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Ulcerative colitis (UC) is an idiopathic, chronic, relapsing inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract. The pathophysiology of UC is complicated and involves several factors including immune, genetic, and environmental factors. Recently, a huge amount of research has concentrated on the role of interleukins including interleukin-6 (IL-6) in its pathophysiology. Thus, this study aims to examine the colo-protective and immunomodulatory effect of Tocilizumab (TCZ) in an experimental model of dextran sulfate sodium (DSS) induced UC. In the current study, we analyzed the inflammatory, immunomodulatory, apoptotic, autophagy, and endoplasmic reticulum (ER) stress markers and other clinical features including stool consistency, rectal bleeding, and edema markers in rats. Our results showed that induction of colitis caused bloody diarrhea and increased IL-6 levels. Treatment with TCZ significantly ameliorated DSS-induced injury via decreasing inflammatory markers of colon injury (IL-6), signal transducer and activator of transcription-3 (STAT-3), and C-reactive protein (CRP). Furthermore, TCZ attenuated the apoptotic marker (caspase-3), and down-regulated endoplasmic reticulum stress sensor proteins (inositol- requiring transmembrane kinase endonuclease-1 (IRE-1) and activated transcription factor-6 (ATF-6)) and autophagy proteins (autophagy-related 16-like protein 1 (ATG16L1) and nucleotide-binding oligomerization domain-containing protein-2 (NOD2)), as compared to DSS group. Altogether, the current data suggest TCZ to be a promising protective therapy against UC., (© 2024. The Author(s).)

Young women suffering from premature ovarian failure after radiotherapy carry a huge burden in the field of cancer therapy including reproductive loss, emotional stress, and physical troubles that reduce their long-term quality of life. Hesperidin (HSP) exhibited antioxidant, anti-inflammatory, and anti-apoptotic properties. HSP enhanced in vitro follicular maturation and preserved in vivo ovarian stockpile. In this research, the role of HSP in radiation-induced POF in rats was investigated besides ascertaining its underlying mechanisms. Female Sprague-Dawley rats were arbitrarily allocated into four groups: control-group, ϒ-irradiated-group (3.2 Gy once on the 7th day), HSP-group (100 mg/kg, orally for 10 days), and HSP/ϒ-irradiated-group (ϒ-radiation was applied one hour after HSP). At the end of experiment, the whole ovaries were collected for histological and biochemical analyses. Administration of HSP preserved the ovarian histoarchitecture and follicular stock, retained ovarian weight, and conserved serum estradiol and AMH levels following radiation exposure. HSP ameliorated the ovarian oxidative damage mediated by radiation through augmenting the activities of glutathione peroxidase, glutathione reductase, and catalase antioxidant enzymes. HSP exhibited remarkable anti-inflammatory activity by downregulating the expression of ovarian TLR-4, NF-ĸB, and TNF-α. Moreover, HSP suppressed the apoptotic machinery triggered by radiation by reducing p53 and Bax while increasing Bcl-2 mRNA expressions alongside diminishing caspase-3 expression. Additionally, HSP regulated estrous cycle disorder of irradiated rats and improved their reproductive capacity reflected by enhancing pregnancy outcomes. Therefore, HSP represents an appealing candidate as an adjunct remedy for female cancer patients during radiotherapy protocols owing to its antioxidant, anti-inflammatory, anti-apoptotic, and hormone-regulatory effects., Competing Interests: Declaration of competing interest The authors declare that they do not have any personal relationships or competing financial interests that would impact this research article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This research identified a marine fungal isolate, Aspergillus sp. strain GAD7, which produces an acidic and sulfated extracellular polysaccharide (EPS) with notable anticoagulant and antioxidant properties. Six fungal strains from the Egyptian Mediterranean Sea were screened for EPS production, with Aspergillus sp. strain GAD7 (EPS-AG7) being the most potent, yielding ~5.19 ± 0.017 g/L. EPS-AG7 was characterized using UV-Vis and FTIR analyses, revealing high carbohydrate (87.5%) and sulfate (24%) contents. HPLC and GC-MS analyses determined that EPS-AG7 is a heterogeneous acidic polysaccharide with an average molecular weight (Mw¯) of ~7.34 × 10 3 Da, composed of mannose, glucose, arabinose, galacturonic acid, galactose, and lyxose in a molar ratio of 6.6:3.9:1.8:1.3:1.1:1.0, linked through α- and β-glycosidic linkages as confirmed by NMR analysis. EPS-AG7 adopted a triple helix-like conformation, as evidenced by UV-Vis (Congo Red experiment) and circular dichroism (CD) studies. This helical arrangement demonstrated stability under various experimental conditions, including concentration, ionic strength, temperature, and lipid interactions. EPS-AG7 exhibited significant anticoagulant activity, doubling blood coagulation time at a concentration of 3.0 mg/mL, and showed significant antioxidant activity, with scavenging activities reaching up to 85.90% and 58.64% in DPPH and ABTS + assays at 5.0 mg/mL, and EC50 values of 1.40 mg/mL and 3.80 mg/mL, respectively. These findings highlight the potential of EPS-AG7 for therapeutic applications due to its potent biological activities.

The reproductive system of males is adversely impacted by lead (Pb), a toxic heavy metal. The present study examined arbutin, a promising hydroquinone glycoside, for its potential ameliorative impact against Pb-induced testicular impairment in rats. The testicular injury was induced by the intraperitoneal administration of Pb acetate (20 mg/kg/day) for 10 consecutive days. Thirty-six rats were divided into six experimental groups ( n = 6 per group): control, control treated with oral arbutin (250 mg/kg), control treated with intraperitoneal arbutin (75 mg/kg), untreated Pb, Pb treated with oral arbutin, and Pb treated with intraperitoneal arbutin. The treatments were administered daily for 10 days. Arbutin was administered by the oral and intraperitoneal routes to compare the efficacy of both routes in mitigating Pb acetate-induced testicular dysfunction. The current data revealed that both oral and intraperitoneal administration of arbutin significantly enhanced serum testosterone and sperm count/motility, indicating the amelioration of testicular dysfunction. In tandem, both routes lowered testicular histopathological aberrations and Johnsen's damage scores. These favorable outcomes were driven by dampening testicular oxidative stress, evidenced by lowered lipid peroxidation and increased glutathione and catalase antioxidants. Moreover, arbutin lowered testicular p-JAK2 and p-STAT3 levels, confirming the inhibition of the JAK2/STAT3 pro-inflammatory pathway. In tandem, arbutin suppressed the testicular NLRP3/caspase-1/NF-B axis and augmented the cytoprotective PK2/PKR2 pathway. Notably, intraperitoneal arbutin at a lower dose prompted a more pronounced mitigation of Pb-induced testicular dysfunction compared to oral administration. In conclusion, arbutin ameliorates Pb-evoked testicular damage by stimulating testicular antioxidants and the PK2/PKR2 pathway and inhibiting the JAK2/STAT3 and NLRP3/caspase-1 pro-inflammatory pathways. Hence, arbutin may be used as an adjunct agent for mitigating Pb-induced testicular impairment.

