Research in Pharmaceutical Sciences最新文献

Background and purpose: Stress, especially immobility stress, is quite common and one of the most important and influential risk factors in neurological disorders. This study aimed to investigate the effect of acute and chronic immobility stress on the level of cortical and hippocampal oxidative stress indicators and memory impairment following global cerebral ischemia.

Experimental approach: In this study, 48 male Wistar rats were randomly divided into 6 groups: 1, sham (S); 2, sham-acute stress (SSA); 3, sham-chronic stress (SSC); 4, ischemia (IS); 5, ischemia-acute stress (ISA); 6, ischemia-chronic stress (ISC). The Morris water maze (MWM) test was performed 14 days after surgery, and cortisol levels and oxidative stress factors such as malondialdehyde MDA and total thiol were measured.

Findings/results: In the MWM test, the time to find the platform (latency time) in the ISC and IS groups significantly increased compared to the S group. The time spent in the target quarter in these two groups was significantly reduced compared to the S group on the day of the probe. The results showed a significant increase in cortisol levels and malondialdehyde concentration in the ISA, ISC, and IS groups compared to the S group, but there was no significant difference in total thiol concentration. No significant difference was observed in the level of oxidative stress factors in the cortex.

Conclusion and implication: Chronic immobility stress could reduce antioxidant factors in the hippocampus and exacerbate memory impairment caused by global ischemia.

Background and purpose: Experimental and clinical studies have shown the potential role of progesterone in relieving neural injury. In addition, emerging data on vitamin D, a steroid hormone, have shown its neuroprotective properties. This study was designed to evaluate the mutual effect of vitamin D and progesterone on neuropathic pain (NP) in male rats.

Experimental approach: Chronic constriction injury (CCI) was induced by inserting four ligatures around the sciatic nerve. Hyperalgesia and allodynia (cold and mechanical) were considered positive behavioral scores of NP. After surgery, Sprague Dawley male rats (weighing 200-250 g) were assigned into 7 groups. Vitamin D (250 and 500 units/kg/day, i.p.) and progesterone (4 and 6 mg/kg/day, i.p.) were injected from the 1^st day after CCI which continued for 21 days. Moreover, one group received the co-administration of vitamin D (500 units/kg/day, i.p.) and progesterone (6 mg/kg/day, i.p.) from the 1^st day until the 21^st post-CCI day. Behavioral tests were performed on the 7^th, 14^th, and 21^st days.

Findings/results: Daily supplementation with vitamin D (250 and 500 units/kg) did not alter nociception. Progesterone (4 and 6 mg/kg/day) was ineffective on thermal hyperalgesia. In the allodynia test, progesterone significantly decreased pain-related behaviors. The co-administration of vitamin D (500 units/kg/day) with progesterone (6 mg/kg/day) significantly relieved thermal hyperalgesia. Finally, the combination significantly decreased cold and mechanical allodynia.

Conclusion and implications: This study showed the mutual effect of progesterone and vitamin D on NP for the first time. Hyperalgesia and allodynia were significantly relieved following co-administration of vitamin D and progesterone.

Background and purpose: Chronic consumption of morphine (Mor) induces tolerance and dependence. This study aimed to survey the effects of pistachio extract (PX) on the induction and expression of Mor analgesic tolerance and physical dependency in mice.

Experimental approach: Animals were randomly separated into six groups (n = 7): control, DMSO, Mor (10 mg/kg), Mor + saline, Mor + PX (10 mg/kg), and Mor + PX (100 mg/kg). Mor was injected (10 mg/kg, twice a day, s.c.) for 7 days to induce tolerance. PX was administered (10 and 100 mg/kg, orally) during the examination period. On each day and 20 min after Mor administration, a tail-flick test was done to measure the analgesic response and induction of tolerance. On day 7, naloxone (5 mg/kg, s.c.) was injected into the Mor-dependent animals to evaluate dependence, and animals were monitored for 30 min for jumping. Also, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were assessed in the brain tissue.

Findings/results: Our results indicated that co-administration of PX with Mor for 7 days diminished the induction of Mor tolerance. PX administration for 7 days alongside Mor reduced the frequency of withdrawal signs in naloxone-injected animals during dependence induction. Also, Mor increased the level of MDA and decreased the activities of SOD and GPx. Treatment with PX (100 mg/kg) restored all of the mentioned abnormalities.

Conclusion and implications: According to the results presented in this study, chronic administration of PX forbade the induction of Mor analgesic tolerance and dependency in mice.

Background and purpose: As an endogenous antioxidant, bilirubin has surprisingly been inversely correlated with the risk of non-alcoholic fatty liver disease (NAFLD). Thereupon, the current evaluation was designed to assess the positive effects of bilirubin on the autophagy flux, as well as the other pathogenic processes and parameters involved in the expansion of NAFLD.

