Targeting the key players of phenotypic plasticity in cancer cells by phytochemicals.

Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed.

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

Capsaicin: A chili pepper bioactive phytocompound with a potential role in suppressing cancer development and progression.

Cancer profoundly influences morbidity and fatality rates worldwide. Patients often have dismal prognoses despite recent improvements in cancer therapy regimens. However, potent biomolecules derived from natural sources, including medicinal and dietary plants, contain biological and pharmacological properties to prevent and treat various human malignancies. Capsaicin is a bioactive phytocompound present in red hot chili peppers. Capsaicin has demonstrated many biological effects, including antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic capabilities. This review highlights the cellular and molecular pathways through which capsaicin exhibits antineoplastic activities. Our work also depicts the synergistic anticancer properties of capsaicin in conjunction with other natural bioactive components and approved anticancer drugs. Capsaicin inhibits proliferation in various cancerous cells, and its antineoplastic actions in numerous in vitro and in vivo carcinoma models impact oncogenesis, tumor-promoting and suppressor genes, and associated signaling pathways. Capsaicin alone or combined with other phytocompounds or approved antineoplastic drugs triggers cell cycle progression arrest, generating reactive oxygen species and disrupting mitochondrial membrane integrity, ultimately stimulating caspases and promoting death. Furthermore, capsaicin alone or in combination can promote apoptosis in carcinoma cells by enhancing the p53 and c-Myc gene expressions. In conclusion, capsaicin alone or in combination can have enormous potential for cancer prevention and intervention, but further high-quality studies are needed to firmly establish the clinical efficacy of this phytocompound.

Osteopathic manipulative treatment for chronic inflammatory diseases.

Chronic inflammatory diseases (CIDs) are debilitating and potentially lethal illnesses that affect a large proportion of the global population. Osteopathic manipulative treatment (OMT) is a manual therapy technique developed and performed by osteopathic physicians that facilitates the body's innate healing processes. Therefore, OMT may prove a beneficial anti-inflammatory modality useful in the management and treatment of CIDs. This work aims to objectively evaluate the therapeutic benefits of OMT in patients with various CIDs. In this review, a structured literature search was performed. The included studies involving asthma, chronic obstructive pulmonary disease, irritable bowel syndrome, ankylosing spondylitis, and peripheral arterial disease were selected for this work. Various OMT modalities, including lymphatic, still, counterstain, and muscle energy techniques, were utilized. Control treatments included sham techniques, routine care, or no treatment. OMT utilization led to variable patient outcomes in individuals with pathologies linked to CID.

Targeting Peroxisome Proliferator-Activated Receptor-ß/δ, Reactive Oxygen Species and Redox Signaling with Phytocompounds for Cancer Therapy.

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-ß/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-ß/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-ß/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-ß/δ.

Pomegranate (Punica granatum L.) phytochemicals target the components of metabolic syndrome.

Pomegranate (Punica granatum L.) is a multipurpose dietary and medicinal plant known for its ability to promote various health benefits. Metabolic syndrome (MetS) is a complex metabolic disorder driving health and socioeconomic challenges worldwide. It may be characterized by insulin resistance, abdominal obesity, hypertension, and dyslipidemia. This study aims to conduct a review of pomegranate's effects on MetS parameters using a mechanistic approach relying on pre-clinical studies. The peel, juice, roots, bark, seeds, flowers, and leaves of the fruit present several bioactive compounds that are related mainly to anti-inflammatory and antioxidant activities as well as cardioprotective, antidiabetic, and antiobesity effects. The use of the juice extract can work as a potent inhibitor of angiotensin-converting enzyme activities, consequently regulating blood pressure. The major bioactive compounds found within the fruit are phenolic compounds (hydrolysable tannins and flavonoids) and fatty acids. Alkaloids, punicalagin, ellagitannins, ellagic acid, anthocyanins, tannins, flavonoids, luteolin, and punicic acid are also present. The antihyperglycemia, antihyperlipidemia, and weight loss promoting effects are likely related to the anti-inflammatory and antioxidant effects. When considering clinical application, pomegranate extracts are found to be frequently well-tolerated, further supporting its efficacy as a treatment modality. We suggest that pomegranate fruit, extract, or processed products can be used to counteract MetS-related risk factors. This review represents an important step towards exploring potential avenues for further research in this area.

Synergistic enhancement: Exploring the potential of piperine in cancer therapeutics through chemosensitization and combination therapies.

Despite significant advancements in chemotherapy, effective treatments for advanced cancer stages remain largely elusive due to chemoresistance. Resistance to anticancer agents in cancer cells can arise through various mechanisms, including multi-drug resistance, inhibition of apoptosis, modification of drug targets, and enhancement of DNA repair capabilities. Consequently, there is a critical need for agents that can suppress the molecular signatures responsible for drug resistance. Piperine, an active alkaloid extracted from Piper nigrum L. (black pepper), is one such agent that has been extensively studied for its potential in addressing chronic diseases, including cancer. Piperine's antineoplastic properties are mediated through the regulation of numerous key cellular signaling pathways and the modulation of various biological processes. Its capability to enhance drug bioavailability and counteract mechanisms of drug resistance, such as the inhibition of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP-1), emphasizes its potential as an adjunct in cancer therapy. Research across various cancer types has demonstrated piperine's role in chemosensitization by targeting P-gp and MRP-1 and altering drug-metabolizing enzymes. This review provides a comprehensive analysis of piperine's pharmacological characteristics and its capacity to modulate several cellular signaling pathways involved in drug resistance. Furthermore, the review emphasizes how piperine, when used in conjunction with other chemotherapeutic agents or natural compounds, can enhance therapeutic effects, leading to improved outcomes in cancer treatment.

Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment.

BACKGROUND: Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential. PURPOSE: The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA. METHODS: Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities. CONCLUSION: BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound.

Litchi (Litchi chinensis Sonn.): A comprehensive and critical review on cancer prevention and intervention.

Litchi (Litchi chinensis Sonn.) is a tropical fruit with various health benefits. The objective of this study is to present a thorough analysis of the cancer preventive and anticancer therapeutic properties of litchi constituents and phytocompounds. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis criteria were followed in this work. Various litchi extracts and constituents were studied for their anticancer effects. In vitro studies showed that litchi-derived components reduced cell proliferation, induced cytotoxicity, and promoted autophagy via increased cell cycle arrest and apoptosis. Based on in vivo studies, litchi flavonoids and other extracted constituents significantly reduced tumor size, number, volume, and metastasis. Major signaling pathways impacted by litchi constituents were shown to stimulate proapoptotic, antiproliferative, and antimetastatic activities. Despite promising antineoplastic activities, additional research, especially in vivo and clinical studies, is necessary before litchi-derived products and phytochemicals can be used for human cancer prevention and intervention.