Aging and agro-waste are major challenges. Natural ingredients are preferred in skincare. This study intended to isolate the essential oils (EO) from the leftover peels obtained from three commonly edible Citrus species fruit peels, namely Citrus paradisi (grapefruit), Citrus sinensis (sweet orange), and Citrus deliciosa (mandarin). Gas chromatography/mass spectrometry analysis identified volatile constituents in EO and headspace aroma. Multivariate analysis distinguished between the three species. The antiaging effects of Citrus EO were assessed in vitro and in silico, studying volatile interactions with target enzymes. C. sinensis peels had the highest oil yield, rich in monoterpenes. C. paradisi and C. deliciosa contained sesquiterpenes. Limonene dominated the hydrodistilled EO: 94.50% in C. paradisi, 96.80% in C. sinensis, and 80.66% in C. deliciosa. Unsupervised multivariate analysis of Citrus species revealed that  d-limonene, γ-terpinene, and β-pinene are the key phytochemical markers contributing to their diverse chemical composition. C. paradisi exhibited the highest enzyme inhibitory activity, with IC 50 values of 12.82, 27.58, and 18.16 µg/mL for tyrosinase, elastase, and collagenase, respectively. In silico studies showed that the volatiles can inhibit the tested antiaging enzymes. According to these findings, the investigated agro-waste might slow aging in skin care., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The healthcare systems of African nations heavily rely on importing and repackaging biological medicine. More than 70% of the pharmaceutical products consumed in Africa are imported. The localization of biosimilar production can have a positive impact on the availability and cost of these products by reducing the expenses for African governments and making essential healthcare products more accessible to the population. However, it is evident that the developing countries, particularly African nations, face various obstacles and difficulties in localizing biosimilar production. These challenges encompass development, manufacturing, evaluation, and registration processes. In this review, we will highlight the significant hurdles and achievements encountered during the localization process of biosimilars., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To assess the feasibility, operative time, clinical outcomes, possible complications, and failure rates of all-through arthroscopic biceps tenodesis using press-fit bony plug technique., Methods: This prospective case series study involved 30 skeletally mature patients with long head of biceps pathology (tendinitis after failure of conservative treatment, subluxation, dislocation, or tendon tears). All patients were followed up for 24 months at least., Results: Twenty-nine patients regained full shoulder and elbow range of motion; one case suffered from reflex sympathetic dystrophy. There was a significant improvement in the constant, ASES, and VAS scores when comparing the pre-operative and post-operative values. The average biceps strength was 96% compared to the opposite healthy side. No cases were complicated by neuro-vascular deficits or failure of the tenodesis., Conclusion: Press-fit biceps tenodesis is safe and accessible with low economic demands. We recommend this technique to be used more often when addressing patients with long head of biceps pathologies., Registration Data: Registration number: N-1562023. Registration date: June 2022 "Retrospectively registered"., (© 2023. The Author(s).)

Benign prostatic hyperplasia (BPH) poses a significant health concern amongst elderly males. Canagliflozin (Cana), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has a powerful anti-inflammatory influence. Nevertheless, its role in treating BPH has not been clarified. Therefore, the study aimed to investigate the potential ameliorative effect of Cana on experimentally induced BPH in rats and explore the underlying mechanisms compared to the standard finasteride (Fin). The study employed histological analysis, biochemical assays using ELISA, and western blotting. Animals were categorized into four groups: Control (2.5 ml/kg CMC, orally + 3 ml/kg olive oil, subcutaneous), BPH (3 mg/kg testosterone, subcutaneous + CMC orally), Fin-treated BPH (5 mg/kg, orally), and Cana-treated BPH (5 mg/kg, orally), for 28 days. The BPH group showed obvious BPH manifestations including an increase in prostate weight (PW), prostate index (PI), dihydrotestosterone (DHT) level, and histological aberrations compared to control. Fin and Cana therapy had a comparable impact. Cana treatment significantly reduced PW and PI, besides it improved prostatic biochemical, and histopathological features compared to BPH, consistent with in silico study findings. Cana was associated with downregulation of the androgen axis, increased miR-128b expression, with a lowered expression of epidermal growth factor (EGF) and its receptor. Phosphorylation of STAT3 and its downstream proliferative markers were significantly reduced suggesting apoptotic activity. Cana markedly rescued the BPH-induced upregulation of IL-1β, and iNOS levels. Altogether, the current study demonstrates that Cana could impede BPH progression, possibly by modulating miR-128b/EGFR/EGF and JAK2/STAT3 pathways and downregulating AR, cyclin D1, and PCNA immunoreactivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effect of systemic administration of omega-3 fatty acids on orthodontic tooth movement (OTM) with histological analysis., Materials and Methods: OTM was induced in 20 adult albino New Zealand rabbits, divided into omega-3 and control groups, with nickel-titanium coil springs for 21 days. Omega-3 or saline was given every day via oral gavage during the experimental period. Animals were sacrificed for histomorphometric analysis of alveolar bone remodeling after 21 days of OTM., Results: A significant difference in OTM amount was found in the third week of OTM with means of 1.445 ± 0.13 and 1.72 ± 0.15 for the experimental and control groups, respectively. Histomorphometric analysis showed a significant reduction in the area of active bone-resorptive lacunae and a significant increase in osteoblastic activity in the omega-3 group after 3 weeks., Conclusions: Strong evidence of the osteoclastic inhibitory effect of systemic omega-3 was found, which reduced the percentage and amount of OTM., (© 2023 by the EH Angle Education and Research Foundation, Inc.)

Pyrus communis L. (cv. Le-Conte) (pears) and Malus domestica Borkh. (cv. Anna) (apples) are economic fruit crops cultivated in Egypt. Their leaves were assessed for their beta-sitosterol content and found to have 9.4 mg/g dried leaves wt and 5 mg/g dried leaves, respectively. So we used the lipoidal leaves extracts in the formulation of eight beta-sitosterol-rich emulgels from which the most stable formulae were tested for their antimicrobial activity. Finally, the formulae which exerted antimicrobial activity were biologically evaluated for wound healing against well-known wound healing ointment Mebo® which is composed mainly of 0.25% beta-sitosterol in a base of sesame oil and beeswax. Wound contraction was statistically different in both formulae F3 and F8 from both control and Mebo ® groups which indicated better wound healing activity of these formulae ensured by further histopathological study of the healed wounds.

Meloxicam has shown significant neuroprotection in experimental models of stroke, Alzheimer's disease, and Parkinson's disease. However, the potential of meloxicam to treat depression-like neuropathology in a chronic restraint stress (CRS) model and the associated molecular changes has been insufficiently explored. The current work aimed to explore the potential neuroprotective actions of meloxicam against CRS-evoked depression in rats. In the current experiments, animals received meloxicam (10 mg/kg/day; i.p.) for 21 days, and CRS was instigated by restraining the animals for 6 h/day during the same period. The sucrose preference test and the forced swimming test were used to explore the depression-linked anhedonia/despair, whereas the open-field test examined the animals' locomotor activity. The current findings revealed that CRS elicited typical depression behavioral anomalies in the animals, including anhedonia, despair, and diminished locomotor activity; these findings were reinforced with Z-normalization scores. These observations were corroborated by brain histopathological changes and increased damage scores. In CRS-exposed animals, serum corticosterone spiked, and the hippocampi revealed decreased monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). Mechanistically, neuroinflammation was evident in stressed animals, as shown by elevated hippocampal TNF-α and IL-1β cytokines. Moreover, the hippocampal COX-2/PGE 2 axis was activated in the rats, confirming the escalation of neuroinflammatory events. In tandem, the pro-oxidant milieu was augmented, as seen by increased hippocampal 8-hydroxy-2'-deoxyguanosine alongside increased protein expression of the pro-oxidants NOX1 and NOX4 in the hippocampi of stressed animals. In addition, the antioxidant/cytoprotective Nrf2/HO-1 cascade was dampened, as evidenced by the lowered hippocampal protein expression of Nrf2 and HO-1 signals. Interestingly, meloxicam administration mitigated depression manifestations and brain histopathological anomalies in the rats. These beneficial effects were elicited by meloxicam's ability to counteract the corticosterone spike and hippocampal neurotransmitter decrease while also inhibiting COX-2/NOX1/NOX4 axis and stimulating Nrf2/HO-1 antioxidant pathway. Together, the present findings prove the neuroprotective/antidepressant actions of meloxicam in CRS-induced depression by ameliorating hippocampal neuroinflammation and pro-oxidant changes, likely by modulating COX-2/NOX1/NOX4/Nrf2 axis.