Experimental approach: Thirty adult male rats weighing 150-200 g with free access to sucrose solution (18%) were randomly subdivided into 5 groups (n = 6). Subsequently, the animals were euthanized, and their blood specimens and liver tissue samples were collected to measure serum biochemical indices, liver histopathological changes, intrahepatic triglycerides content, and tissue stereological alterations. Furthermore, the expression levels of autophagy-related genes (Atgs) were measured to assess the state of the autophagy flux.

Findings/results: Fasting blood glucose, body weight, as well as liver weight, liver-specific enzyme activity, and serum lipid profile indices markedly decreased in rats that underwent a six-week bilirubin treatment compared to the control group. In addition, histopathological studies showed that hepatic steatosis, fibrosis, inflammation, and necrosis significantly decreased in the groups that received bilirubin compared to the control animals. Bilirubin also caused significant alterations in the expression levels of the Atgs, as well as the Beclin- 1 protein.

Conclusion and implication: Bilirubin may have potential ameliorative effects on NAFLD-associated liver damage. Moreover, the beneficial effects of bilirubin on intrahepatic lipid accumulation and steatosis were comparable with the group that did not ever receive bilirubin.

Background and purpose: Glioblastoma (GBM) is an aggressive and malignant brain cancer with the highest mortality and low survival rates. To discover a more specific and efficient treatment for GBM, we synthesized and examined the cytotoxic effect of arazyme-interleukin-13 (Ara-IL13) fusion protein on GBM cells.

Experimental approach: At first, the araA-IL13 chimeric gene in the pET28a (+) vector was designed and synthesized. After transformation into Escherichia coli BL21 (DE3), the chimeric gene was verified by colony polymerase chain reaction. Expression optimization and purification of the AraA-IL13 fusion protein was performed and subsequently evaluated by 10% SDS-PAGE. The protein was purified and concentrated using the Amicon^® Ultra- 15 centrifugal filter unit. The presence of AraA-IL13 was investigated by the western blotting technique. The enzyme was evaluated for proteolytic activity after purification on skim milk agar. The cytotoxic effect of the AraA-IL13 fusion protein was evaluated by MTT assay on U251 and T98G cell lines in vitro.

Findings/results: The chimeric protein had no proteolytic activity on skim milk agar despite high expression. Furthermore, no cytotoxic effect of this fusion protein (up to 400 μg/mL) was observed on the U251 and T98G cell lines.

Conclusion and implications: The lack of proteolytic activity and cytotoxic effect of AraA-IL13 may be due to the disruption of the three-dimensional structure of the protein or the large structure of the arazyme coupled with the ligand and the lack of proper folding of the arazyme to make the active site of the enzyme inaccessible.

Background and purpose: Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice.

Experimental approach: 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7^th to the 14^th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7^th to the 14^th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed.

Findings/results: Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants.

Conclusion and implications: CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-kB/Nox4 pathway.

Background and purpose: Carboplatin, a second-generation platinum-containing compound is associated with renal tubular injury and hepatic damage in cancer patients. Tribulus terrestris (TT) is widely used in Indian traditional medicine for its anti-inflammatory properties. The present study aimed to evaluate TT's beneficial effects against liver and kidney damage induced by carboplatin.

Experimental approach: An in-vivo study was conducted on thirty rats. All the groups, except the control, received intraperitoneal carboplatin 90 mg/kg on day 5; the three treatment groups received TT extract (1 g/kg, 1.25, and 1.5 g/kg) for 14 days. Serum and tissue parameters for liver functions, kidney functions, oxidative stress, and inflammatory marker interleukin 6 were measured along with histopathological assessment.

Findings/results: TT at 1.5 g/kg on day 14 significantly reduced creatinine and aspartate transaminase levels compared to the carboplatin group. The increase in malondialdehyde levels and decrease in glutathione levels was significantly reversed in the groups treated with TT 1.25 and 1.5 g/kg. Interleukin 6 showed a significant decrease in treatment groups when compared to the carboplatin group. Carboplatin distorted hepatic architecture and caused diffused inflammatory cell infiltration in the peritubular interstitial spaces in the kidney. The histopathological evaluation confirmed that TT extract ameliorated hepatic and kidney damage by restoring to normal architecture.

Conclusion and implications: Aqueous extract of TT demonstrated a therapeutic effect against nephrotoxicity and hepatotoxicity caused by carboplatin. The observed benefits can be attributed to its anti-inflammatory action and antioxidant properties.

Background and purpose: Diabetic nephropathy leads to end-stage renal disease. The present study aimed to evaluate the prophylactic effect of pioglitazone-loaded mesoporous silica and alumina scaffold on renal function and the underlying mechanisms in streptozotocin-induced diabetic rats.

