Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression. Full article

The transmembrane glycoprotein mucin 1 (MUC1) is a mucin family member that has different functions in normal and cancer cells. Owing to its structural and biochemical properties, MUC1 can act as a lubricant, moisturizer, and physical barrier in normal cells. However, in cancer cells, MUC1 often undergoes aberrant glycosylation and overexpression. It is involved in cancer invasion, metastasis, angiogenesis, and apoptosis by virtue of its participation in intracellular signaling processes and the regulation of related biomolecules. This review introduces the biological structure and different roles of MUC1 in normal and cancer cells and the regulatory mechanisms governing these roles. It also evaluates current research progress and the clinical applications of MUC1 in cancer therapy based on its characteristics. Full article

Several medical plants, such as Passiflora incarnata L., contain C-glycosylated flavonoids, which may contribute to their efficacy. Information regarding the bioavailability and metabolism of these compounds is essential, but not sufficiently available. Therefore, the metabolism of the C-glycosylated flavones orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin was investigated using the Caco-2 cell line as an in vitro intestinal and epithelial metabolism model. Isovitexin, orientin, and isoorientin showed broad ranges of phase I and II metabolites containing hydroxylated, methoxylated, and sulfated compounds, whereas schaftoside, isoschaftoside, and vitexin underwent poor metabolism. All metabolites were identified via UHPLC-MS or UHPLC-MS/MS using compound libraries containing all conceivable metabolites. Some structures were confirmed via UHPLC-MS experiments with reference compounds after a cleavage reaction using glucuronidase and sulfatase. Of particular interest is the observed cleavage of the C–C bonds between sugar and aglycone residues in isovitexin, orientin, and isoorientin, resulting in unexpected glucuronidated or sulfated luteolin and apigenin derivatives. These findings indicate that C-glycosidic flavones can be highly metabolized in the intestine. In particular, flavonoids with ortho-dihydroxy groups showed sulfated metabolites. The identified glucuronidated or sulfated aglycones demonstrate that enzymes expressed by Caco-2 cells are able to potentially cleave C–C bonds in vitro. Full article

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53^MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53^WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma. Full article

Osteoporosis is a chronic disease characterized by low bone mass caused by increased bone turnover and impaired bone microarchitecture. In treatment, we use antiresorptive or anabolic drugs, which usually have a unidirectional effect, i.e., they inhibit the activity of osteoclasts or stimulate the effect of osteoblasts. Strontium ranelate is an anti-osteoporosis drug with a unique mechanism of action (used primarily in postmenopausal women). Unlike other medicines, it has a multidirectional effect on bone tissue, intensifying osteoblastogenesis while inhibiting osteoclastogenesis. It turns out that this effect is demonstrated by strontium ions, an element showing physical and chemical similarity to calcium, the basic element that builds the mineral fraction of bone. As a result, strontium acts through the calcium-sensing receptor (CaSR) receptor in bone tissue cells. In recent years, there has been a significant increase in interest in the introduction of strontium ions in place of calcium ions in ceramics used as bone replacement materials for the treatment of bone fractures and defects caused by osteoporosis. The aim of this study was to summarize current knowledge about the role of strontium in the treatment of osteoporosis, its effects (in various forms), and the ways in which it is administered. Full article

Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling. Full article

Hydrogen Sulfide (H₂S), an endogenously produced gasotransmitter, is involved in various important physiological and disease conditions, including vasodilation, stimulation of cellular bioenergetics, anti-inflammation, and pro-angiogenesis. In cancer, aberrant up-regulation of H₂S-producing enzymes is frequently observed in different cancer types. The recognition that tumor-derived H₂S plays various roles during cancer development reveals opportunities to target H₂S-mediated signaling pathways in cancer therapy. In this review, we will focus on the mechanism of H₂S-mediated protein persulfidation and the detailed information about the dysregulation of H₂S-producing enzymes and metabolism in different cancer types. We will also provide an update on mechanisms of H₂S-mediated cancer progression and summarize current options to modulate H₂S production for cancer therapy. Full article

Psoriasis (PSO) is a common skin disease that affects about 1%–3% of the general population. It is a great medical, social and economic burden since PSO is associated with many comorbidities, of which the most common are cardiometabolic disorders. Psoriatic patients suffer more frequently from obesity, dyslipidemia, atherosclerosis, and nonalcoholic fatty liver disease. Research shows that lipid expression and metabolism disorders are present more often in such patients. This review focuses on a variety of aberrations in lipids in the skin, blood, and adipose tissue in psoriatic patients and their multifactorial impact on the pathogenesis of psoriasis. Full article

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget’s “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed. Full article

The aim of the study was to quantify the micro-architectural changes of the jaw bone in response to ovariectomy, exposed or not to bisphosphonate treatment. A total of 47 Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and exposed to osteoporosis preventive treatment for eight weeks either with bisphosphonates (alendronate, ALN; group OVX-ALN) three days/week at a dose of 2 mg/kg or with saline solution (untreated control condition; group OVX). The bone morphometric parameters of the trabecular jaw bone were assessed using ex vivo micro-computed tomography. The regions of interest investigated in the maxilla were the inter-radicular septum of the second molar and the tuber. The regions quantified in the mandible included the three molar regions and the condyle. A one-way analysis of variance followed by pairwise comparison using Tukey’s HSD and the Games–Howell test was conducted to explore significant differences between the groups. In the maxilla, OVX decreased the bone volume in the inter-radicular septum of the second molar. Bisphosphonate treatment was able to prevent this deterioration of the jaw bone. The other investigated maxillary regions were not affected by (un)treated ovariectomy. In the mandible, OVX had a significant negative impact on the jaw bone in the buccal region of the first molar and the inter-radicular region of the third molar. Treatment with ALN was able to prevent this jaw bone loss. At the condyle site, OVX significantly deteriorated the trabecular connectivity and shape, whereas preventive bisphosphonate treatment showed a positive effect on this trabecular bone region. No significant results between the groups were observed for the remaining regions of interest. In summary, our results showed that the effects of ovariectomy-induced osteoporosis are manifested at selected jaw bone regions and that bisphosphonate treatment is capable to prevent these oral bone changes. Full article

