Levodopa is the most widely used medication for the symptomatic treatment of Parkinson\'s disease and, despite being an \"old\" drug, is still considered the gold standard for offering symptomatic relief. The pharmacokinetic and pharmacodynamics of levodopa have been studied extensively. Our review explores the molecular mechanisms that affect the absorption of this drug, focusing on the large intra- and interindividual variability of absorption that is commonly encountered in daily clinical practice, and on the interaction with other medications. In addition, we will explore the clinical implications of levodopa absorption variability and address current and future strategies for researchers and clinicians.

Cardiotoxicity is a serious challenge cancer patients face today. Various factors are involved in cardiotoxicity. Circular RNAs (circRNAs) are one of the effective factors in the occurrence and prevention of cardiotoxicity. circRNAs can lead to increased proliferation, apoptosis, and regeneration of cardiomyocytes by regulating the molecular pathways, as well as increasing or decreasing gene expression; some circRNAs have a dual role in cardiomyocyte regeneration or death. Identifying each of the pathways related to these processes can be effective on managing patients and preventing cardiotoxicity. In this study, an overview of the molecular pathways involved in cardiotoxicity by circRNAs and their effects on the downstream factors have been discussed.

OBJECTIVE: This study aimed to find global mechanisms related to carnosine synthesis in slow-growing Korat chickens (KRC) using a proteomic approach.
METHODS: M. pectoralis major samples were collected from 10-week-old female KRC including low-carnosine (LC, 2,756.6±82.88 μg/g; n = 5) and high-carnosine (HC, 4,212.5 ±82.88 μg/g; n = 5).
RESULTS: We identified 152 common proteins, and 8 of these proteins showed differential expression between the LC and HC groups (p<0.05). Heat shock 70 kDa protein 8, Heat shock 70 kDa protein 2, protein disulfide isomerase family A, member 6, and endoplasmic reticulum resident protein 29 were significantly involved in protein processing in the endoplasmic reticulum pathway (false discovery rate<0.05), suggesting that the pathway is related to differential carnosine concentration in the M. pectoralis major of KRC. A high concentration of carnosine in the meat is mainly involved in low abundances of Titin isoform Ch12 and Connectin and high abundances of M-protein to maintain homeostasis during muscle contraction. These consequences improve meat characteristics, which were confirmed by the principal component analysis.
CONCLUSIONS: Carnosine synthesis may occur when muscle cells need to recover homeostasis after being interfered with carnosine synthesis precursors, leading to improved muscle function. To the best of our knowledge, this is the first study to describe in detail the global molecular mechanisms in divergent carnosine contents in meat based on the proteomic approach.

Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma.

Cancer refers to the proliferation and multiplication of aberrant cells inside the human body, characterized by their capacity to proliferate and infiltrate various anatomical regions. Numerous biochemical pathways and signaling molecules have an impact on the cancer auto biogenesis process. The regulation of crucial cellular processes necessary for cell survival and proliferation, which are triggered by phytochemicals, is significantly influenced by signaling pathways. These pathways or components are regulated by phytochemicals. Medicinal plants are a significant reservoir of diverse anticancer medications employed in chemotherapy. The anticancer effects of phytochemicals are mediated by several methods, including induction of apoptosis, cessation of the cell cycle, inhibition of kinases, and prevention of carcinogenic substances. This paper analyzes the phytochemistry of seven prominent plant constituents, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins, focusing on the involvement of the MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, and actin dynamics. Hence, this review has examined a range of phytochemicals, encompassing their structural characteristics and potential anticancer mechanisms. It has underscored the significance of plant-derived bioactive compounds in the prevention of cancer, utilizing diverse molecular pathways. In addition, this endeavor also seeks to incentivize scientists to carry out clinical trials on anticancer medications derived from plants.

GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient\'s iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy.