Exposure to Lead -causes testicular dysfunction through oxidative stress, inflammation, and apoptosis; however, naringenin (NGN) therapeutic impact against lead-evoked testicular dysfunction remains elusive. Herein, the point of the study was to examine the defensive impact of NGN on testicular dysfunction initiated by lead. Seventy-Two male Wistar rats were allotted into nine groups; control group, drug control groups, lead acetate group, as well as NGN treated groups (10, 25, and 50 mg/kg) respectively, given 5 days before lead acetate treatment. The result showed clearly the impact of lead on reduced sperm count, sperm motility as well as serum testosterone and LH levels. Additionally, it caused a significant rise in testicular inflammatory markers TNF-α, IL-1β, and TGFβ, effects that were accompanied by a reduction of AKT and mTOR levels. Lead acetate also caused degenerative changes in the testis, atrophy, and loss of spermatogenic series. Our findings revealed that NGN in a dose-dependent manner improved spermiotoxicity induced by lead acetate via restoration of the testicular function, preservation of spermatogenesis, halting inflammatory cytokines along with the enhancement of germ cell survival using upregulation of AKT/mTOR expressions. The present study discloses that NGN suppresses lead acetate toxicity that is involved in the antioxidant effect in a dose-dependent manner, besides its anti-inflammatory property., (© 2023 Wiley Periodicals LLC.)

Doxorubicin (DOX) is one of the basic anticancer drugs, nonetheless its use is restricted due to noxious side effects. Kidney failure is one of the main side effects that restrict its medical use. The current study assessed the nephroprotective effects of fenofibrate and pioglitazone against the renal injury induced by doxorubicin in rats and illustrated the probable mechanisms underlying these protective effects. For this purpose, Male Sprague-Dawley rats weighing (200-230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen were remarkably elevated. Moreover, renal glutathione was significantly reduced while tissue lipid peroxidation malondialdehyde, tumor necrosis factor-α, nuclear factor-kappa B p65 (NF-κB p65), interleukin-1β, p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly augmented. Treatment with fenofibrate and pioglitazone either alone or in combination markedly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, fenofibrate, pioglitazone, and their combination possess potential prophylactic effects against doxorubicin-induced renal injury through modulation of p38-MAPK/NF-κB p65 pathway with superiority to the combination., (© 2023 Wiley Periodicals LLC.)

Background: Tyrosine kinase inhibitors remain a cornerstone in managing metastatic clear cell renal cell carcinoma (RCC). The 4 weeks on/2 weeks off intermittent sunitinib schedule could result in rebound angiogenesis and tumor progression in the 2-week rest period. We propose using bevacizumab during this period for continuous antiangiogenic effects., Method: This was a phase I/II study of patients with advanced clear cell RCC. Sunitinib was given 50 mg daily on a 4-week on/2-week off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. The bevacizumab starting dose was 5 mg/kg, and the dose was escalated to 10 mg if there was no dose-limiting toxicity. The primary endpoints were response rate and progression-free survival (PFS)., Results: Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose-limiting toxicity was observed with 5 mg bevacizumab. One patient achieved a complete response, and 12 achieved a partial response (52% response rate). At a median follow-up of 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median PFS duration was 16.5 months (95% CI 4.1-28.8), and the median overall survival time was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity; the most common were thrombocytopenia (32%), lymphopenia (32%), hypertension (28%), and fatigue (24%)., Conclusion: Continuous angiogenesis blockade by adding bevacizumab to the sunitinib on/off regimen for advanced RCC yields significant antitumor activity with manageable increased toxicity., (© The Author(s) 2023. Published by Oxford University Press.)

Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to investigate the neuroprotective potential of magnesium sulfate in a rat model of CRS-triggered depression-like behavioral disturbance and the underlying molecular mechanisms. Herein, CRS was induced by placing rats into restraining tubes for 6 h/day for 21 days and the animals were intraperitoneally injected with magnesium sulfate (100 mg/kg/day) during the study period. After stress cessation, the depression-like behavior was examined by the open-field test, sucrose preference test, and forced swimming test. The present data demonstrated that CRS triggered typical depression-like behavioral changes which were confirmed by the Z-normalization scores. Mechanistically, serum circulating corticosterone levels spiked, and the hippocampi of CRS-exposed animals demonstrated a significant decline in serotonin, norepinephrine, and dopamine neurotransmitters. At the molecular level, the hippocampal pro-inflammatory TNF-alpha and IL-1β cytokines and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-HG) increased in stressed animals. In tandem, enhancement of hippocampal ER stress was evidenced by the activation of iNOS/PERK/GRP78/CHOP axis seen by increased protein expression of iNOS, PERK, GRP78, and CHOP signal proteins in the hippocampi of stressed rats. Interestingly, magnesium sulfate administration attenuated the depression-like behavioral outcomes and the histopathological changes in the brain hippocampi. These favorable actions were driven by magnesium sulfate's counteraction of corticosterone spike, and hippocampal neurotransmitter decline, alongside the attenuation of neuroinflammation, pro-oxidation, and ER stress. In conclusion, the current results suggest the promising neuroprotective/antidepressant actions of magnesium sulfate in CRS by dampening inflammation, ER stress, and the associated PERK/GRP78/CHOP pathway.

Burkholderia mallei, the causative agent of glanders, is a clonal descendant of Burkholderia pseudomallei, the causative agent of melioidosis, which has lost its environmental reservoir and has a restricted host range. Despite limitations in terms of sensitivity and specificity, complement fixation is still the official diagnostic test for glanders. Therefore, new tools are needed for diagnostics and to study the B. mallei epidemiology. We recently developed a highly sensitive serodiagnostic microarray test for human melioidosis based on the multiplex detection of B. pseudomallei proteins. In this study, we modified our array tests by using anti-horse IgG conjugate and tested sera from B. mallei-infected horses ( n  = 30), negative controls ( n  = 39), and horses infected with other pathogens ( n  = 14). Our array results show a sensitivity of 96.7% (confidence interval [CI] 85.5 to 99.6%) and a specificity of 100.0% (CI, 95.4 to 100.0%). The reactivity pattern of the positive sera on our array test allowed us to identify a set of 12 highly reactive proteins of interest for glanders diagnosis. The B. mallei variants of the three best protein candidates were selected for the development of a novel dipstick assay. Our point-of-care test detected glanders cases in less than 15 min with a sensitivity of 90.0% (CI, 75.7 to 97.1%) and a specificity of 100.0% (CI, 95.4 to 100.0%). The microarray and dipstick can easily be adopted for the diagnosis of both B. mallei and B. pseudomallei infections in different animals. Future studies will show whether multiplex serological testing has the potential to differentiate between these pathogens.

