Red Sea Sponge Callyspongia siphonella Extract Induced Growth Inhibition and Apoptosis in Breast MCF-7 and Hepatic HepG-2 Cancer Cell Lines in 2D and 3D Cell Cultures.

Introduction: The increasing incidence of cancer diseases necessitates the urgent exploration of new bioactive compounds. One of the trends in drug discovery is marine sponges which is gaining significant support due to the abundant production of natural pharmaceutical compounds obtained from marine ecosystems. This study evaluates the anticancer properties of an organic extract from the Red Sea sponge Callyspongia siphonella (C. siphonella) on HepG-2 and MCF-7 cancer cell lines. Methods: C. siphonella was collected, freeze-dried, and extracted using a methanol-dichloromethane mixture. The extract was analyzed via Liquid Chromatography-Mass Spectrometry. Cytotoxic effects were assessed through cell viability assays, apoptosis detection, cell cycle analysis, mitochondrial membrane potential assays, scratch-wound healing assays, and 3D cell culture assays. Results: Fifteen compounds were identified in the C. siphonella extract. The extract showed moderate cytotoxicity against MCF-7 and HepG-2 cells, with IC50 values of 35.6 ± 6.9 µg/mL and 64.4 ± 8 µg/mL, respectively, after 48 hours of treatment. It induced cell cycle arrest at the G2/M phase in MCF-7 cells and the S phase in HepG-2 cells. Apoptosis increased significantly in both cell lines, accompanied by reduced mitochondrial membrane potential. The extract inhibited cell migration, with notable reductions after 24 and 48 hours. In 3D cell cultures, the extract had IC50 values of 5.1 ± 2 µg/mL for MCF-7 and 166.4 ± 27 µg/mL for HepG-2 after 7 days of treatment, showing greater potency in MCF-7 spheres compared to HepG-2 spheres. Discussion and Conclusion: The anticancer activity is attributed to the bioactive compounds. The C. siphonella extract's ability to induce apoptosis, disrupt mitochondrial membrane potential, and arrest the cell cycle highlights its potential as a novel anticancer agent. Additional research is required to investigate the underlying mechanism by which this extract functions as a highly effective anticancer agent.

Ziziphus spina-christi L. extract attenuates bleomycin-induced lung fibrosis in mice via regulating TGF-ß1/SMAD pathway: LC-MS/MS Metabolic profiling, chemical composition, and histology studies.

Ancient Egyptians (including Bedouins and Nubians) have long utilized Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, to alleviate swellings and inflammatory disorders. It is also mentioned in Christian and Muslim traditions. Ziziphus spina-christi L. (Family: Rhamnaceae) is a plentiful source of polyphenols, revealing free radical scavenging, antioxidant, metal chelating, cytotoxic, and anti-inflammatory activities. Herein, different classes of the existing bioactive metabolites in Z. spina-christi L. were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. The study also aimed to assess the anti-inflammatory and antifibrotic properties of Z. spina-christi L. extract against bleomycin-induced lung fibrosis in an experimental mouse model. 32 male Swiss Albino mice were assigned into 4 groups; the first and second were the normal control group and the bleomycin positive control (single 2.5 U/kg bleomycin intratracheal dose). The third and fourth groups received 100 and 200 mg/kg/day Z. spina-christi L. extract orally for 3 weeks, 2 weeks before bleomycin, and 1 week after. The bioactive metabolites in Z. spina-christi L. extract were identified as phenolic acids, catechins, flavonoids, chalcones, stilbenes, triterpenoid acids, saponins, and sterols. The contents of total phenolic compounds and flavonoids were found to be 196.62 mg GAE/gm and 33.29 mg QE/gm, respectively. In the experimental study, histopathological examination revealed that lung fibrosis was attenuated in both Z. spina-christi L.- treated groups. Z. spina-christi L. extract downregulated the expression of nuclear factor kappa B (NF-κB) p65 and decreased levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and c-Jun N-terminal kinase (JNK) in lung tissue. Z. spina-christi L. also downregulated the expression of the fibrotic parameters collagen-1, alpha-smooth muscle actin (α-SMA), transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9) and SMAD3, with upregulation of the antifibrotic SMAD7 in lung tissue. Overall, the present study suggests a potential protective effect of Z. spina-christi L. extract against bleomycin-induced lung fibrosis through regulation of the TGF-ß1/SMAD pathway.

