Exploring the Biological and Phytochemical Potential of Jordan's Flora: A Review and Update of Eight Selected Genera from Mediterranean Region.

Jordan's flora is known for its rich diversity, with a grand sum of 2978 plant species that span 142 families and 868 genera across four different zones. Eight genera belonging to four different plant families have been recognized for their potential natural medicinal properties within the Mediterranean region. These genera include Chrysanthemum L., Onopordum Vaill. Ex. L., Phagnalon Cass., and Senecio L. from the Asteraceae family, in addition to Clematis L. and Ranunculus L. from the Ranunculaceae family, Anchusa L. from the Boraginaceae family, and Eryngium L. from the Apiaceae family. The selected genera show a wide variety of secondary metabolites with encouraging pharmacological characteristics including antioxidant, antibacterial, cytotoxic, anti-inflammatory, antidiabetic, anti-ulcer, and neuroprotective actions. Further research on these genera and their extracts will potentially result in the formulation of novel and potent natural pharmaceuticals. Overall, Jordan's rich flora provides a valuable resource for exploring and discovering new plant-based medicines.

In Vitro Cytotoxic Potential of Selected Jordanian Flora and Their Associated Phytochemical Analysis.

Traditional medicines are a significant source of phytochemicals with potential anticancer effects. Ten Jordanian plants were chosen to be tested for cytotoxicity on human colorectal (HT-29) and breast adenocarcinoma (MCF-7) cell lines. The ethanol extracts were screened for their potential cytotoxic effects using a Sulforhodamine B (SRB) colorimetric assay, using doxorubicin as positive control. Plants extracts exhibiting marked cytotoxic activity were further investigated by qualitative and quantitative phytochemical methods. Total phenolics were quantified using the Folin-Ciocalteu reagent, while flavonoids were quantified using aluminum chloride. The total saponins of the n-butanol fraction were estimated using diosgenin as a standard. The total alkaloids and total terpenoids were also evaluated using the gravimetric method. As results, Senecio leucanthemifolius (IC50: 13.84 µg/mL) and Clematis cirrhosa (IC50: 13.28 µg/mL) exhibited marked cytotoxic effects on human colorectal adenocarcinoma (HT-29) cell lines. Total phenolics, flavonoids, saponins, alkaloids, and terpenoids found in Senecio leucanthemifolius were (91.82, 14.90, 14.27, 101, and 135.4 mg/g of dry extract), respectively. They were revealed to be (68.18, 7.16, 31.25, 73.6, and 180 mg/g of dry extract) in Clematis cirrhosa, respectively. Senecio leucanthemifolius and Clematis cirrhosa have been found to possess cytotoxicity against colorectal (HT-29). In conclusion, the findings of this study offer a new perspective on Jordanian plant extracts anticancer activity research.

New insights into the role of berberine against 3-nitropropionic acid-induced striatal neurotoxicity: Possible role of BDNF-TrkB-PI3K/Akt and NF-κB signaling.

Berberine (Berb) is a major alkaloid with potential protective effects against multiple neurological disorders. Nevertheless, its positive effect against 3-nitropropionic acid (3NP) induced Huntington's disease (HD) modulation has not been fully elucidated. Accordingly, this study aimed to assess the possible action mechanisms of Berb against such neurotoxicity using an in vivo rats model pretreated with Berb (100 mg/kg, p.o.) alongisde 3NP (10 mg/kg, i.p.) at the latter 2 weeks to induce HD symptoms. Berb revealed its capacity to partially protect the striatum as mediated via the activation of BDNF-TrkB-PI3K/Akt signaling and amelioration of neuroinflammation status by blocking NF-κB p65 with a concomitant reduction in its downstream cytokines TNF-α and IL-1ß. Moreover, its antioxidant potential was evidenced from induction of Nrf2 and GSH levels concurrent with a reduction in MDA level. Furthermore, Berb anti-apoptotic effect was manifested through the induction of pro-survival protein (Bcl-2) and down-regulation of the apoptosis biomarker (caspase-3). Finally, Berb intake ascertained its striatum protective action by improving the motor and histopathological abnormalities with concomitant dopamine restoration. In conclusion, Berb appears to modulate 3NP-induced neurotoxicity by moderating BDNF-TrkB-PI3K/Akt signaling besides its anti-inflammatory, antioxidant, as well as anti-apoptotic effect.

Glycyrrhizin prevents 3-nitropropionic acid-induced neurotoxicity by downregulating HMGB1/TLR4/NF-κB p65 signaling, and attenuating oxidative stress, inflammation, and apoptosis in rats.

