Bee (Apis mellifera L. 1758) wax restores adipogenesis and lipid accumulation of 3T3-L1 cells in cancer-associated cachexia condition.

Cachexia is associated with various diseases, such as heart disease, infectious disease, and cancer. In particular, cancer-associated cachexia (CAC) accounts for more than 20% of mortality in cancer patients worldwide. Adipose tissue in CAC is characterized by adipocyte atrophy, mainly due to excessively increased lipolysis and impairment of adipogenesis. CAC is well known for the loss of skeletal muscle mass and/or fat mass. CAC induces severe metabolic alterations, including protein, lipid, and carbohydrate metabolism. The objectives of this study were to evaluate the effects of bee wax (Apis mellifera L. 1758) (BW) extract on adipogenesis, lipolysis, and mitochondrial oxygen consumption through white adipocytes, 3T3-L1. To achieve this study, cancer-associated cachexia condition was established by incubation of 3T3-L1 with colon cancer cell line CT26 cultured media. BW extract recovered the reduced adipogenesis under cachectic conditions in CT26 media. Treatment of BW showed increasing lipid accumulation as well as adipogenic gene expression and its target gene during adipogenesis. The administration of BW to adipocytes could decrease lipolysis. Also, BW could significantly downregulated the mitochondrial fatty acid oxidation-related genes, oxygen consumption rate, and extracellular acidification rate. Our results suggest that BW could improve metabolic disorders such as CAC through the activation of adipogenesis and inhibition of lipolysis in adipocytes, although we need further validation in vivo CAC model to check the effects of BW extract. Therefore, BW extract supplements could be useful as an alternative medicine to reverse energy imbalances.

Novel insights into regulators and functional modulators of adipogenesis.

Adipogenesis is a process that differentiates new adipocytes from precursor cells and is tightly regulated by several factors, including many transcription factors and various post-translational modifications. Recently, new roles of adipogenesis have been suggested in various diseases. However, the molecular mechanisms and functional modulation of these adipogenic genes remain poorly understood. This review summarizes the regulatory factors and modulators of adipogenesis and discusses future research directions to identify novel mechanisms regulating adipogenesis and the effects of adipogenic regulators in pathological conditions. The master adipogenic transcriptional factors PPARγ and C/EBPα were identified along with other crucial regulatory factors such as SREBP, Kroxs, STAT5, Wnt, FOXO1, SWI/SNF, KLFs, and PARPs. These transcriptional factors regulate adipogenesis through specific mechanisms, depending on the adipogenic stage. However, further studies related to the in vivo role of newly discovered adipogenic regulators and their function in various diseases are needed to develop new potent therapeutic strategies for metabolic diseases and cancer.

Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.

Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated ß-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.

Gonadal efficacy of Thymus quinquecostatus Celakovski: Regulation of testosterone levels in aging mouse models.

Late-onset hypogonadism (LOH) is an age-related disease in men characterized by decreased testosterone levels with symptoms such as decreased libido, erectile dysfunction, and depression. Thymus quinquecostatus Celakovski (TQC) is a plant used as a volatile oil in traditional medicine, and its bioactive compounds have anti-inflammatory potential. Based on this knowledge, the present study aimed to investigate the effects of TQC extract (TE) on LOH in TM3 Leydig cells and in an in vivo aging mouse model. The aqueous extract of T. quinquecostatus Celakovski (12.5, 25, and 50 µg/mL concentrations) was used to measure parameters such as cell viability, testosterone level, body weight, and gene expression, via in vivo studies. Interestingly, TE increased testosterone levels in TM3 cells in a dose-dependent manner without affecting cell viability. Furthermore, TE significantly increased the expression of genes involved in the cytochrome P450 family (Cyp11a1, Cyp17a1, Cyp19a1, and Srd5a2), which regulate testosterone biosynthesis. In aging mouse models, TE increased testosterone levels without affecting body weight and testicular tissue weight tissue of an aging animal group. In addition, the high-dose TE-treated group (50 mg/kg) showed significantly increased expression of the cytochrome p450 enzymes, similar to the in vitro results. Furthermore, HPLC-MS analysis confirmed the presence of caffeic acid and rosmarinic acid as bioactive compounds in TE. Thus, the results obtained in the present study confirmed that TQC and its bioactive compounds can be used for LOH treatment to enhance testosterone production.