Design, Synthesis and Anticancer Evaluation of New 1-allyl-4-oxo-6-(3,4,5- trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile Bearing Pyrazole Moieties.

AIM: pyrimidine and pyrazole have various biological and pharmaceutical applications such as antibacterial, antifungal, antileishmanial, anti-inflammatory, antitumor, and anti-cancer. INTRODUCTION: In this search, the goal is to prepare pyrimidine-pyrazoles and study their anticancer activity. METHODS: 1-allyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile bearing pyrazoles (4,6-8) have been synthesized. Firstly, the reaction of 1-allyl-2-(methylthio)-4-oxo-6- (3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile (1) with chalcones 2a-b produced the intermediates 3a-b. The latter was reacted with hydrazine hydrate to give the targets 4a-b. On the other hand, hydrazinolysis of compound 1 yielded the hydrazino derivative 5 which upon reaction with chalcones 2c-i or 1,3-bicarbonyl compounds afforded the compounds 6-8. Finally, the new compounds were characterized by spectral data (IR, 1H NMR, 13C NMR) and elemental analysis. Moreover, they were evaluated for Panc-1, MCF-7, HT-29, A-549, and HPDE cell lines as anticancer activity. RESULTS: All the tested compounds 3,4,6-8 showed IC50 values > 50 µg/mL against the HPDE cell line. Compounds 6a and 6e exhibited potent anticancer activity where the IC50 values in the range of 1.7- 1.9, 1.4-182, 1.75-1.8, and 1.5-1.9 µg/mL against Panc-1, MCF-7, HT-29, and A-549 cell lines. CONCLUSION: New pyrimidine-pyrazole derivatives were simply synthesized, in addition, some of them showed potential anticancer activity.

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach.

Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.

Synthesis, Antimicrobial, Anti-Virulence and Anticancer Evaluation of New 5(4H)-Oxazolone-Based Sulfonamides.

Since the synthesis of prontosil the first prodrug shares their chemical moiety, sulfonamides exhibit diverse modes of actions to serve as antimicrobials, diuretics, antidiabetics, and other clinical applications. This inspiring chemical nucleus has promoted several research groups to investigate the synthesis of new members exploring new clinical applications. In this study, a novel series of 5(4H)-oxazolone-based-sulfonamides (OBS) 9a-k were synthesized, and their antibacterial and antifungal activities were evaluated against a wide range of Gram-positive and -negative bacteria and fungi. Most of the tested compounds exhibited promising antibacterial activity against both Gram-positive and -negative bacteria particularly OBS 9b and 9f. Meanwhile, compound 9h showed the most potent antifungal activity. Moreover, the OBS 9a, 9b, and 9f that inhibited the bacterial growth at the lowest concentrations were subjected to further evaluation for their anti-virulence activities against Pseudomonas aeruginosa and Staphylococcus aureus. Interestingly, the three tested compounds reduced the biofilm formation and diminished the production of virulence factors in both P. aeruginosa and S. aureus. Bacteria use a signaling system, quorum sensing (QS), to regulate their virulence. In this context, in silico study has been conducted to assess the ability of OBS to compete with the QS receptors. The tested OBS showed marked ability to bind and hinder QS receptors, indicating that anti-virulence activities of OBS could be due to blocking QS, the system that controls the bacterial virulence. Furthermore, anticancer activity has been further performed for such derivatives. The OBS compounds showed variable anti-tumor activities, specifically 9a, 9b, 9f and 9k, against different cancer lines. Conclusively, the OBS compounds can serve as antimicrobials, anti-virulence and anti-tumor agents.

Effect of Altitude Level on Surgical Outcomes of Laparoscopic Sleeve Gastrectomy for Patients With Morbid Obesity: A Multicentre Prospective Study.