AIMS: Glycyrrhizin (Glyc) is a saponin triterpenoid that has signified its efficacy against Huntington's disease (HD). Nonetheless, its mechanism has not been fully clarified. Accordingly, this study was designed to evaluate the plausible mechanism of action of Glyc against 3-nitropropionic acid (3-NP)-induced HD. MAIN METHODS: Rats were treated with Glyc (50 mg/kg, i.p.) for 3 weeks and 3-NP (10 mg/kg, i.p.) was administered at the latter 2 weeks alongside to induce HD. KEY FINDINGS: Animals exposed to 3-NP revealed a reduction in body weight, neurobehavioral abnormalities, and various deleterious effects related to overexpression of HMGB1 such as oxidative stress, apoptosis, and inflammation. Promisingly, Glyc administration provided valuable effects by reversing the decline in body weight with improved neurobehavioral deficits. Ameliorating oxidative stress via restoring GSH, SOD, and Nrf2 alongside with MDA suppression was evident. Furthermore, Glyc switched the HMGB1/TLR4/NF-κB p65 signaling off, reduced IL-6, IL-ß, TNF-α, caspase-3, and increased Bcl-2 as well as BDNF. All these beneficial effects were mirrored by a better histopathological picture upon using Glyc that suppressed gliosis by reducing GFAP expression as observed in the immunohistochemistry results. SIGNIFICANCE: Accordingly, the current study demonstrated a promising neuroprotective effect of Glyc against experimentally induced HD through alleviating deleterious events by diverse mechanisms.

Upregulation of neuronal progranulin mediates the antinociceptive effect of trimetazidine in paclitaxel-induced peripheral neuropathy: Role of ERK1/2 signaling.

Neuronal progranulin (PGRN) overexpression is an endogenous adaptive pain defense following nerve injury. It allows the survival of injured neurons to block enhanced nociceptive responses. Trimetazidine (TMZ) is widely used by cardiac patients as an anti-anginal drug, reflecting its anti-ischemic property. TMZ promotes axonal regeneration of sciatic nerves after crush injury. This study explored the interplay between PGRN and extracellular signal-regulated kinases (ERK1/2) to address mechanisms underlying neuropathic pain alleviation following paclitaxel (PTX) administration. Rats were given four injections of PTX (2 mg/kg, i.p.) every other day. Two days after the last dose, rats received TMZ (25 mg/kg) with or without the ERK inhibitor, PD98059, daily for 21 days. TMZ preserved the integrity of myelinated nerve fibers, as evidenced by an obvious reduction in axonal damage biomarkers. Accordingly, it alleviated PTX-evoked thermal, cold, and mechanical hyperalgesia/allodynia. TMZ also promoted ERK1/2 phosphorylation with a profound upsurge in PGRN content. These effects were associated with a substantial increase in Notch1 receptor gene expression and a prominent anti-inflammatory effect with a marked increase in mRNA expression of secretory leukocyte protease inhibitor. Further, TMZ decreased oxidative stress and caspase-3 activity in the sciatic nerve. Conversely, co-administration of PD98059 completely abolished these beneficial effects. Thus, the robust antinociceptive effect of TMZ is largely attributed to upregulating PGRN and Notch1 receptors via ERK1/2 activation.

Berberine-loaded nanostructured lipid carriers mitigate warm hepatic ischemia/reperfusion-induced lesion through modulation of HMGB1/TLR4/NF-κB signaling and autophagy.

OBJECTIVE: Berberine (BBR) is a known alkaloid that has verified its protective effects against ischemia/reperfusion (I/RN) lesion in multiple organs but its poor oral bioavailability limited its use. Despite the previous works, its possible impact on the warm hepatic I/RN-induced lesion is not clear. Accordingly, a nanostructured lipid carrier of BBR (NLC BBR) was developed for enhancing its efficiency and to inspect its protective mechanistic against warm hepatic I/RN. METHODS: NLC BBR formula was evaluated pharmaceutically. Wistar rats were orally pre-treated with either BBR or NLC BBR (100 mg/kg) for 2 weeks followed by hepatic I/RN (30 min/24 h). Biochemical, ELISA, qPCR, western blot, histopathological, and immunohistochemical studies were performed. KEY FINDINGS: Optimized NLC BBR was prepared with a particle size of 130 ± 8.3 nm. NLC BBR divulged its aptitude to safeguard the hepatic tissues partly due to anti-inflammatory capacity through downsizing the HMGB1/TLR4/NF-κB trajectory with concomitant rebating of TNF-α, iNOS, COX-2, and MPO content. Furthermore, NLC BBR antiapoptotic trait was confirmed by boosting the prosurvival protein (Bcl-2) and cutting down the pro-apoptotic marker (Bax). Moreover, its antioxidant nature was confirmed by TAC uplifting besides MDA subsiding. On the other hand, NLC BBR action embroiled autophagy flux spiking merit exemplified in Beclin-1 and LC3-II enhancement. Finally, NLC BBR administration ascertained its hepatocyte guarding action by recovering the histopathological ailment and diminishing serum transaminases. CONCLUSION: NLC BBR purveyed reasonable shielding mechanisms and subsided incidents contemporaneous to warm hepatic I/RN lesion in part, by moderating HMGB1/TLR4/NF-κB inflammatory signaling, autophagy, and apoptosis.

