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The chemical composition of cactus pear seed oil (Opuntia ficus-indica [L.] Mill.) was analyzed in terms of its fatty acid composition, tocopherol content, phenolic identification, and the oil's phenolic-rich fraction antioxidant power was determined.Fatty acid profiling was performed by gas chromatography coupled to an FI detector. Tocopherols and phenolic compounds were analyzed by LC-FLD/UV, and the oil's phenolic-rich fraction antioxidant power was determined by phosphomolybdenum, DPPH assay and β-carotene bleaching test.Fatty acid composition was marked by a high unsaturation level (83.22 ± 0.34%). The predominant fatty acid was linoleic acid (66.79 ± 0.78%), followed by oleic acid (15.16 ± 0.42%) and palmitic acid (12.70 ± 0.03%). The main tocopherol was γ-tocopherol (172.59 ± 7.59 mg/kg. In addition, Tyrosol, vanillic acid, vanillin, ferulic acid, pinoresinol, and cinnamic acid were identified as phenolic compounds in the analyzed seed oil. Moreover, the oil's phenolics-rich fraction showed a significant total antioxidant activity, scavenged DPPH up to 97.85%, and effectively protected β-carotene against bleaching (97.56%).The results support the potential use of cactus pear seed oil as a functional food.

Opuntia dillenii is a medicinal plant with frequent usage in folk medicine to treat many illnesses. The present study aims to investigate the protective effect of Opuntia dillenii seed oil against gentamicin-induced nephrotoxicity in rats. The animals (rats) were randomly divided into three groups (i) the normal control group treated only with distilled water (10 mL/kg), (ii) the gentamicin group treated with distilled water (10 mL/kg) and received an intraperitoneal injection of gentamicin (80 mg/kg), and (iii) the group treated with the Opuntia dillenii seed oil (2 mL/kg) and also received an intraperitoneal injection of gentamicin (80 mg/kg). The rats received their following treatments for 14 consecutive days orally. Serum urea, creatinine, gamma-glutamyl transferase, albumin, and electrolyte levels were quantified as the markers of acute renal and liver failure. Besides, the kidney and liver relative weight, kidney malondialdehydes, and kidney histological analysis were determined. The results have shown that daily pretreatment with Opuntia dillenii seed oil (2 mL/kg) prevented severe alterations of biochemical parameters and disruptions of kidney tissue structures. In addition, the results of the present study showed for the first time that Opuntia dillenii seed oil reduced renal toxicity in gentamicin-induced nephrotoxicity in rats. Therefore, Opuntia dillenii seed oil may represent a new therapeutic avenue to preserve and protect renal function in gentamicin-treated patients.

This study aims to assess the safety of the Opuntia dillenii (Ker-Gawl) haw. seed oil (ODSO) and its effect on the glucose absorption activity of the isolated rat hemidiaphragm. This oil’s safety was studied by exploring its acute (doses 1, 3, 5, and 7 mL/kg) and subacute (doses 1 and 2 mL/kg) toxicities in albino mice and Wistar rats, respectively. The safety of the ODSO was also assessed by studying its effect on the HepG2 cell viability in vitro. The effect of ODSO, or combined with the insulin, on the glucose absorption activity of isolated rat hemidiaphragm was evaluated at the dose 1 g/L in vitro. The results demonstrated the safety of ODSO. Indeed, this study showed that this oil does not produce any mortality or signs of toxicity after the single-dose administration in mice. Additionally, the daily intake of the ODSO during four weeks does not induce a significant variation in the biochemical parameters and body weight of rats compared with the control group. Besides, the cell viability of HepG2 did not change in the presence of ODSO. On the other hand, the ODSO increased the glucose absorption activity of the isolated rat hemidiaphragm, and this activity was significantly enhanced when combined with insulin. This study confirms, on one side, the safety of this oil and its efficacy and, on the other side, encourages its potential use as a complement to treat diabetes.

A key aspect to consider for vaccinal protection is the induction of a local line of defense consisting of nonrecirculating tissue-resident memory T cells (TRM), in parallel to the generation of systemic memory CD8+ T cell responses. The potential to induce TRM has now been demonstrated for a number of pathogens and viral vectors. This potential, however, has never been tested for recombinant adeno-associated virus (rAAV) vectors, which are weakly inflammatory and poor transducer of dendritic cells. Using a model rAAV2/1-based vaccine, we determined that a single intradermal immunization with rAAV2/1 vectors in mice induces fully functional TRM at the local site of immunization. The optimal differentiation of rAAV-induced transgene-specific skin TRM was dependent on local transgene expression and additional CD4+ T cell help. Transgene expression in dendritic cells, however, appeared to be dispensable for the priming of transgene-specific skin TRM, suggesting that this process solely depends on the cross-presentation of transgene products. Overall, this study provides needed information to properly assess rAAV vectors as T cell-inducing vaccine carriers.IMPORTANCE rAAVs display numerous characteristics that could make them extremely attractive as vaccine carriers, including an excellent safety profile in humans and great flexibility regarding serotypes and choice of target tissue. Studies addressing the ability of rAAV to induce protective T cell responses, however, are scarce. Notably, the potential to induce a tissue-resident memory T cell response has never been described for rAAV vectors, strongly limiting further interest for their use as vaccine carriers. Using a model rAAV2/1 vaccine delivered to the skin, our study demonstrated that rAAV vectors can induce bona fide skin resident TRM and provides additional clues regarding the cellular mechanisms underlying this process. These results will help widen the field of rAAV applications.