OBJECTIVE: To determine the dysregulated signaling pathways of head and neck squamous cell carcinoma associated with circulating tumor cells (CTCs) via single-cell molecular characterization.
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) has a significant global burden and is a disease with poor survival. Despite trials exploring new treatment modalities to improve disease control rates, the 5 year survival rate remains low at only 60%. Most cancer malignancies are reported to progress to a fatal phase due to the metastatic activity derived from treatment-resistant cancer cells, regarded as one of the most significant obstacles to develope effective cancer treatment options. However, the molecular profiles of cancer cells have not been thoroughly studied.
METHODS: Here, we examined in-situ HNSCC tumors and pairwisely followed up with the downstream circulating tumor cells (CTCs)-based on the surrogate biomarkers to detect metastasis that is established in other cancers - not yet being fully adopted in HNSCC treatment algorithms.
RESULTS: Specifically, we revealed metastatic HNSCC patients have complex CTCs that could be defined through gene expression and mutational gene profiling derived from completed single-cell RNASeq (scRNASeq) that served to confirm molecular pathways inherent in these CTCs. To enhance the reliability of our findings, we cross-validated those molecular profiles with results from previously published studies.
CONCLUSIONS: Thus, we identified 5 dysregulated signaling pathways in CTCs to derive HNSCC biomarker panels for screening HNSCC in situ tumors.
ObjectivesInvestigating the dysregulated signaling pathways of head and neck squamous cell carcinoma (HNSCC) linked with circulating tumor cells (CTCs) using single-cell molecular characterization.IntroductionHNSCC poses a significant global health burden with poor survival rates despite advancements in treatment. Metastatic activity from treatment-resistant cancer cells remains a major challenge in developing effective treatments. However, the molecular profiles of cancer cells, particularly CTCs, are not well-understood.MethodsWe analyzed in-situ HNSCC tumors and corresponding CTCs using surrogate biomarkers to detect metastasis, a technique not widely used in HNSCC treatment protocols.ResultsOur study revealed complex CTCs in metastatic HNSCC patients characterized by gene expression and mutational gene profiling via single-cell RNASeq (scRNASeq). These profiles confirmed molecular pathways inherent in CTCs, further validated by previous research.ConclusionThrough our research, we identified five dysregulated signaling pathways in CTCs, suggesting potential biomarker panels for HNSCC screening in situ tumors.

Traumatic brain injury (TBI) is a leading cause of disability worldwide, with an estimated annual incidence of 27-69 million. TBI is a severe condition that can lead to high mortality rates and long-term cognitive, behavioral, and physical impairments in young adults. It is a significant public health concern due to the lack of effective treatments available. Quercetin, a natural flavonoid found in various fruits and vegetables, has demonstrated therapeutic potential with anti-inflammatory, antioxidant, and neuroprotective properties. Recently, some evidence has accentuated the ameliorating effects of quercetin on TBI. This review discusses quercetin\'s ability to reduce TBI-related damage by regulating many cellular and molecular pathways. Quercetin in vitro and in vivo studies exhibit promise in reducing inflammation, oxidative stress, apoptosis, and enhancing cognitive function post-TBI. Further clinical investigation into quercetin\'s therapeutic potential as a readily available adjuvant in the treatment of TBI is warranted in light of these findings. This review adds to our knowledge of quercetin\'s potential in treating TBI by clarifying its mechanisms of action.

Pancreatic cancer is one of the most aggressive, heterogeneous, and fatal types of human cancer; therefore, more effective therapeutic drugs are urgently needed. Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been identified as a cornerstone in this pathology. The aim of this review is to identify HER2 membrane overexpression in relation to pancreatic cancer pathways that can be used in order to develop a targeted therapy. After searching the keywords, 174 articles were found during a time span of 10 years, between 2013 and 2023, but only twelve scientific papers were qualified for this investigation. The new era of biomolecular research found a significant relationship between HER2 overexpression and pancreatic cancer cells in 25-30% of cases. The variables are dependent on tumor-derived cells, with differences in receptor overexpression between PDAC (pancreatic ductal adenocarcinoma), BTC (biliary tract cancer), ampullary carcinoma, and PNETs (pancreatic neuroendocrine tumors). HER2 overexpression is frequently encountered in human pancreatic carcinoma cell lines, and the ERBB family is one of the targets in the near future of therapy, with good results in phase I, II, and III studies evaluating downregulation and tumor downstaging, respectively.

Elevated plasma fibrinogen (Fg) levels consistently correlate with an unfavorable prognosis in various tumor patient cohorts. Within the tumor microenvironment, aberrant deposition and expression of Fg have been consistently observed, interacting with multiple cellular receptors and thereby accentuating its role as a regulator of inflammatory processes. Specifically, Fg serves to stimulate and recruit immune cells and pro-inflammatory cytokines, thereby contributing to the promotion of tumor progression. Additionally, Fg and its fragments exhibit dichotomous effects on tumor angiogenesis. Notably, Fg also facilitates tumor migration through both platelet-dependent and platelet-independent mechanisms. Recent studies have illuminated several tumor-related signaling pathways influenced by Fg. This review provides a comprehensive summary of the intricate involvement of Fg in tumor biology, elucidating its multifaceted role and the underlying mechanisms.