Molecular Insights into Abiotic Stresses in Mango.

Mango (Mangifera indica L.) is one of the most economically important fruit crops across the world, mainly in the tropics and subtropics of Asia, Africa, and Central and South America. Abiotic stresses are the prominent hindrance that can adversely affect the growth, development, and significant yield loss of mango trees. Understanding the molecular physiological mechanisms underlying abiotic stress responses in mango is highly intricate. Therefore, to gain insights into the molecular basis and to alleviate the abiotic stress responses to enhance the yield in the mere future, the use of high-throughput frontier approaches should be tied along with the baseline investigations. Taking these gaps into account, this comprehensive review mainly speculates to provide detailed mechanisms and impacts on physiological and biochemical alterations in mango under abiotic stress responses. In addition, the review emphasizes the promising omics approaches in unraveling the candidate genes and transcription factors (TFs) responsible for abiotic stresses. Furthermore, this review also summarizes the role of different types of biostimulants in improving the abiotic stress responses in mango. These studies can be undertaken to recognize the roadblocks and avenues for enhancing abiotic stress tolerance in mango cultivars. Potential investigations pointed out the implementation of powerful and essential tools to uncover novel insights and approaches to integrate the existing literature and advancements to decipher the abiotic stress mechanisms in mango. Furthermore, this review serves as a notable pioneer for researchers working on mango stress physiology using integrative approaches.

Understanding the relationship between cancer associated cachexia and hypoxia-inducible factor-1.

Cancer-associated cachexia (CAC) is a multifactorial disorder characterized by an unrestricted loss of body weight as a result of muscle and adipose tissue atrophy. Cachexia is influenced by several factors, including decreased metabolic activity and food intake, an imbalance between energy uptake and expenditure, excessive catabolism, and inflammation. Cachexia is highly associated with all types of cancers responsible for more than half of cancer-related mortalities worldwide. In healthy individuals, adipose tissue significantly regulates energy balance and glucose homeostasis. However, in metastatic cancer patients, CAC occurs mainly because of an imbalance between muscle protein synthesis and degradation which are organized by certain extracellular ligands and associated signaling pathways. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1α) accumulated and translocated to the nucleus and activate numerous genes involved in cell survival, invasion, angiogenesis, metastasis, metabolic reprogramming, and cancer stemness. On the other hand, the ubiquitination proteasome pathway is inhibited during low O2 levels which promote muscle wasting in cancer patients. Therefore, understanding the mechanism of the HIF-1 pathway and its metabolic adaptation to biomolecules is important for developing a novel therapeutic method for cancer and cachexia therapy. Even though many HIF inhibitors are already in a clinical trial, their mechanism of action remains unknown. With this background, this review summarizes the basic concepts of cachexia, the role of inflammatory cytokines, pathways connected with cachexia with special reference to the HIF-1 pathway and its regulation, metabolic changes, and inhibitors of HIFs.

Unlocking Prognostic Genes and Multi-Targeted Therapeutic Bioactives from Herbal Medicines to Combat Cancer-Associated Cachexia: A Transcriptomics and Network Pharmacology Approach.