Background: The peritoneum frequently is the only recurrence site after radical resection of gastric cancer. Data suggest that hyperthermic intraperitoneal chemotherapy (HIPEC) and intraoperative radiotherapy (IORT) reduce peritoneal recurrence and possibly improve survival for patients with resected gastric and serosal involvement. This study aimed to evaluate the efficacy of combining prophylactic HIPEC and IORT after radical resection of localized gastric cancer., Methods: In this retrospective study, the medical records of adult patients with histologically proven gastric/gastroesophageal adenocarcinoma who underwent radical resection with curative intent were evaluated for recurrence and survival according to whether they received prophylactic HIPEC and IORT., Results: The eligibility criteria were met by 58 patients, 33 of whom underwent prophylactic HIPEC and IORT after radical surgery. Overall, 91% the HIPEC/IORT group and 72% of the surgery-only group had ≤pT3 disease. The median follow-up period was 26.6 months for the HIPEC/IORT group and 50.6 months for the surgery group. Locoregional recurrence occurred for six patients (18.1%) in the HIPEC/IORT group and five patients (20%) in the surgery-only group, with peritoneal metastasis (PM) occurring in respectively three (9%) and six (24%) patients. The median recurrence-free survival (RFS) duration was 23.2 months (95% confidence interval [CI] 6.5-39.9 months) for the HIPEC/IORT group versus 24.8 months (95% CI 0.0-51.1 months) for the surgery-only group (p = 0.88), and the corresponding 5-year overall survival (OS) estimates were 69% and 58%., Conclusion: Prophylactic HIPEC and IORT after radical surgery for localized gastric or gastroesophageal cancer did not improve RFS or OS for an unselected group of patients at risk for peritoneal recurrence., (© 2022. Society of Surgical Oncology.)

Background Gastric cancer (GC) carries a poor survival outcome despite the availability of many therapeutic agents active in treatment. In this study, we aimed to evaluate the survival outcomes of metastatic GC treatment from a single center in Saudi Arabia and identify possible prognostic factors. Methodology Data on patients diagnosed with metastatic GC between December 2009 and November 2013 were collected and analyzed. Results During this period, 41 patients were diagnosed with a median age at diagnosis of 52 years, and 56.1% of patients were males. Only four (9.2%) patients had human epidermal growth factor receptor 2 overexpression. Overall, 83% were treated with oxaliplatin-based chemotherapy. The median progression-free survival (PFS) and overall survival (OS) were 4.1 and 15.4 months, respectively. Female sex was an independent prognostic factor for better PFS and OS. Normal lymphocyte count was associated with improved PFS. Conclusions Our study highlights poor outcomes in patients with metastatic GC and the need for further research in this field., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Aseafan et al.)

Background: Locally advanced breast cancer (LABC), the most aggressive form of the disease, is a serious threat for women's health worldwide. The AU-rich RNA-binding factor 1 (AUF1) promotes the formation of chemo-resistant breast cancer stem cells. Thereby, we investigated the power of AUF1 expression, in both cancer cells and their stromal fibroblasts, as predictive biomarker for LABC patients' clinical outcome following neoadjuvant treatment., Methods: We have used immunohistochemistry to assess the level of AUF1 on formalin-fixed paraffin-embedded tissues. Immunoblotting was utilized to show the effect of AUF1 ectopic expression in breast stromal fibroblasts on the expression of various genes both in vitro and in orthotopic tumor xenografts. Cytotoxicity was evaluated using the WST1 assay, while a label-free real-time setting using the xCELLigence RTCA technology was utilized to assess the proliferative, migratory and invasive abilities of cells., Results: We have shown that high AUF1 immunostaining (≥ 10%) in both cancer cells and their adjacent cancer-associated fibroblasts (CAFs) was significantly associated with higher tumor grade. Kaplan-Meier univariate analysis revealed a strong correlation between high AUF1 level in CAFs and poor patient's survival. This correlation was highly significant in patients with triple negative breast cancer, who showed poor disease-free survival (DFS) and overall survival (OS). High expression of AUF1 in CAFs was also associated with poor OS of ER+/Her2- patients. Similarly, AUF1-positive malignant cells tended to be associated with shorter DFS and OS of ER+/Her2+ patients. Interestingly, neoadjuvant therapy downregulated AUF1 to a level lower than 10% in malignant cells in a significant number of patients, which improved both DFS and OS. In addition, ectopic expression of AUF1 in breast fibroblasts activated these cells and enhanced their capacity to promote, in an IL-6-dependent manner, the epithelial-to-mesenchymal transition and stemness processes. Furthermore, these AUF1-expressing cells enhanced the chemoresistance of breast cancer cells and their growth in orthotopic tumor xenografts., Conclusions: The present findings show that the CAF-activating factor AUF1 has prognostic/predictive value for breast cancer patients and could represent a great therapeutic target in order to improve the precision of cancer treatment., (© 2022. The Author(s).)

Polydatin (PD) is a polyphenolic compound found naturally in many fruits such as grapes. It has anti-oxidant and anti-inflammatory activities that are of paramount importance for its pharmacological actions. This study aimed to explore possible protective effects of PD against methotrexate (MTX)-induced pulmonary fibrosis in rats. A single oral dose of MTX (14 mg/kg) per week for 2 weeks caused a significant decrease in glutathione (GSH) content with a marked increase in transforming growth factor-beta (TGF-β), alpha-smooth muscle actin (α-SMA), pulmonary content of malondialdehyde (MDA), interleukin-1β (IL-1β), Hydroxyproline, tumor necrosis factor-alpha (TNF-α), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as compared with the control group. Contrarily, daily administration of PD (25, 50, and 100 mg/kg, p.o.) for 14 days concomitantly with MTX ameliorated MTX-induced pulmonary fibrosis as indicated by mitigation of the previously mentioned biochemical parameters and histopathological changes in a dose-dependent manner. In conclusion, the protective effect of PD against pulmonary fibrosis induced by MTX in rats might be attributed to its anti-oxidant, anti-inflammatory as well as anti-fibrotic effects., (© 2022 Wiley Periodicals LLC.)

Background: Numerous chemotherapeutic agents have antitumor activity in recurrent/metastatic (R/M) nasopharyngeal cancer (NPC). Evidence of capecitabine's effectiveness as monotherapy is limited. Capecitabine tolerability in solid malignancies has ethnic and geographical variability. We investigated capecitabine's tolerability and identified potential prognostic factors for clinical outcomes in R/M NPC., Methods: A consecutive retrospective cohort of patients who received capecitabine as the first recurrence, second- or third-line monotherapy for metastatic NPC (2011-2019) was reviewed concerning patient characteristics, pathological features, treatment outcomes, and toxicity., Results: Fifty-one patients were eligible (median age at diagnosis: 42 [35.5-52.5] years). Most patients (78.4%) tolerated a standard oral dose of 1,250 mg/m 2 capecitabine (2 weeks on/1 week off) in a 3-week cycle. The objective response rate was 49%, and the disease control rate was 66.7%, with a median response duration of 6.2 months. Hand-foot syndrome (HFS) was associated with a higher objective response rate (odds ratio, 5.1 [95% confidence interval: 1.18-21.98]; P = 0.02). The median follow-up duration was 17.8 (interquartile range: 7.8-30.4) months. The median (95% confidence interval) progression-free survival and overall survival were 6.6 (4.3-8.8) and 32.7 (25.9-39.5) months, respectively. HFS ( P = 0.02), better performance status ( P = 0.02), and absence of brain metastasis ( P = 0.04) were associated with prolonged progression-free survival., Conclusion: Capecitabine monotherapy is effective and well-tolerated as a palliative treatment for R/M NPC. Despite the lower incidence of HFS in our patients, it remained a favorable prognostic factor for objective response and progression-free survival., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2022 Bader Alshamsan et al.)