Experimental approach: The mesoporous nanoparticles were synthesized by chemical methods from tetraethylorthosilicate and aluminum isopropoxide and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. The soaking method was applied to load pioglitazone into the mesoporous silica and alumina. Subsequently, the most capable formulation was evaluated for lipid profile, blood glucose, renal function biomarkers, malondialdehyde, and kidney histopathological changes in diabetic rats.

Findings/results: Pioglitazone loaded in the mesoporous included a superior release of about 80%. No interaction was observed in Fourier transform infrared spectroscopy and X-ray diffraction was shown crystalline. Scanning electron microscopy showed the size of the nanometer in the range of 100 - 300 nm. Mesoporous silica containing the drug significantly decreased urinary parameters, triglycerides, low-density lipoprotein, blood urea nitrogen, blood glucose, malondialdehyde, and creatinine. In addition, it showed increased high-density lipoprotein, significantly. The renal histopathological changes indicated improvement compared with the untreated diabetic group.

Conclusion and implications: It was concluded that the mesoporous was potent to serve as a promising drug carrier and a platform aimed at the delivery of poorly water-soluble drugs for improving oral bioavailability. Furthermore, it has the potential to provide a beneficial effect on the changes in diabetic parameters.

Background and purpose: Nowadays, herbal medicine has been utilized to treat various diseases such as cancer, which showed successful therapeutic efficacy in previous studies. This study for the first time evaluated the cytotoxic potential of cinnamaldehyde (CIN) alone and in combination with doxorubicin (DOX), a well-known potent anti-tumor agent, on the proliferation of prostatic cancer cell line (PC3).

Experimental approach: The cytotoxicity and apoptotic activities of CIN and DOX, either separately or together, were determined on PC3 cells by the MTT test and Annexin V/PI assay, respectively. To further investigate which apoptotic pathway participated in cell death a collection of prominent markers of apoptosis induction including caspase-3/7 activations, mitochondrial membrane potential (MMP), and phosphatidyl serine translocation were detected.

Findings/results: The different concentrations of CIN and DOX significantly inhibited the proliferation of PC3 cells in a concentration-dependent way within a 24-h treatment. In addition, the induction of apoptosis by CIN was accompanied by an increase in the activation of caspase-3/7 in PC3 cells with IC₅₀ concentrations of 12.5 and 10 μg/mL for CIN and DOX, respectively. Moreover, the morphological observations obtained from flow cytometry MMP and caspase-3/7 activity assays, altogether, revealed the potential effect of CIN on apoptosis induced in PC3 cells by DOX.

Conclusions and implications: Taken together, the current study concluded that the combination of CIN and DOX could lead to the production of a potential therapeutic agent for prostate cancer. However, further in vivo and clinical studies are still needed to validate this combination in prostate cancer therapy.

Background and purpose: Epilepsy is a group of chronic neurological diseases caused by a complex set of neuronal hyper electrical activities and oxidative stress of neurons. Crocin is a natural bioactive agent of saffron with different pharmacological properties and low bioavailability. This study aimed to evaluate crocin-loaded solid lipid nanoparticles (SLNC) for neuroprotection activity and efficacy against pentylenetetrazol (PTZ)- induced epilepsy.

Experimental approach: The rats were pretreated with SLNC and pure-crocin (PC; 25 and 50 mg/kg/day; P.O.) for 28 days before PTZ induction. Behavioral functions were evaluated by passive avoidance learning (PAL) tasks. Then, total antioxidant capacity (TAC), malondialdehyde (MDA), and pro-inflammatory factors were measured in the brain tissue using ELISA kits. Gene expression levels were analyzed with real-time polymerase chain reaction and immunohistochemical assay was used to assess the protein expression of sirtuin1 SIRT 1).

Findings/results: SLNC was prepared with an average particle size of 98.25 nm and 98.33% encapsulation efficiency. Memory deficit improved in rats treated with SLNC. Administering SLNC at 25 and 50 mg/kg significantly reduced MDA and proinflammatory cytokines while increasing TAC. Additionally, administering SLNC before treatment increased the levels of SIRT1, peroxisome proliferator-activated receptor coactivator 1α, cAMP-regulated enhancer binding protein, and brain-derived neurotrophic factor. Furthermore, SLNC administration resulted in the downregulation of caspase-3 and inflammation factor expression.

Conclusion and implications: Overall, the obtained results showed that SLNC has better protective effects on oxidative stress in neurons, neurocognitive function, and anti-apoptotic and neuromodulatory activity than PC, suggesting that it is a promising therapeutic strategy for inhibiting seizures.