Thanks to the analysis of an Interspecific Recombinant Congenic Strain (IRCS), we previously defined the Mafq1 quantitative trait locus as an interval on mouse Chromosome 1 associated with male hypofertility and ultrastructural abnormalities. We identified the Spermatogenesis associated protein 3 gene (Spata3 or Tsarg1) as a pertinent candidate within the Mafq1 locus and performed the CRISPR-Cas9 mediated complete deletion of the gene to investigate its function. Male mice deleted for Spata3 were normally fertile in vivo but exhibited a drastic reduction of efficiency in in vitro fertilization assays. Mobility parameters were normal but ultrastructural analyses revealed acrosome defects and an overabundance of lipids droplets in cytoplasmic remnants. The deletion of the Spata3 gene reproduces therefore partially the phenotype of the hypofertile IRCS strain.

Glycylation regulates axonemal dyneins Physiological functions of the microtubule cytoskeleton are expected to be regulated by a variety of posttranslational tubulin modifications. For instance, tubulin glycylation is almost exclusively found in cilia and flagella, but its role in the function of these organelles remains unclear. Gadadhar et al. now demonstrate in mice that glycylation, although nonessential for the formation of cilia and flagella, coordinates the beat waveform of sperm flagella. This activity is a prerequisite for progressive sperm swimming and thus for male fertility. At the ultrastructural level, lack of glycylation perturbed the distribution of axonemal dynein conformations, which may explain the observed defects in flagellar beat. Science , this issue p. eabd4914

Origanum genus is one of the most widely used herbs in folk medicine for its biological properties. The present investigation aims to characterize, for the first time, endemic Origanum grosii collected from the Taounate region, Morocco. This characterization was realized by determining the concentration of metals in different parts of the plant (flowers, leaves, and stems) by ICP-MS, and the results were studied statistically by Principal Component Analysis (PCA). Phytochemical screening with the dosage of polyphenols and flavonoids has been conducted. To know more about this species, antihyperglycemic tests have been performed to highlight the presence or absence of the antidiabetic effect for this plant. An Oral Glucose Tolerance Test (OGTT) has been performed on normal mice which were divided into two groups of six mice each. Group 1 (control group) was treated with distilled water, and group 2 was treated with an aqueous extract of O. grosii by gavage at 150 mg/kg. Digestive enzyme α-amylase inhibition assay has also been evaluated to study the inhibition effect of the studied extract using acarbose as a control. The results showed that the leaves exhibited a high concentration of trace elements (Ca, Mg, and K) and total absence of heavy metals, which were found in small quantities (Cr, Ni, and B) on the stems, and this makes the plant safe to use. On the other hand, tannins, flavonoids, triterpenes, and steroids were the major families strongly present in this species. The antidiabetic results showed that O. grosii have significantly reduced postprandial hyperglycemia after glucose loading in normal rats. It showed also that this species has a significant antihyperglycemic activity reflected by the inhibition of α-amylase. The one responsible for this property could be the synergy between the trace elements and the nature of the chemical families of O. grosii species, which can make this plant useful in the management of postprandial hyperglycemia.

