Agents; Dendrites; Dendritic Spines; Drug Synergism; Hindlimb Suspension; Ketamine; Male; Mice; Motor Activity; Oncogene Protein v-akt; Prefrontal Cortex; Ribosomal Protein S6 Kinases; Signal Transduction; Synapses
PubMed: 32659382
DOI: 10.1016/j.expneurol.2020.113398 -
Materials (Basel, Switzerland) May 2023One of the major impediments to the computational investigation and design of complex alloys such as steel is the lack of effective and versatile interatomic potentials...
One of the major impediments to the computational investigation and design of complex alloys such as steel is the lack of effective and versatile interatomic potentials to perform large-scale calculations. In this study, we developed an RF-MEAM potential for the iron-carbon (Fe-C) system to predict the elastic properties at elevated temperatures. Several potentials were produced by fitting potential parameters to the various datasets containing forces, energies, and stress tensor data generated using density functional theory (DFT) calculations. The potentials were then evaluated using a two-step filter process. In the first step, the optimized RSME error function of the potential fitting code, MEAMfit, was used as the selection criterion. In the second step, molecular dynamics (MD) calculations were employed to calculate ground-state elastic properties of structures present in the training set of the data fitting process. The calculated single crystal and poly-crystalline elastic constants for various Fe-C structures were compared with the DFT and experimental results. The resulting best potential accurately predicted the ground state elastic properties of B1, cementite, and orthorhombic-Fe7C3 (O-Fe7C3), and also calculated the phonon spectra in good agreement with the DFT-calculated ones for cementite and O-Fe7C3. Furthermore, the potential was used to successfully predict the elastic properties of interstitial Fe-C alloys (FeC-0.2% and FeC-0.4%) and O-Fe7C3 at elevated temperatures. The results were in good agreement with the published literature. The successful prediction of elevated temperature properties of structures not included in data fitting validated the potential's ability to model elevated-temperature elastic properties.
PubMed: 37241405
DOI: 10.3390/ma16103779 -
Frontiers in Fungal Biology 2022Fluconazole-resistant (FLZR-CP) outbreaks are a growing public health concern and have been reported in numerous countries. Patients infected with FLZR-CP isolates show...
Fluconazole-resistant (FLZR-CP) outbreaks are a growing public health concern and have been reported in numerous countries. Patients infected with FLZR-CP isolates show fluconazole therapeutic failure and have a significantly increased mortality rate. Because fluconazole is the most widely used antifungal agent in most regions with outbreaks, it is paramount to restore its antifungal activity. Milbemycin oxim (MOX), a well-known canine endectocide, is a potent efflux pump inhibitor that significantly potentiates the activity of fluconazole against FLZR . and . However, the FLZ-MOX combination has not been tested against FLZR-CP isolates, nor is it known whether MOX may also potentiate the activity of echinocandins, a different class of antifungal drugs. Furthermore, the extent of involvement of efflux pumps and and ergosterol biosynthesis enzyme and their link with gain-of-function (GOF) mutations in their transcription regulators (, , and ) are poorly characterized among FLZR-CP isolates. We analyzed 25 C. isolates collected from outbreaks in Turkey and Brazil by determining the expression levels of , , and , examining the presence of potential GOF mutations in their transcriptional regulators, and assessing the antifungal activity of FLZ-MOX and micafungin-MOX against FLZR and multidrug-resistant (MDR) . isolates. was found to be universally induced by fluconazole in all isolates, while expression of was unchanged. Whereas mutations in and were not detected, was overexpressed in three Brazilian FLZR-CP isolates, which also carried a novel mutation. Of these three isolates, one showed increased basal expression of , while the other two overexpressed only in the presence of fluconazole. Interestingly, MOX showed promising antifungal activity against FLZR isolates, reducing the FLZ MIC 8- to 32-fold. However, the MOX and micafungin combination did not exert activity against an MDR . isolate. Collectively, our study documents that the mechanisms underpinning FLZR are region specific, where mutations were the sole mechanism of FLZR in Turkish FLZR-CP isolates, while simultaneous overexpression of was observed in some Brazilian counterparts. Moreover, MOX and fluconazole showed potent synergistic activity, while the MOX-micafungin combination showed no synergy.
PubMed: 37746198
DOI: 10.3389/ffunb.2022.906681 -
BioRxiv : the Preprint Server For... Dec 2023The CXCL12-CXCR4 chemokine axis plays a significant role in modulating T-cell infiltration into the pancreatic tumor microenvironment. Despite promising preclinical...