Possible Implication of Nrf2, PPAR-γ and MAPKs Signaling in the Protective Role of Mangiferin against Renal Ischemia/Reperfusion in Rats.

Mangiferin (Mang) is a known glucosylxanthone that has proven its shielding effect against ischemia/reperfusion (Is/R). However, its full underlying mechanistic perspective against renal Is/R induced lesions is not fully revealed. Consequently, the purpose of this study is to track further non-investigated modulatory signals of Mang against the renal Is/R model involving nuclear factor erythroid 2-related factor (Nrf)2/heme oxygenase (HO)-1, peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling. To ratify our aim, Mang was administrated (20 mg/kg, i.p for seven days) before the induction of bilateral Is/R. Mechanistic maneuver revealed that Mang balanced oxidative state via increasing the expression of the antioxidant Nrf2/HO-1 cue with subsequent enhancement of GSH besides MDA lessening. Additionally, Mang enhanced PPAR-γ mRNA expression and declined p-p38 MAPK and p-JNK expression with concomitant NF-κB downsizing leading to iNOS/NOx and TNF-α rebating. Furthermore, the Mang anti-apoptotic trait was affirmed by enriching Bcl-2 expression as well as decreasing Bax and caspase-3 expression. All these potentials were in the line with the molecular docking results and the improved histopathological findings and renal function biomarkers. Consequently, Mang provided plausible protective mechanisms against renal Is/R-related events, possibly by amending oxidative status, inflammatory mediators, and apoptotic cell death through the involvement of Nrf2, PPAR-γ, MAPK, JNK, and NF-κB signaling.

Cilostazol mitigates mesenteric ischemia/reperfusion-induced lung lesion: Contribution of PPAR-γ, NF-κB, and STAT3 crosstalk.

AIMS: Cilostazol (Cilo), a phosphodiesterase-III inhibitor, has signified its efficacy against different ischemia/reperfusion (IS/RE) models. Nevertheless, it has not fully illuminated its potential effect against intestinal IS/RE-induced lung injury. Consequently, the study was fashioned to evaluate the feasible mechanism of action of Cilo against intestinal IS/RE-induced lung injury. MAIN METHODS: Wistar rats were treated with Cilo (0.1 g/kg, p.o.) or with a vehicle for 14 days prior to IS/RE, induced by clamping of the superior mesenteric artery for 30 min with subsequent clamp removal for 2 h. KEY FINDINGS: The mechanistic study disclosed that Cilo protected the two studied organs, viz., lung, and intestine partially by intensifying the expression/content of PPAR-γ accompanied by reducing the expression/content of NF-қB-p65 and STAT3. In addition to normalizing MDA, iNOS, and NOx, the Cilo antioxidant power was confirmed by intensifying tissues content of the total antioxidant capacity. With regard to the anti-inflammatory effect, Cilo reduced the effects of TNF-α, IL-6, and ICAM-1, which were reflected in MPO activity. Furthermore, Cilo had an anti-apoptotic attribute demonstrated by enhancing Bcl-2 content and lessening caspase-3 level. SIGNIFICANCE: Cilo provided conceivable protective mechanisms to modulate events concomitant with mesenteric IS/RE partly by modulating oxidative stress, inflammation, and apoptosis feasibly via the participation of PPAR-γ, STAT3, and NF-κB p65 signaling pathways.

The potential curative effect of rebamipide in hepatic ischemia/reperfusion injury.

Rebamipide (Reba), a gastroprotective drug, has signified its hepatoprotective activity; however, its possible post-therapeutic intervention in hepatic ischemia/reperfusion (I/R) remains elusive. Consequently, the intent of this study was to test Reba modulatory effect on nuclear factor (NF)-κB signaling in hepatic I/R model. Rats were randomized into sham, I/R, Reba 60, and Reba100 (60 and 100 mg/kg, respectively) groups. Ischemia was induced for 30 min followed by 3-day reperfusion to set up a model of partial (70%) warm hepatic ischemia. Post-treatment with Reba reduced the serum level of alanine transaminase, improved histopathological alterations of the liver, and elevated hepatic adenosine triphosphate. It also lowered hepatic lipid peroxides and increased both total antioxidant capacity and nitric oxide. Besides, Reba decreased tumor necrosis factor-α, interferon-γ, intercellular adhesion molecule-1, myeloperoxidase, prostaglandin E2, cyclooxygenase-2 expression/content, and caspase-3 activity. Reba also upregulated the gene expression/content of sirtuin 1 (SIRT-1), while it downregulated that of high mobility group box (HMGB)1 and reduced the expression/content of NF-κB p65/pS536-NF-κB and the content of pT180/Y182-p38MAPK. Reba provided tenable hepato-therapeutic mechanisms to mitigate events concomitant with hepatic I/R via inhibition of NF-κB p65 and modulation of its influential signals (SIRT-1, HMGB1, p38MAPK) associated with its antiinflammatory, antioxidant, and antiapoptotic impacts.