Objective. In Morocco, Thymelaea hirsuta (T. hirsuta) (Thymelaeacea) is a medicinal plant widely used to treat and prevent diabetes. The present study aimed to evaluate the medium-term antidiabetic effect of aqueous extract (AqTh) and ethyl acetate fraction (EaTh) of Th and to investigate their putative protective effect on pancreatic islet degeneration, diabetic nephropathy, and liver damages in streptozotocin (STZ)-diabetic rats. Methods. Experimental diabetes in rats was induced by a single intraperitoneal injection of 50 mg/kg of STZ. During the treatment period (4 weeks), 200 mg/kg AqTh and 50 mg/kg EaTh were orally administrated daily to STZ-diabetic rats. A group of parameters including fasting blood glucose, biochemical parameters, and intestinal α-glucosidase inhibition were studied. Furthermore, histological study of the pancreas, kidney, liver, and aorta was also realized. Results. At the end of the treatment, both AqTh and EaTh had normalized fasting blood glucose to 1.08 and 1.25 g/l, respectively. AqTh has also reduced urinary creatinine and HbAc1. The EaTh showed inhibitory activity against intestinal α-glucosidase, whereas AqTh did not have this inhibitory effect. Furthermore, pancreas hematoxylin and eosin staining showed that AqTh or EaTh prevents pancreatic islet cell degeneration. As the same kidney, Masson’s trichrome staining has shown a significant prevention of renal fibrosis in AqTh- or EaTh-treated diabetic rats. On the other hand, liver hematoxylin and eosin staining showed that AqTh and EaTh prevent liver damage. Conclusion. We conclude that medium-term administration of AqTh and EaTh exerts significant antihyperglycemic effect in STZ-diabetic rats possibly through intestinal α-glucosidase inhibition and protection against pancreatic islet cell damage. Moreover, AqTh and EaTh treatment prevent nephropathy and liver complications in STZ-diabetic rats.

The present study aims to evaluate the hepatoprotective activity of stem aqueous extract of Caralluma europaea (AECe) on carbon tetrachloride- (CCl4-) induced hepatic damage in Wistar rats. The animals were daily treated with the aqueous extract of C. europaea at a dose of 250 mg/kg body weight for 14 days. CCl4 was injected (1 ml/kg, i.p.) two times, on the 7th and 14th days. At the end of the experimental period, all rats were anesthetized to collect blood for the assessment of biochemical parameters and then sacrificed to collect the liver for weighing. Hepatotoxicity was evaluated by measuring the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin (total and direct), malondialdehyde (MDA), total protein (TP), triglycerides (TG), total cholesterol, very low-density lipoprotein (VLDL-c ), low-density lipoprotein (LDL-c), high-density lipoprotein (HDL-c), urea, creatinine, and uric acid. Based on the results obtained in this study, the administration of C. europaea before exposure to the administration of CCl4 conferred favorable hepatoprotective effect in rats. The treatment with AECe (250 mg/kg) exhibits a significant hepatoprotective effect by ameliorating CCl4-induced alterations of these biochemical parameters. Hence, C. europaea could be a potential medicinal herb that can be used in the future to prevent liver intoxication.

Ethnopharmacological relevance Origanum majorana L. (Lamiaceae) was usually used in Moroccan folk medicine to treat infantile colic and abdominal discomfort. Materials and methods The essential oil from the aerial part of the dry Origanum majorana L. (EOOM) was obtained through hydro distillation and analyzed by gas chromatography/mass spectrometry (GC/MS). The effect of EOOM on muscle relaxation was measured on rabbit and rat intestinal smooth muscle mounted in an isotonic transducer. Results 1) The main compounds obtained from the aqueous extract of this plant were alpha Terpineol, L-terpinen-4-ol and Beta.-Linalool. 2) EOOM inhibited in a concentration-dependent manner spontaneous contraction of rabbit jejunum, with an IC50 = 64.08 ± 2.42 μg/mL. 3) In rat intestine, EOOM induced the relaxation of the tissue in concentration-dependent manner with an IC50 = 39.70 ± 2.29 μg/mL when the tissue was pre-contracted with CCh 10-6 M, and 48.70 ± 2.26 μg/mL when the tissue was pre-contracted with 25 mM KCl. 4) The relaxation effect induced by EOOM was more important than that obtained in the presence of atropine, hexamethonium, Nifedipine, L-NAME and Blue of methylene. Conclusion the present result indicates that essential oil of Origanum majorana L. exhibit an effect on intestinal relaxation in vitro. This effect further validates the traditional use of Origanum majorana L. to treat infantile colic and abdominal discomfort.

International audience; Clathrin plaques are stable features of the plasma membrane observed in several cell types. They are abundant in muscle, where they localize at costameres that link the contractile apparatus to the sarcolemma and connect the sarcolemma to the basal lamina. Here, we show that clathrin plaques and surrounding branched actin filaments form microdomains that anchor a three-dimensional desmin intermediate filament (IF) web. Depletion of clathrin plaque and branched actin components causes accumulation of desmin tangles in the cytoplasm. We show that dynamin 2, whose mutations cause centronuclear myopathy (CNM), regulates both clathrin plaques and surrounding branched actin filaments, while CNM-causing mutations lead to desmin disorganization in a CNM mouse model and patient biopsies. Our results suggest a novel paradigm in cell biology, wherein clathrin plaques act as platforms capable of recruiting branched cortical actin, which in turn anchors IFs, both essential for striated muscle formation and function.