BACKGROUND: This study aimed to evaluate the impact of altitude level on surgical outcomes of laparoscopic sleeve gastrectomy (LSG) for patients with morbid obesity. METHODS: At the normal altitude level, 808 patients underwent LSG, and 467 patients underwent LSG in high-altitude regions. The primary outcome was evaluated based on the postoperative morbidity rate. Secondary outcomes were evaluated based on operating time, mortality, hospital stay, percentage of total weight loss (TWL), and comorbidities improvement. RESULTS: No significant differences were noted in-hospital stay, time to start oral intake, gastric leakage, overall complications, and hospital mortality between the 2 groups. Deep vein thrombosis, pulmonary embolism, and mesenteric vascular occlusion were significantly higher in high altitude [11 (1.3%) vs. 14 (3%), P=0.04; 8 (0.7%) vs. 11 (2.4%), P=0.01; 4 (0.5%) vs. 8 (1.7%), P=0.03, respectively]. Patients with normal altitude recorded a better %TWL than those at high altitude after 12 months (41±9 vs. 39±9.6, P=0.002) and after 24 months (41±8 vs. 40±9, P=0.009). In both groups, a significant improvement was noted in comorbidity after LSG. CONCLUSION: The %TWL significantly achieved with LSG in normal and high altitudes. After 12 and 24 months, the %TWL is significantly higher with LSG at normal altitudes. High altitude is associated with a high incidence of deep vein thrombosis, pulmonary embolism, and superior mesenteric vascular occlusion with LSG.

Unique challenges in the management of a Giant retroperitoneal Schwannoma associated with vertebral body destruction and spinal canal invasion.

Retroperitoneal schwannomas are rare, and giant lesions associated with osteolysis are unique clinical entities for which management guidelines are lacking. Herein, we present our experience with treating a large paraspinal retroperitoneal schwannoma, compare it with previously reported cases, highlight the challenges faced with its management, and propose a treatment plan. A 56-year-old female patient presented with back and left leg radicular pains. Contrast-enhanced CT and MRI scanning and histological analysis confirmed the presence of a giant retroperitoneal schwannoma causing near-complete destruction of the fourth lumbar vertebral body and spinal canal invasion. The tumor was totally removed by a two-step operation with no adverse consequences. The patient recovered well and remained in good clinical and radiological status 9 months post-surgery. Therefore, retroperitoneal schwannomas causing bone destruction and spinal canal invasion are best treated through a combined posterior-anterior approach.

Celastrol Modulates Multiple Signaling Pathways to Inhibit Proliferation of Pancreatic Cancer via DDIT3 and ATF3 Up-Regulation and RRM2 and MCM4 Down-Regulation.

BACKGROUND: Pancreatic cancer is one of the most serious and lethal human cancers with a snowballing incidence around the world. The natural product celastrol has also been widely documented as a potent anti-inflammatory, anti-angiogenic, and anti-oxidant. PURPOSE: To elucidate the antitumor effect of celastrol on pancreatic cancer cells and its modulatory role on whole genome expression. METHODS: The antitumor activity of celastrol on a panel of pancreatic cancer cells has been evaluated by Sulforhodamine B assay. Caspase 3/7 and histone-associated DNA fragments assays were done for apoptosis measurement. Additionally, prostaglandin (PGE2) inhibition was evaluated. Moreover, a microarray gene expression profiling was carried out to detect possible key players that modulate the antitumor effects of celastrol on cells of pancreatic cancer. RESULTS: Our findings indicated that celastrol suppresses the cellular growth of pancreatic cancer cells, induces apoptosis, and inhibits PGE2 production. Celastrol modulated many signaling genes and its cytotoxic effect was mainly mediated via over-expression of ATF3 and DDIT3, and down-expression of RRM2 and MCM4. CONCLUSION: The current study aims to be a starting point to generate a hypothesis on the most significant regulatory genes and for a full dissection of the celastrol possible effects on each single gene to prevent the pancreatic cancer growth.

Potential Benefits of N-Acetylcysteine in Preventing Pregabalin-Induced Seeking-Like Behavior.

Substance-use disorder is globally prevalent and responsible for numerous social and medical problems. Pregabalin (Lyrica), typically used to treat diabetic neuropathy, has recently emerged as a drug of abuse. Drug abuse is associated with several neuronal changes, including the downregulation of glutamate transporters such as glutamate transporter 1 and cystine/glutamate antiporter. We investigated the effects of N-acetylcysteine, a glutamate transporter 1 and xCT upregulator, on pregabalin addiction using a conditioned place preference paradigm. Pregabalin (60 mg/kg) was found to induce conditioned place preference when compared to a vehicle. A 100 mg/kg dose of N-acetylcysteine was found to block pregabalin-seeking behaviors. These results support previous findings showing that glutamate transporters play an important role in pregabalin-induced seeking behaviors. N-acetylcysteine may represent a beneficial agent in preventing the abuse potential of pregabalin.