There are different approaches for reconstruction of little finger and dorsal hand defects. The ulnar parametacarpal flap, first introduced by Backhach et al in 1995, is considered a good option for reconstructing such defects. In this study, we elevated this flap on one perforator and applied it as a propeller flap. We then discussed the reliability of this flap and which perforator (the proximal or the distal one) is more reliable., Methods: This study was carried out on 20 patients with different little finger and dorsal hand defects between June 2017 and March 2019. All defects were covered by perforator-based ulnar parametacarpal flaps. Ten flaps were based on the proximal perforator, whereas the other 10 were based on the distal perforator., Results: With a period of follow-up ranging from 6 months to 1 year, all flaps that were raised on the proximal perforator survived completely, whereas two of 10 flaps raised on the distal perforator showed venous congestion and also one flap showed partial necrosis of the distal one-third due to ischemia., Conclusions: The perforator based ulnar parametacarpal flap is a reliable option for reconstruction of little finger and dorsal hand defects. It is more reliable when it is raised on the proximal perforator rather than on the distal one., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Depression is a widespread, withering illness, resulting in a massive personal suffering and economic loss. The chronic exposure to stress may be involved in the etiology of human psychiatric disorders; such as depression. In the current study, the animals were subjected to chronic unpredictable mild stress (CUMS) for 14 days. Saxagliptin (SAXA) is a member of dipeptidyl peptidase-4 (DPP-4) inhibitors class. The current study was the first one to examine the anti-depressive effect of SAXA in an experimental model of CUMS-induced depression in rats and the possible underlying mechanisms. Animals were orally treated with SAXA (0.5, 1 and 2 mg/kg) for 14 days. SAXA treatment reversed the CUMS-induced alterations in the behavioral, biochemical as well as histopathological parameters. Moreover, it hindered the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers. On the other hand, it increased the monoamines levels and the neurogenic brain derived neurotrophic factor (BDNF). In addition, SAXA treatment increased the incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are linked to the activation of protein kinase B (AKT)/phosphatidylinositol3-kinase (PI3K) pathway. In conclusion, the current study revealed that the modulation of the interplay between the key events involved in depression, including oxidative stress, inflammation, and GLP-1/PI3K/AKT signaling pathway, can explain the anti-depressant activity of SAXA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway., Materials and Methods: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA., Key Findings: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1β levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway., Significance: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Doxorubicin (DOX) is a potent chemotherapeutic agent widely used for the treatment of several malignancies. Despite its effectiveness, DOX has been implicated in induced neurotoxicity manifested as cognitive dysfunction with varying degrees, commonly referred to as chemobrain. DOX-induced chemobrain is presumed to be due to cytokine-induced inflammatory, oxidative, and apoptotic responses damaging the brain. Atorvastatin (ATV), 3-hydroxy 3-methylglutaryl co-enzyme A (HMG Co-A) reductase inhibitor, is a cholesterol-lowering statin possessing beneficial pleiotropic effects, including anti-inflammatory, antioxidant, and anti-apoptotic properties. Therefore, this study aims to investigate the potential neuroprotective effects of ATV against DOX-induced cognitive impairment studying the possible involvement of heme oxygenase-1 (HO-1) and endoplasmic reticulum (ER) stress biomarkers. Rats were treated with DOX (2 mg/kg/week), i.p. for 4 weeks. Oral treatment with ATV (10 mg/kg) ameliorated DOX-induced behavioral alterations, protected brain histological features, and attenuated DOX-induced inflammatory, oxidative, and apoptotic biomarkers. In addition, ATV upregulated the protective HO-1 expression levels and downregulated the DOX-induced apoptotic ER stress biomarkers. In conclusion, ATV (10 mg/kg) exhibited neuroprotective properties against DOX-induced cognitive impairment which could possibly be attributed to their anti-inflammatory, antioxidant, and anti-apoptotic effects in the brain.

Cyclosporine (CsA) is a widely used immunosuppressive agent that incurs marked nephrotoxicity in the clinical setting. Thus, there is a need for finding safe/effective agents that can attenuate CsA-induced kidney injury. Meanwhile, the underlying mechanisms for CsA-associated nephrotoxicity are inadequately investigated, in particular, the AKT/eNOS/NO pathway. Here, the present work aimed to explore the potential of camel milk, a natural product with distinguished antioxidant/anti-inflammatory actions, to ameliorate CsA-induced nephrotoxicity in rats. The molecular mechanisms related to renal oxidative aberrations and apoptosis were studied, including Nrf2/HO-1 and AKT/eNOS/NO pathways. The kidney tissues were inspected using histopathology, ELISA, Western blotting, and immunohistochemistry. The present findings demonstrated that camel milk (10 ml/kg) significantly lowered creatine, BUN, and NGAL nephrotoxicity markers and the aberrant histopathology, with similar efficacy to the reference quercetin. Moreover, camel milk suppressed the renal oxidative stress, as evidenced by significantly lowering NOX-1 and lipid peroxides and significantly augmenting the renal antioxidant moieties (GSH, GPx, and SOD), thereby, driving the restoration of Nrf2/HO-1 pathway. Meanwhile, camel milk counteracted the pro-apoptotic reactions by significantly lowering Bax protein expression, caspase-3 activity/cleavage, and PARP cleavage, alongside significantly increasing the expression of the proliferation signal PCNA. Regarding the anti-apoptotic AKT/eNOS/NO pathway, camel milk activated its signaling by significantly increasing the protein expression of PI3Kp110, p-AKT(Ser473)/total AKT, and p-eNOS (Ser1177)/total eNOS besides significantly boosting the renoprotective NO levels. In conclusion, these findings reveal that camel milk may be a promising candidate for the alleviation of CsA-induced nephrotoxicity., Competing Interests: No conflict of interest is declared by the authors., (© 2021 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Aims: Cadmium (Cd) is a prevalent environmental contaminant that incurs deleterious health effects, including testicular impairment. Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated marked cardio-, hepato-, and reno-protective actions, however, its impact on Cd-triggered testicular dysfunction has not been formerly investigated. Hence, the present study aimed to explore the probable beneficial impact of sitagliptin against Cd-evoked testicular impairment which may add to its potential clinical utility. The underlying mechanisms pertaining to the balance between testicular autophagy and apoptosis were explored, including the AMPK/mTOR and Nrf2/HO-1 pathways., Materials and Methods: The testicular tissues were examined using histopathology, immunohistochemistry, Western blotting, and ELISA. Sitagliptin (10 mg/kg/day, by gavage) was administered for 4 consecutive weeks., Key Findings: Sitagliptin attenuated the testicular impairment via improvement of the relative testicular weight, sperm count/motility, sperm abnormalities, and serum testosterone. Additionally, sitagliptin counteracted Cd-induced histologic aberrations/disrupted spermatogenesis. Interestingly, sitagliptin augmented the defective autophagy as demonstrated by upregulating Beclin 1 protein expression and lowering p62 SQSTM1 protein accumulation. These effects were mediated via the activation of testicular AMPK/mTOR pathway as proven by increasing p-AMPK (Ser485, Ser491)/total AMPK and diminishing p-mTOR (Ser2448)/total mTOR protein expression. Additionally, sitagliptin suppressed the testicular apoptotic events via downregulating Bax and upregulating Bcl-2 protein expression. In tandem, sitagliptin suppressed the oxidative stress through lowering lipid peroxides and activating Nrf2/HO-1 pathway via upregulating the protein expression of Nrf2, and the downstream effectors HO-1 and GPx., Significance: Sitagliptin attenuated Cd-induced testicular injury via boosting the autophagy/apoptosis ratio through activation of AMPK/mTOR and Nrf2/HO-1 pathways., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Human epidermal growth factor receptor 2 (HER-2) targeted therapy regimens can improve tumor response in HER-2-positive metastatic breast cancer (MBC), with overall survival benefits., Objective: We evaluated the efficacy of dual HER-2 blockade combined with chemotherapy for HER-2-positive MBC patients as a first-line therapy in our patient population., Patients and Methods: We identified 75 patients at King Faisal Specialist Hospital and Research Center that received trastuzumab, pertuzumab, and docetaxel as a first-line therapy in HER-2 positive MBC in 2013-2016., Results: Median age at diagnosis was 45 years; 54.7% were estrogen receptor (ER)-positive. 10% of patients presented with only bone metastasis. The median follow-up time was 36 months with an objective response rate of 74.7% (complete response [CR] 18.7%; partial response [PR] 56%). The 5-year progression-free survival (PFS) and overall survival (OS) were 21% and 71.9% respectively, with a median PFS of 36 months (95% confidence interval [CI] 23.6-48.4). The 5-year OS for ER-negative and ER-positive patients was 93.9% and 59.4% respectively ( p = 0.189); 23 patients experienced grade 1/2 toxicity and 2 patients had grade 3/4 toxicity. In terms of OS and PFS, the site of metastasis did not make any significant difference., Conclusions: First line pertuzumab, trastuzumab, and docetaxel for HER-2-positive MBC patients was found to be an effective and safe therapy in the Saudi population. This finding was consistent with the results seen in the CLEOPATRA trials., Competing Interests: All authors declare that they have no competing interests., (Copyright © 2020 by S. Karger AG, Basel.)

Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin. Graphical abstract.

Cisplatin is one of the standard anti-cancer agents that are used to treat variety of solid tumors. Nevertheless, due to the accumulation of cisplatin in the renal epithelial cells, nephrotoxicity was found to be the main side effect that limits its clinical use. The current study was conducted to assess the potential nephroprotective effect of dibenzazepine, a Notch inhibitor, against cisplatin-induced nephrotoxicity in rats as well as the possible mechanisms underlying this nephroprotection. The rats were pre-treated with 2 mg/kg dibenzazepine for 7 days before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Cisplatin induced acute nephrotoxicity, where blood urea nitrogen and serum creatinine levels were significantly increased. Besides, lipid peroxidation was markedly elevated and the levels of reduced glutathione and catalase were significantly reduced. Also, the tissue levels of the pro-inflammatory mediators; IL-1β, TNF-α, and NF-kB, were significantly increased in the cisplatin group. The pre-treatment with dibenzazepine significantly mitigated the nephrotoxic effects of cisplatin, the oxidative stress and inflammatory status as well as decreased caspase-3 expression, as compared to the cisplatin group. Furthermore, the up-regulation of Notch-1 and Hes-1 was found to be involved in cisplatin-induced nephrotoxicity and their expression was significantly reduced by dibenzazepine. The nephroprotective effect of dibenzazepine was further confirmed by the histopathological assessment. Moreover, dibenzazepine pre-treatment of hela and PC3 cells in vitro did not antagonize the cisplatin anti-cancer activity. In conclusion, these findings show that dibenzazepine provides protection against cisplatin-induced nephrotoxicity. Moreover, the up-regulation of the Notch pathway was shown to play a role in the pathogenesis of cisplatin-induced renal injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Abd El-Rhman, El-Naga, Gad, Tadros and Hassaneen.)

Background: The multidrug resistance (MDR) of cancer cells is a major obstacle to cancer treatment. Glutathione S-transferase Pi (GSTP1-1) catalyzes the conjugation of glutathione with anticancer drugs and therefore reduces their efficacy. Phenolic compounds have the potential to inhibit GST P1-1 activity, which is a promising goal to overcome MDR and increase the efficacy of chemotherapy., Results: Three fractions (dichloromethane, ethyl acetate, and n-butanol) were prepared from Tamarindus indica seeds to determine their phenolic and flavonoid properties as well as their antioxidant/pro-oxidant properties. The n-butanol fraction displayed the highest levels of phenol ( 378 ± 11.7 mg gallic acid equivalent/g DW) and flavonoids (83 ± 6.0 mg rutin equivalent/g DW). Inhibiting effects on purified GSTP1-1 activity in human erythrocytes (eGST), placenta (pGST), and hGSTP1-1 have been studied. The n-butanol fraction was the most effective in inhibiting eGST, hGSTP1-1, and pGST with IC 50 values of 3.0 ± 0.7, 4.85 ± 0.35, and 6.6 ± 1.2 μg/ml, respectively. Cellular toxicity was investigated for the T. indica n-butanol fraction on various human cancerous cell lines. The only ones affected were MCF-7 cell lines (72%) and HePG2 (52%) indicated cytotoxicity. The value of IC 50 is 68.5 μg/ml of T. indica n-butanol fraction was observed compared to 1.7 μg/ml tamoxifen in MCF-7 cell lines. The combination of treatment of T. indica extract with the medicinally approved drug tamoxifen had unexpected effects; complete elimination of the cytotoxic inhibition effect of tamoxifen and the plant extract was observed., Conclusions: However T. indica extract has a cytotoxic effect on the MCF-7 cell line; in certain situations, plant products can have an opposite effect to the intended drug, which decreases the impact of the drug.

Many cancer patients treated with chemotherapy develop chemotherapy-induced cognitive impairment (CICI), often referred to as chemo-brain, which manifest during or post-treatment with variable degrees, onset and duration thereby affecting the patients' quality of life. Several chemotherapeutic agents have been studied to determine its possible association with cognitive impairment and to fully comprehend their contribution to CICI. A vast number of studies have emerged proposing several candidate underlying mechanisms and etiologies contributing to CICI such as direct neurotoxicity, BBB disruption, decreased hippocampal neurogenesis, white matter abnormalities, secondary neuro-inflammatory response and increased oxidative stress; however, the exact underlying mechanisms are still not well defined. This review summarizes CICI associated with most commonly used chemotherapeutic agents with emphasizes the possible underlying pathogenesis in both animal and clinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Depression is a common mental illness that possesses a noteworthy effect on patients' lives. Many theories are recently studied for their plausible involvement in depression pathogenesis, especially oxidative stress and inflammation. Morin (2',3,4',5,7-pentahydroxyflavone), a natural flavonoid, is characterized by its potent anti-inflammatory, and anti-oxidant activities. Accordingly, the aim of the current study was to investigate its potential protective anti-depressant effect in the model of chronic unpredictable mild stress (CUMS) in experimental rats. Moreover, the conceivable neuro-protective mechanisms, especially those related to the inflammasome pathway, were explored. Several, mild, unpredictable stressors were applied for 4 weeks concomitantly with the oral administration of morin (15 and 30 mg/Kg). Morin hydrate supplementations exhibited a significant improvement in the scores of the forced swimming and sucrose preference tests. In addition, it prompted a marked elevation in the ambulation, rearing as well as grooming scores of the open field test. The morin-treated groups showed a great improvement in the biochemical parameters in both the cortex and hippocampus, where it significantly elevated the serotonin, epinephrine, and norepinephrine levels. Also, it significantly increased reduced glutathione levels and decreased malondialdehyde levels. Regarding the inflammasome pathway, morin significantly decreased the tissue levels of tumor necrosis factor-alpha, toll-like receptor-4, interleukin-1beta, NOD-like receptor pyrin domain-containing protein-3, and caspase-1 levels. Morin also significantly decreased the level of the key apoptotic marker, caspase-3. In conclusion, these findings propose that morin might show a promising anti-depressant effect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antibody-modified gold nanomaterials are central to many novel biosensing technologies for example the lateral flow assays technology. The combination of the specificity, provided by antibody-antigen interactions, and the unique optical properties of nanomaterials provide excellent properties for biosensors. Here, we present the use of gold nanorods (GNR) with the localized Surface Plasmon Resonance (LSPR) peak in the visible range for biomarker detection. The colour of the GNR can be tuned by the reaction conditions to provide multi-coloured gold nanorod conjugates. These antibody functionalized GNR have the potential to provide significant improvements in multiplexed analysis and sensitivity compared to conventional gold nanoparticle based lateral flow assays. However, a major challenge is the synthesis of stable conjugates that resist aggregation in samples with high ionic strength, (e.g. salt solutions) and allow highly sensitive detection of proteins. A detailed investigation of different reagents for the functionalization of gold nanorod materials are reported. An antibody modified GNR based lateral flow assay is validated for the determination of C-reactive Protein (CRP)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a chronic, inflammatory, and neurodegenerative autoimmune disease. MS is a devastating disorder that is characterized by cognitive and motor deficits. Cuprizone-induced demyelination is the most widely experimental model used for MS. Cuprizone is a copper chelator that is well characterized by microgliosis and astrogliosis and is reproducible for demyelination and remyelination. Secukinumab (SEC) is a fully human monoclonal anti-human antibody of the IgG1/kappa isotype that selectively targets IL-17A. Expression of IL-17 is associated with MS. Also, IL-17 stimulates microglia and astrocytes resulting in progression of MS through chemokine production and neutrophil recruitment. This study aimed to investigate the neuroprotective effects of SEC on cuprizone-induced demyelination with examining the underlying mechanisms. Locomotor activity, short-term spatial memory function, staining by Luxol Fast Blue, myelin basic protein, gliasosis, inflammatory, and oxidative-stress markers were assessed to evaluate neuroprotective, anti-inflammatory and antioxidant effects. Moreover, the safety profile of SEC was evaluated. The present study concludes the efficacy of SEC in Cup-induced demyelination experimental model. Interestingly, SEC had neuroprotective and antioxidant effects besides its anti-inflammatory effect in the studied experimental model of MS. Graphical abstract.