At present, the clinically most advanced strategy to treat Duchenne muscular dystrophy (DMD) is the exon-skipping strategy. Whereas antisense oligonucleotide-based clinical trials are underway for DMD, it is essential to determine the dystrophin restoration threshold needed to ensure improvement of muscle physiology at the molecular level. A preclinical trial has been conducted in golden retriever muscular dystrophy (GRMD) dogs treated in a forelimb by locoregional delivery of rAAV8-U7snRNA to promote exon skipping on the canine dystrophin messenger. Here, we exploited rAAV8-U7snRNA-transduced GRMD muscle samples, well characterized for their percentage of dystrophin-positive fibers, with the aim of defining the threshold of dystrophin rescue necessary for normalization of the status of neuronal nitric oxide synthase mu (nNOSμ), inducible nitric oxide synthase (iNOS), and ryanodine receptor-calcium release channel type 1 (RyR1), crucial actors for efficient contractile function. Results showed that restoration of dystrophin in 40% of muscle fibers is needed to decrease abnormal cytosolic nNOSμ expression and to reduce overexpression of iNOS, these two parameters leading to a reduction in the NO level in the muscle fibers. Furthermore, the same percentage of dystrophin-positive fibers of 40% was associated with the normalization of RyR1 nitrosylation status and with stabilization of the RyR1-calstabin1 complex that is required to facilitate coupled gating. We concluded that a minimal threshold of 40% of dystrophin-positive fibers is necessary for the reinstatement of central proteins needed for proper muscle contractile function, and thus identified a rate of dystrophin expression significantly improving, at the molecular level, the dystrophic muscle physiology.

The objective was to study the effect of Calamintha officinalis methanolic fraction in the prevention of thrombosis and to explore its effect on primary and secondary hemostasis. The antithrombotic activity was evaluated by using the pulmonary thromboembolism experimental model. Platelet aggregation, tail bleeding time and coagulation assays were explored to elucidate the antithrombotic mechanism. For aggregation, washed platelets were incubated in presence of Calamintha officinalis methanolic fraction and then activated by different agonists (thrombin, ADP, collagen). The bleeding time was determined to measure the time between the tail incision and the moment the bleeding stops. The coagulation was explored by measuring prothrombin time, activated partial thromboplastin time, thrombin time and plasmatic fibrinogen concentration. For ex vivo study, the animals were treated by the Calamintha officinalis methanolic fraction (250 mg/kg/day) for 4 weeks. Then, platelet aggregation, tail bleeding time and coagulation parameters was studied. The results indicate that C. officinalis methanol fraction seems to exert in vivo an antithrombotic action (40% of protection). The in vitro investigations also show that this fraction significantly inhibits aggregation, increases bleeding time, coagulation times and reduces fibrinogen concentration. The chronic treatment of animals confirms the precedent data. This study demonstrates an antithrombotic effect of C. officinalis. The observed antiaggregant and anticoagulant effects could explain this activity.

Many medicinal plants around the world are used for therapeutic purposes against several diseases, including diabetes mellitus. Due to their composition of natural substances that are effective and do not represent side effects for users, unlike synthetic drugs, in this study, we investigated the inhibitory effect of Caralluma europaea (CE) on α-glucosidase activity in vitro; then the kinetics of the enzyme were studied with increasing concentrations of sucrose in order to determine the inhibition type of the enzyme. In addition, this effect of Caralluma europaea (CE) was confirmed in vivo using rats as an experimental animal model. Among the five fractions of CE, only the ethyl acetate fraction of C. europaea (EACe) induced a significant inhibition of α-glucosidase and its inhibition mode was competitive. The in vivo studies were conducted on mice and rats using glucose and sucrose as a substrate, respectively, to determine the oral glucose tolerance test (OGTT). The results obtained showed that the EACe and the aqueous extract of C. europaea (AECe) have significantly reduced the postprandial hyperglycemia after sucrose and glucose loading in normal and diabetic rats. AECe, also, significantly decreased intestinal glucose absorption, in situ. The results obtained showed that Caralluma europaea has a significant antihyperglycemic activity, which could be due to the inhibition of α-glucosidase activity and enteric absorption of glucose.

International audience; We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcripts. We developed 5 0-RNA pretrans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level. Further analyses performed in primary myotubes derived from an LMNA-related congenital muscular dystrophy (L-CMD) mouse model led to a partial rescue of the mutant phenotype. Finally, we tested this approach in vivo using adeno-associated virus (AAV) delivery in newborn mice and showed that trans-splicing events occurred in WT mice 50 days after AAV delivery, although at a low rate. Altogether, while these results provide the first evidence for reprogramming LMNA mRNA in vitro, strategies to improve the rate of trans-splicing events still need to be developed for efficient application of this therapeutic approach in vivo.