Cachexia is a devastating fat tissue and muscle wasting syndrome associated with every major chronic illness, including cancer, chronic obstructive pulmonary disease, kidney disease, AIDS, and heart failure. Despite two decades of intense research, cachexia remains under-recognized by oncologists. While numerous drug candidates have been proposed for cachexia treatment, none have achieved clinical success. Only a few drugs are approved by the FDA for cachexia therapy, but a very low success rate is observed among patients. Currently, the identification of drugs from herbal medicines is a frontier research area for many diseases. In this milieu, network pharmacology, transcriptomics, cheminformatics, and molecular docking approaches were used to identify potential bioactive compounds from herbal medicines for the treatment of cancer-related cachexia. The network pharmacology approach is used to select the 32 unique genes from 238 genes involved in cachexia-related pathways, which are targeted by 34 phytocompounds identified from 12 different herbal medicines used for the treatment of muscle wasting in many countries. Gene expression profiling and functional enrichment analysis are applied to decipher the role of unique genes in cancer-associated cachexia pathways. In addition, the pharmacological properties and molecular interactions of the phytocompounds were analyzed to find the target compounds for cachexia therapy. Altogether, combined omics and network pharmacology approaches were used in the current study to untangle the complex prognostic genes involved in cachexia and phytocompounds with anti-cachectic efficacy. However, further functional and experimental validations are required to confirm the efficacy of these phytocompounds as commercial drug candidates for cancer-associated cachexia.

Global proteomic analysis deciphers the mechanism of action of plant derived oleic acid against Candida albicans virulence and biofilm formation.

Candida albicans is a commensal fungus in humans, mostly found on the mucosal surfaces of the mouth, gut, vagina and skin. Incidence of ever increasing invasive candidiasis in immunocompromised patients, alarming occurrence of antifungal resistance and insufficient diagnostic methods demand more focused research into C. albicans pathogenicity. Consequently, in the present study, oleic acid from Murraya koenigii was shown to have the efficacy to inhibit biofilm formation and virulence of Candida spp. Results of in vitro virulence assays and gene expression analysis, impelled to study the protein targets which are involved in the molecular pathways of C. albicans pathogenicity. Proteomic studies of differentially expressed proteins reveals that oleic acid induces oxidative stress responses and mainly targets the proteins involved in glucose metabolism, ergosterol biosynthesis, lipase production, iron homeostasis and amino acid biosynthesis. The current study emphasizes anti-virulent potential of oleic acid which can be used as a therapeutic agent to treat Candida infections.

Synergistic Effect of Quinic Acid Derived From Syzygium cumini and Undecanoic Acid Against Candida spp. Biofilm and Virulence.

In recent decades, fungal infections have incredibly increased with Candida genus as the major cause of morbidity and mortality in hospitalized and immunocompromised patients. Most of the Candida species are proficient in biofilm formation on implanted medical devices as well as human tissues. Biofilm related Candida infections are very difficult to treat using common antifungal agents owing to their increased drug resistance. To address these issues, the present study investigated the antibiofilm and antivirulent properties of Syzygium cumini derived quinic acid in combination with known antifungal compound undecanoic acid. Initially, antibiofilm potential of S. cumini leaf extract was assessed and the active principles were identified through gas chromatography and mass spectrometry analysis. Among the compounds identified, quinic acid was one of the major compounds. The interaction between quinic acid and undecanoic acid was found to be synergistic in the Fractional inhibitory concentration index (≤0.5). Results of in vitro assays and gene expression analysis suggested that the synergistic combinations of quinic acid and undecanoic acid significantly inhibited virulence traits of Candida spp. such as the biofilm formation, yeast-to-hyphal transition, extracellular polymeric substances production, filamentation, secreted hydrolases production and ergosterol biosynthesis. In addition, result of in vivo studies using Caenorhabditis elegans demonstrated the non-toxic nature of QA-UDA combination and antivirulence effect against Candida spp. For the first time, synergistic antivirulence ability of quinic acid and undecanoic acid was explored against Candida spp. Thus, results obtained from the present study suggest that combination of phytochemicals might be used an alternate therapeutic strategy for the prevention and treatment of biofilm associated Candida infection.

Green synthesized silver nanoparticles demonstrating enhanced in vitro and in vivo antibiofilm activity against Candida spp.