The COVID-19 pandemic caused by SARS-CoV-2 coronavirus deeply affected the world community. It gave a strong impetus to the development of not only approaches to diagnostics and therapy, but also fundamental research of the molecular biology of this virus. Fluorescence microscopy is a powerful technology enabling detailed investigation of virus–cell interactions in fixed and live samples with high specificity. While spatial resolution of conventional fluorescence microscopy is not sufficient to resolve all virus-related structures, super-resolution fluorescence microscopy can solve this problem. In this paper, we review the use of fluorescence microscopy to study SARS-CoV-2 and related viruses. The prospects for the application of the recently developed advanced methods of fluorescence labeling and microscopy—which in our opinion can provide important information about the molecular biology of SARS-CoV-2—are discussed. Full article

Gastrodia elata is a well-known medicinal and heterotrophic orchid. Its germination, limited by the impermeability of seed coat lignin and inhibition by abscisic acid (ABA), is triggered by symbiosis with fungi such as Mycena spp. However, the molecular mechanisms of lignin degradation by Mycena and ABA biosynthesis and signaling in G. elata remain unclear. In order to gain insights into these two processes, this study analyzed the transcriptomes of these organisms during their dynamic symbiosis. Among the 25 lignin-modifying enzyme genes in Mycena, two ligninolytic class II peroxidases and two laccases were significantly upregulated, most likely enabling Mycena hyphae to break through the lignin seed coats of G. elata. Genes related to reduced virulence and loss of pathogenicity in Mycena accounted for more than half of annotated genes, presumably contributing to symbiosis. After coculture, upregulated genes outnumbered downregulated genes in G. elata seeds, suggesting slightly increased biological activity, while Mycena hyphae had fewer upregulated than downregulated genes, indicating decreased biological activity. ABA biosynthesis in G. elata was reduced by the downregulated expression of 9-cis-epoxycarotenoid dioxygenase (NCED-2), and ABA signaling was blocked by the downregulated expression of a receptor protein (PYL12-like). This is the first report to describe the role of NCED-2 and PYL12-like in breaking G. elata seed dormancy by reducing the synthesis and blocking the signaling of the germination inhibitor ABA. This study provides a theoretical basis for screening germination fungi to identify effective symbionts and for reducing ABA inhibition of G. elata seed germination. Full article

ATP-binding cassette (ABC) transporter proteins are a gene super-family in plants and play vital roles in growth, development, and response to abiotic and biotic stresses. The ABC transporters have been identified in crop plants such as rice and buckwheat, but little is known about them in soybean. Soybean is an important oil crop and is one of the five major crops in the world. In this study, 255 ABC genes that putatively encode ABC transporters were identified from soybean through bioinformatics and then categorized into eight subfamilies, including 7 ABCAs, 52 ABCBs, 48 ABCCs, 5 ABCDs, 1 ABCEs, 10 ABCFs, 111 ABCGs, and 21 ABCIs. Their phylogenetic relationships, gene structure, and gene expression profiles were characterized. Segmental duplication was the main reason for the expansion of the GmABC genes. Ka/Ks analysis suggested that intense purifying selection was accompanied by the evolution of GmABC genes. The genome-wide collinearity of soybean with other species showed that GmABCs were relatively conserved and that collinear ABCs between species may have originated from the same ancestor. Gene expression analysis of GmABCs revealed the distinct expression pattern in different tissues and diverse developmental stages. The candidate genes GmABCB23, GmABCB25, GmABCB48, GmABCB52, GmABCI1, GmABCI5, and GmABCI13 were responsive to Al toxicity. This work on the GmABC gene family provides useful information for future studies on ABC transporters in soybean and potential targets for the cultivation of new germplasm resources of aluminum-tolerant soybean. Full article

Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C-terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in humans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function. Full article

Hollow nerve guidance conduits are approved for clinical use for defect lengths of up to 3 cm. This is because also in pre-clinical evaluation they are less effective in the support of nerve regeneration over critical defect lengths. Hydrogel luminal fillers are thought to improve the regeneration outcome by providing an optimized matrix inside bioartificial nerve grafts. We evaluated here a modified hyaluronic acid-laminin-hydrogel (M-HAL) as luminal filler for two clinically approved hollow nerve guides. Collagen-based and chitosan-based nerve guides were filled with M-HAL in two different concentrations and the regeneration outcome comprehensively studied in the acute repair rat sciatic nerve 15 mm critical defect size model. Autologous nerve graft (ANG) repair served as gold-standard control. At 120 days post-surgery, all ANG rats demonstrated electrodiagnostically detectable motor recovery. Both concentrations of the hydrogel luminal filler induced improved regeneration outcome over empty nerve guides. However, neither combination with collagen- nor chitosan-based nerve guides resulted in functional recovery comparable to the ANG repair. In contrast to our previous studies, we demonstrate here that M-HAL slightly improved the overall performance of either empty nerve guide type in the critical defect size model. Full article