Background: Melioidosis, caused by Burkholderia pseudomallei, is a severe infectious disease with high mortality rates, but is under-recognized worldwide. In endemic areas, there is a great need for simple, low-cost and rapid diagnostic tools. In a previous study we showed, that a protein multiplex array with 20 B. pseudomallei-specific antigens detects antibodies in melioidosis patients with high sensitivity and specificity. In a subsequent study the high potential of anti-B. pseudomallei antibody detection was confirmed using a rapid Hcp1 single protein-based assay. Our protein array also showed that the antibody profile varies between patients, possibly due to a combination of host factors but also antigen variations in the infecting B. pseudomallei strains. The aim of this study was to develop a rapid test, combining Hcp1 and the best performing antigens BPSL2096, BPSL2697 and BPSS0477 from our previous study, to take advantage of simultaneous antibody detection., Methods and Principal Findings: The 4-plex dipstick was validated with sera from 75 patients on admission plus control groups, achieving 92% sensitivity and 97-100% specificity. We then re-evaluated melioidosis sera with the 4-plex assay that were previously misclassified by the monoplex Hcp1 rapid test. 12 out of 55 (21.8%) false-negative samples were positive in our new dipstick assay. Among those, 4 sera (7.3%) were Hcp1 positive, whereas 8 (14.5%) sera remained Hcp1 negative but gave a positive reaction with our additional antigens., Conclusions: Our dipstick rapid test represents an inexpensive, standardized and simple diagnostic tool with an improved serodiagnostic performance due to multiplex detection. Each additional band on the test strip makes a false-positive result more unlikely, contributing to its reliability. Future prospective studies will seek to validate the gain in sensitivity and specificity of our multiplex rapid test approach in different melioidosis patient cohorts., Competing Interests: All authors have declared that no competing interests exist. AG and HHS are employees of Senova Gesellschaft für Biowissenschaft und Technik mbH the company that manufacturers the Dipsticks. This does not affect the authors' adherence to all the PLOS policies on sharing data and materials.

Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest concerning this article., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

With the alarming rise in incidence of antibiotic-resistant bacteria and the scarcity of newly developed antibiotics, it is imperative that we design more effective formulations for already marketed antimicrobial agents. Fusidic acid (FA), one of the most widely used antibiotics in the topical treatment of several skin and eye infections, suffers from poor water-solubility, sub-optimal therapeutic efficacy, and a significant rise in FA-resistant Staphylococcus aureus (FRSA). In this work, the physico-chemical characteristics of FA were modified by nanocrystallization and lyophilization to improve its therapeutic efficacy through the dermal route. FA-nanocrystals (NC) were prepared using a modified nanoprecipitation technique and the influence of several formulation/process variables on the prepared FA-NC characteristics were optimized using full factorial statistical design. The optimized FA-NC formulation was evaluated before and after lyophilization by several in-vitro, ex-vivo, and microbiological tests. Furthermore, the lyophilized FA-NC formulation was incorporated into a cream product and its topical antibacterial efficacy was assessed in vivo using a rat excision wound infection model. Surface morphology of optimized FA-NC showed spherical particles with a mean particle size of 115 nm, span value of 1.6 and zeta potential of -11.6 mV. Differential scanning calorimetry and powder X-ray diffractometry confirmed the crystallinity of FA following nanocrystallization and lyophilization. In-vitro results showed a 10-fold increase in the saturation solubility of FA-NC while ex-vivo skin permeation studies showed a 2-fold increase in FA dermal deposition from FA-NC compared to coarse FA. Microbiological studies revealed a 4-fofd decrease in the MIC against S. aureus and S. epidermidis from FA-NC cream compared to commercial Fucidin cream. In-vivo results showed that FA-NC cream improved FA distribution and enhanced bacterial exposure in the infected wound, resulting in increased therapeutic efficacy when compared to coarse FA marketed as Fucidin cream.