Candida species are opportunistic fungal pathogens, which are known for their biofilm associated infections on implanted medical devices in clinical settings. Broad spectrum usage of azole groups and other antifungal agents leads to the occurrence of drug resistance among Candida species. Most of the antifungal agents have failed to treat the biofilm mediated Candida infections. In the present study, silver nanoparticles (AgNPs) were synthesized using Dodonaea viscosa and Hyptis suoveolens methanolic leaf extracts and characterized by ultraviolet-visible absorption spectroscopy, X-ray diffraction analysis, Fourier transform infrared spectroscopy and Scanning electron microscopy, Dynamic light scattering, and Zeta potential analysis. The main goal of this study was to assess the AgNPs for their antibiofilm efficacy against Candida spp. through microscopic analysis and in vitro virulence assays. The results revealed that AgNPs strongly inhibited more than 80% biofilm formed by Candida spp. Furthermore, the AgNPs also reduced the yeast-to-hyphal transition, exopolysaccharide biosynthesis, secreted aspartyl proteinase production which are the major virulence factors of Candida species. This study reveals that biosynthesized AgNPs can be considered for the treatment of biofilm related Candida infections.

Usnic acid inhibits biofilm formation and virulent morphological traits of Candida albicans.

Biofilm formation and the yeast to hyphal switch are considered to be important virulence factors of Candida albicans. The present study reports about the potential of usnic acid, a lichen secondary metabolite inhibiting these virulent factors. Usnic acid, at its biofilm inhibitory concentration (BIC) largely reduced the viability of the metabolically active cells in matured C. albicans biofilms, exhibited significant biofilm inhibition (65%) and prevented the property of adhesion. Light microscopic images revealed that usnic acid effectively inhibited the yeast to hyphal switch and confocal microscopy showed that usnic acid greatly reduced the thickness of matured biofilms. Furthermore, usnic acid was able to reduce various sugars present in the exopolysaccharide layer (EPS) which was also confirmed by FT-IR analysis. Taken together, the present study showcases usnic acid as a potent anti-virulent compound against C. albicans and opens up a new avenue for bioprospecting lichen secondary metabolites as anti-virulent compounds.

Usnic acid, a lichen secondary metabolite inhibits Group A Streptococcus biofilms.

Group A Streptococci (GAS) are involved in a number of life threatening diseases and biofilm formation by these pathogens are considered as an important virulence determinant as it mediates antibiotic resistance among them. In the present study, we have explored the ability of (+)-usnic acid, a lichen secondary metabolite, as an antibiofilm agent against four serotypes of Streptococcus pyogenes causing pharyngitis. Usnic acid inhibited the biofilms of M serotypes M56, st38, M89 efficiently and the biofilm of M74 to a lesser extent. Confocal imaging of the treated samples showed that usnic acid reduced the biomass of the biofilms when compared to that of the control. Fourier Transfer Infrared (FT-IR) spectroscopy indicated that usnic acid reduced the cellular components (proteins and fatty acids) of the biofilms. Interestingly, the FT-IR spectrum further revealed that usnic acid probably acted upon the fatty acids of the biofilms as evident from the disappearance of a peak at 2,455-2,100 cm(-1) when compared to the control only in serotypes M56, st38 and M89 but not in M74. The present study shows, for the first time, that usnic acid can act as an effective antibiofilm agent against GAS.

Inhibition of Candida albicans virulence factors by novel levofloxacin derivatives.

Candida albicans is an important opportunistic fungal pathogen, responsible for biofilm associated infections in immunocompromised patients. The aim of the present study was to investigate the antibiofilm properties of novel levofloxacin derivatives on C. albicans biofilms. The levofloxacin derivatives at their Biofilm Inhibitory Concentrations (BIC) were able to inhibit the biofilms of C. albicans, the yeast-to-hyphal transition and were also able to disrupt their mature biofilms. Furthermore, Real-time PCR analysis showed that the expression of ergosterol biosynthesis pathway gene (ERG11) and the efflux pump-encoding genes (CDR1 and MDR1) was decreased upon treatment with the levofloxacin derivatives. The total ergosterol content quantified using UV spectrophotomer showed decrease in ergosterol in the presence of levofloxacin derivatives. Overall, levofloxacin derivatives (6a, 6c and 7d) are capable of inhibiting C. albicans virulence factors. Therefore, these compounds with potential therapeutic implications can be used as new strategy to treat biofilm-related candidal infections.