PURPOSE
The CXCL12-CXCR4 chemokine axis plays a significant role in modulating T-cell infiltration into the pancreatic tumor microenvironment. Despite promising preclinical findings, clinical trials combining inhibitors of CXCR4 (AMD3100/BL-8040) and anti-programmed death 1/ligand1 (anti-PD1/PD-L1) have failed to improve outcomes.
EXPERIMENTAL DESIGN
We utilized a novel ex vivo autologous patient-derived immune/organoid (PDIO) co-culture system using human peripheral blood mononuclear cells and patient derived tumor organoids, and in vivo the autochthonous LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) pancreatic cancer mouse model to interrogate the effects of either monotherapy or all combinations of gemcitabine, AMD3100, and anit-PD1 on CD8+ T cell activation and survival.
RESULTS
We demonstrate that disruption of the CXCL12-CXCR4 axis using AMD3100 leads to increased migration and activation of CD8+ T-cells. In addition, when combined with the cytotoxic chemotherapy gemcitabine, CXCR4 inhibition further potentiated CD8+ T-cell activation. We next tested the combination of gemcitabine, CXCR4 inhibition, and anti-PD1 in the KPC pancreatic cancer mouse model and demonstrate that this combination markedly impacted the tumor immune microenvironment by increasing infiltration of natural killer cells, the ratio of CD8+ to regulatory T-cells, and tumor cell death while decreasing tumor cell proliferation. Moreover, this combination extended survival in KPC mice.
CONCLUSIONS
These findings suggest that combining gemcitabine with CXCR4 inhibiting agents and anti-PD1 therapy controls tumor growth by reducing immunosuppression and potentiating immune cell activation and therefore may represent a novel approach to treating pancreatic cancer.
PubMed: 38234792
DOI: 10.1101/2023.12.24.573257 -
BioRxiv : the Preprint Server For... Mar 2024While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility....
While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes is not known. We combine single cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.
PubMed: 37292824
DOI: 10.1101/2023.05.15.540704 -
Intestinal Research Apr 2020Patients with Crohn's disease (CD) commonly develop bowel strictures, which may contain various degrees of inflammation and fibrosis. While predominantly inflammatory... (Review)
Review
Patients with Crohn's disease (CD) commonly develop bowel strictures, which may contain various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment approach, fibrotic strictures would require endoscopic balloon dilation or surgery. Cross-sectional imaging surpasses endoscopy for characterization of stenotic segments and potentially may contribute to the optimal clinical management of these patients. This short review aims to discuss the potentialities and limitations of cross-sectional imaging techniques for assessing bowel fibrosis in patients with CD.
PubMed: 32326668
DOI: 10.5217/ir.2020.00015 -
The Journal of International Advanced... Jan 2023Migraine and vertigo are common complaints seen in clinical practice, and in a few such cases, we also find epileptic manifestations, including migraine-triggered...
Diagnosis of Patients Presenting with Vertigo, Headache, and Epileptic Seizure: Evaluating Vestibular Patients by Using Cervical Vestibular Evoked Myogenic Potential and Auditory Middle Latency Responses in the Clinical Setting.
Migraine and vertigo are common complaints seen in clinical practice, and in a few such cases, we also find epileptic manifestations, including migraine-triggered seizures. Currently, patients presenting with vertigo and headache are diagnosed according to established diagnostic criteria for Meniere's disease, vestibular migraine, or vestibular migraine/Meniere's disease overlapping syndrome. In addition to using those diagnostic criteria and the patient's history, cervical vestibular evoked myogenic potential and auditory middle latency responses are useful tools to better understand the physiological background of these patients and also to confirm the diagnosis. Here we report 2 cases: 1 of vestibular migraine/ Meniere's disease overlapping syndrome and 1 of vestibular migraine with epileptic manifestations. Each patient showed potentiation (lack of habituation) in auditory middle latency response, and each showed endolymphatic hydrops in cervical vestibular evoked myogenic potential. The potentiation in auditory middle latency response might be attributable to neuronal hyperexcitability in those patients with migraine or epilepsy, and neurogenic inflammation caused by migraine episodes might affect inner ear function.
Topics: Humans; Meniere Disease; Vestibular Evoked Myogenic Potentials; Vertigo; Vestibule, Labyrinth; Epilepsy; Seizures; Headache; Migraine Disorders
PubMed: 36718039
DOI: 10.5152/iao.2023.21457