Impact of referral pattern and timing of repair on surgical outcome after reconstruction of post-cholecystectomy bile duct injury: A multicenter study.

BACKGROUND: Bile duct injury (BDI) after cholecystectomy remains a significant surgical challenge. No guideline exists to guide the timing of repair, while few studies compare early versus late repair BDI. This study aimed to analyze the outcomes in patients undergoing immediate, intermediate, and delayed repair of BDI. METHODS: We retrospectively analyzed 412 patients with BDI from March 2015 to January 2020. The patients were divided into three groups based on the time of BDI reconstruction. Group 1 underwent an immediate reconstruction (within the first 72 hours post-cholecystectomy, n = 156); group 2 underwent an intermediate reconstruction (from 4 days to 6 weeks post-cholecystectomy, n = 75), and group 3 underwent delayed reconstruction (after 6 weeks post-cholecystectomy, n = 181). RESULTS: Patients in group 2 had significantly more early complications including anastomotic leakage and intra-abdominal collection and late complications including anastomotic stricture and secondary liver cirrhosis compared with groups 1 and 3. Favorable outcome was observed in 111 (71.2%) patients in group 1, 31 (41.3%) patients in group 2, and 157 (86.7%) patients in group 3 (P = 0.0001). Multivariate analysis identified that complete ligation of the bile duct, level E1 BDI and the use of external stent were independent factors of favorable outcome in group 1, the use of external stent was an independent factor of favorable outcome in group 2, and level E4 BDI was an independent factor of unfavorable outcome in group 3. Transected BDI and level E4 BDI were independent factors of unfavorable outcome. CONCLUSIONS: Favorable outcomes were more frequently observed in the immediate and delayed reconstruction of post-cholecystectomy BDI. Complete ligation of the bile duct, level E1 BDI and the use of external stent were independent factors of a favorable outcome.

Sex differences in pregabalin-seeking like behavior in a conditioned place preference paradigm.

Substance abuse is a chronic, relapsing disorder characterized by compulsive drug use regardless of negative consequences. Incremental increases in pregabalin abuse have been observed in Saudi Arabia and throughout the world. In previous studies, the potential for pregabalin abuse with escalating doses of the drug (30, 60, 90, and 120 mg/kg) were investigated in male mice. Notably, researchers have argued that women may exhibit a greater tendency to consume drugs without a prescription to alleviate stress and depression. Moreover, female subjects are more prone to impulsivity in drug intake or abuse than their male counterparts. Therefore, in the present study, we compared the potential for pregabalin abuse between male and female mice using a conditioned place preference paradigm. Male and female BALB/c mice were divided into four groups based on the pregabalin dose administered (30, 60, 90, or 120 mg/kg, intraperitoneal). Preference scores were then calculated and compared between male and female mice in each dosage group. Interestingly, preference scores were significantly higher in female mice than in male mice at dosages of 30 and 120 mg/kg. These findings indicate that female mice may be more prone to pregabalin abuse and tolerance than male mice. These results might be helpful to the healthcare providers and policymakers to consider these sex differences in choosing therapeutic plans and consider alternatives to the misused prescription medications.

Intrapancereatic abscess due to arteriovenous malformation involving the entire pancreas: A case report and review of the literature.

INTRODUCTION: The described case is a patient with pancreatic arteriovenous malformation involving the entire pancreas and complicated with intrapancereatic abscess. PRESENTATION OF CASE: A 47 years-old was suffering from episodes of abdominal pain and vomiting with multiple hospital visits without reaching a diagnosis for four months. Contrast-enhanced computed tomography scan (CECT) done which shows a 1.6×1.4cm fluid collection was seen in uncinate process of the pancreas, Magnetic resonance imaging (MRI) demonstrates abnormal vasculature involving the pancreas. Therefore patient diagnosed as a case of pancreatic arteriovenous malformation (P-AVM), which confirmed by Selective Computed Tomography Angiogram (CT Angiogram). DISCUSSION: Normal investigations in the first attempts can lead to miss pancreatic arteriovenous malformation (P-AVM), and can lead to serious and fatal. CONCLUSION: Early diagnosis and treatment of (P-AVM) is very important even in asymptomatic patients. Conservative treatment in complicated and big P-AVM appears ineffective as surgical resection.

Maternal Glucose Supplementation in a Murine Model of Chorioamnionitis Alleviates Dysregulation of Autophagy in Fetal Brain.

Fetal brain injury induced by intrauterine inflammation is a major risk factor for adverse neurological outcomes, including cerebral palsy, cognitive dysfunction, and behavioral disabilities. There are no adequate therapies for neuronal protection to reduce fetal brain injury, especially new strategies that may apply promptly and conveniently. In this study, we explored the effect of maternal glucose administration in a mouse model of intrauterine inflammation at term. Our results demonstrated that maternal glucose supplementation significantly increased survival birth rate and improved the neurobehavioral performance of pups exposed to intrauterine inflammation. Furthermore, we demonstrated that maternal glucose administration improved myelination and oligodendrocyte development in offspring exposed to intrauterine inflammation. Though the maternal blood glucose concentration was temporally prevented from decrease induced by intrauterine inflammation, the glucose concentration in fetal brain was not recovered by maternal glucose supplementation. The adenosine triphosphate (ATP) level and autophagy in fetal brain were regulated by maternal glucose supplementation, which may prevent dysregulation of cellular metabolism. Our study is the first to provide evidence for the role of maternal glucose supplementation in the cell survival of fetal brain during intrauterine inflammation and further support the possible medication with maternal glucose treatment.

Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury.

Preterm birth is a major risk factor for adverse neurological outcomes in ex-preterm children, including motor, cognitive, and behavioral disabilities. N-acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes.

Effect of bariatric surgery on semen parameters and sex hormone concentrations: a prospective study.

Obesity has become a major health concern, with a prevalence rate approaching epidemic states. An inverse relationship between men's body weight and semen parameters has been observed, suggesting a favourable role for weight loss in improving fertility. This prospective study included 46 patients undergoing sleeve gastrectomy, who were investigated with semen analysis and serum hormone tests before and 12 months after surgery. Patients were divided into three groups according to their initial sperm concentration; median loss of body mass index was used as a cut-off to further classify patients according to extent of weight loss. Patients' preoperative seminal investigations revealed azoospermia in 13 (28.3%), oligospermia in 19 (41.3%) and normal sperm concentration in 14 (30.4%). Overall, only serum testosterone significantly increased after surgery (P < 0.001). Between study groups, the increase in sperm concentration was statistically significant in men with azoospermia and oligospermia (both P < 0.05), whereas serum testosterone was statistically significant in all groups (P < 0.001). Changes in semen and hormone tests were not affected by the extent of weight loss experienced by patients. Weight loss from bariatric surgery had a favourable effect on serum testosterone levels and semen parameters of patients with pre-existing azoospermia and oligospermia.

Pancreaticopleural fistula: an overlooked entity.

Pleuropulmonary complications of pancreatitis are well known. Less commonly encountered is pancreaticopleural fistula. We describe the case of a 15-year-old boy with a presumed episode of pancreatitis, complicated by pseudocyst and development of a pancreaticopleural fistula. Successful medical management was achieved, and he made a full recovery. This case demonstrates that the rarity of such a condition leads to delay as well as challenges in diagnosis and management.

Helicobacter pylori eradication in nonulcer dyspepsia: does it really matter?

One-half of the world's population has Helicobacter pylori (H. pylori) infection while dyspeptic symptoms affect one-third of the adult population, at least in the Western world. Data from epidemiological studies are controversial in terms of the association of H. pylori with non-ulcer dyspepsia (NUD) symptoms. Despite the frequency of occurrence of this clinical condition, no effective therapy exists in treating this disorder. With the strategic aim of treating NUD, a vast amount of evidence has accumulated towards eradicating H. pylori, while an equally compelling amount of evidence exists that counters this very strategy. It is, therefore, vital that there is reliable evidence for the efficacy of treatments prescribed to NUD patients. The arguments for and against the eradication of this organism continues unabated. We aim to address both sides of this fundamental divide and present the differing perspective in light of the prevalent evidence.