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms., Methods: Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-β)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed., Key Findings: Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-β/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-β/SMAD/MAPK signaling pathways., Conclusion: The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-β/SMAD/MAPK signaling pathways., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: Reduced male fertility has been regarded as a serious complication of rheumatoid arthritis. Phytochemicals have been described as protective agents against rheumatoid arthritis-linked testicular impairment. The current study aimed to investigate the potential protective effects of ellagic acid on rheumatoid arthritis-evoked testicular dysfunction vis-à-vis the reference anti-inflammatory celecoxib., Experimental Approach: Ellagic acid (50 mg/kg/day) and celecoxib (5 mg/kg/day) were administered orally for 20 days in adjuvant-induced arthritic rats., Key Findings: Current data revealed that ellagic acid counteracted rheumatoid arthritis-evoked testicular histopathologic changes, disrupted sperm characteristics and low gonadosomatic index with comparable efficacy to celecoxib. Ellagic acid also enhanced the testicular steroidogenesis via upregulating the gene expression of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein with consequent boosting of serum testosterone. Notably, ellagic acid attenuated the testicular inflammatory responses through suppression of myeloperoxidase, tumor necrosis factor-α and cyclo-oxygenase-2 protein expression together with enhancing the anti-inflammatory signal interleukin 10. Ellagic acid also curbed the redox alterations via lowering the production of lipid peroxides and nitric oxide and elevation of the anti-oxidant reduced glutathione. In support of cell survival, ellagic acid combated testicular apoptosis through downregulating caspase-3 protein expression., Significance: The present work accentuates the beneficial actions of ellagic acid in rheumatoid arthritis-incurred testicular impairment and disrupted spermatogenesis via combating the inflammatory, oxidative and apoptotic aberrations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cadmium(Cd) is a serious environmental and occupational contaminant that represents a serious health hazard to humans and other animals. Reproductive health problems have been reported in men exposed to Cd. Testicular damage is one of the deleterious effects due to Cd exposure. Cd-induced testicular toxicity is mediated through oxidative stress, inflammation, testosterone inhibition and apoptosis. Thus, the present study was performed to assess the possible protective role of infliximab (IFX), anti-TNFα agent, against Cd-induced testicular damage and spermiotoxicity in rats. The rats were randomly allotted into six experimental groups: control, Cd sulphate treated, Cd sulphate treated with infliximab (5 mg/kg), Cd sulphate with infliximab (7 mg/kg), infliximab alone (5 mg/kg), and infliximab alone (7 mg/kg). The control group received saline. To induce testicular damage, Cd sulphate (1.5 mg/100 gm body weight/day) was dissolved in normal saline and orally administrated for 3 consecutive weeks. The rats in infliximab-treated groups were given a weekly dose of 5 mg/kg/week or 7 mg/kg/week of infliximab intraperitoneally. In the current study Cd exposure reduced sperm count, markers of testicular function, sperm motility as well as gene expression of testicular 3β-HSD and 17β-HSD and serum testosterone level. Additionally, it increased testicular oxidative stress, inflammatory and apoptotic markers. The histopathologic studies supported the biochemical findings. Treatment with infliximab significantly attenuated Cd-induced injury verified by the restoration of testicular architecture, enhancement of steroidogenesis, preservation of spermatogenesis, modulation of the inflammatory reaction along with suppression of oxidative stress and apoptosis. It was concluded that infliximab, through its antioxidant, anti-inflammatory and anti-apoptotic effects, represents a potential therapeutic option to protect the testicular tissue from the detrimental effects of Cd., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Methotrexate (MTX) is commonly used to treat several types of cancer and autoimmune diseases. However, there is increasing concern over its organs toxicities particularly liver toxicity. Liraglutide, a glucagon like peptide-1 agonist, possesses antioxidant and anti-inflammatory features. This study aimed to explore the potential protective effect of liraglutide pre-treatment in ameliorating MTX-induced hepatotoxicity and to further investigate the underlying mechanisms. Rats received 1.2 mg/kg liraglutide intraperitoneal twice daily for 7 days before MTX. Results revealed that liraglutide significantly decreased activities of liver enzymes and oxidative stress in hepatocytes. Furthermore, NF-kB expression and related inflammatory markers (TNF-α, COX-2 and IL-6) were reduced in the pre-treatment group of liraglutide. These data validate the advantageous effects of liraglutide in MTX hepatotoxic animals. In addition, liraglutide increased the expression of the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf-2), along with the transcription of downstream phosphorylated cAMP response element-binding protein (pCREB) which increases the activity of Nrf-2. Additionally, caspase-3 expression/activity and BAX/Bcl-2 ratio were decreased following liraglutide pre-treatment. In conclusion, it was confirmed that liraglutide enhanced the antioxidant activity of liver cells by activating the Nrf-2 and pCREB signaling, thereby, reducing liver cell inflammation and apoptosis induced by MTX., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic and progressive autoimmune inflammatory disease associated with irreversible joint destruction that leads to permanent motor disability and compromised quality of life. However, the main cause of RA is still unknown though stimulation of immune system and cells plays pivotal role in disease development and progression. Ramucirumab (RAM) is the monoclonal antibody against VEGF- receptor. This study aimed to investigate and evaluate the therapeutic effect of RAM with or without Methotrexate (MTX) against adjuvant-induced arthritis in rats. Complete Freund's adjuvant (CFA)-induced arthritic rats were treated for three consecutive weeks with MTX or RAM alone and MTX-RAM co-therapy. Arthritic score, gait score, ankle diameter, paw thickness, angiogenic, inflammatory cytokines, bone erosion markers, and apoptotic markers were assessed to evaluate the anti-arthritic effect. RAM monotherapy exhibited anti-inflammatory, anti-angiogenic and anti-apoptotic effects similar to MTX alone to treat RA in the current study. Furthermore, RAM alone had a protective effect on bone and cartilage health better than standard anti-rheumatic agent MTX. Interestingly, combined therapy of MTX and RAM produced significant differences in comparison with MTX or RAM monotherapy in all tested parameters. Moreover, the current study proved that MTX-RAM co-therapy has a synergistic effect., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nicorandil ameliorated doxorubicin-induced nephrotoxicity; this study aimed to show and explain the mechanism of this protection. A precise method was elucidated to study the effect of nicorandil on doxorubicin-induced nephrotoxicity in rats depending on the critical inflammation pathway TLR4/MAPK P38/NFκ-B. Adult male rats were subdivided into four groups. The 1st group was normal control, the 2nd group received nicorandil (3 mg/kg; p.o., for 4 weeks), the 3rd group received doxorubicin (2.6 mg/kg, i.p., twice per week for 4 weeks), and the fourth group was combination of doxorubicin and nicorandil for 4 weeks. Nephrotoxicity was assessed by biochemical tests through measuring Kidney function biomarkers such as [serum levels of urea, creatinine, albumin and total protein] besides renal kidney injury molecule-1 (KIM-1) and cystatin C], oxidative stress parameters such as [renal tissue malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase and nrf-2], mediators of inflammation such as [Toll like receptor 4 (TLR-4), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), p38 MAPK, Interleukin 1 beta (IL-1 β), and Tumor necrosis factor alpha (TNF-α)] and markers of apoptosis [BAX and Bcl-2 in renal tissue]. Finally, our data were supported by histopathology examination. Nicorandil pretreatment resulted in a significant decrease in nephrotoxicity biomarkers, oxidative stress markers, inflammatory mediators and prevented apoptosis through decreasing BAX and increasing Bcl-2 in renal tissues. Nicorandil prevented all the histological alterations caused by doxorubicin. Nicorandil is a promising antidote against doxorubicin-induced nephrotoxicity by neutralizing all toxicity mechanisms caused by doxorubicin through normalizing inflammatory cascade of TLR4/MAPK P38/NFκ-B., (Copyright © 2019. Published by Elsevier B.V.)

Cisplatin, a platinum chemotherapeutic agent, is used in a diversity of malignancies; nevertheless, the excessive nephrotoxicity following cisplatin treatment is the dose-limiting devastating reaction. This study was designed to explore the possible nephroprotective impact of wogonin, a forceful anti-oxidant, anti-inflammatory, and anti-tumor agent, in a rat model of cisplatin-induced renal injury. The potential nephroprotective mechanisms were additionally investigated. Wogonin was given at a dose of 40 mg/kg. Acute nephrotoxicity was indicated by a significant rise in BUN, and serum creatinine levels in cisplatin-injected rats. Also, cisplatin enhanced the lipid peroxidation, diminished GSH, catalase, and PPAR-γ levels. Additionally, cisplatin-injected rats showed a significant rise in tissue levels of IL-1β, TNF-α, NF-kB, and caspase-3 enzymatic activity. Notably, the pre-treatment with wogonin ameliorated the nephrotoxicity indices, oxidative stress, inflammation, and apoptosis induced by cisplatin. Also, wogonin up-regulated PPAR-γ expression. The involvement of Wnt/β-catenin pathway was debatable; however, our findings showed that it was significantly induced by cisplatin. Wogonin pre-treatment markedly attenuated Wnt/β-catenin pathway. Collectively, these findings imply that wogonin is a promising nephroprotective agent that improves the therapeutic index of cisplatin via reducing oxidative stress, inflammation as well as inducing PPAR-γ. Also, Wnt/β-catenin pathway is partially involved in the pathogenesis of cisplatin nephrotoxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Rheumatoid arthritis is usually accompanied by various comorbidities especially on the psychological side such as depression. This study aimed at revealing the potential curative effects of venlafaxine (VFX), a serotonin/norepinephrine reuptake inhibitor (SNRI), on experimentally-induced arthritis in rats., Methods: Arthritis was induced by injecting complete Freund's adjuvant (CFA, 0.1 ml, s.c.). One day thereafter, VFX (50 mg/kg, p.o.) was given for 21 days. Methotrexate was used as a standard disease modifying anti-rheumatic drug., Key Findings: CFA injection caused prominent arthritis evident by the increase in the hind paw and ankle diameter accompanied by elevating tumor necrosis factor-alpha, interleukin-6, interleukin-17 and matrix metalloproteinase-3 levels, effects that were diminished by VFX. Moreover, VFX down regulated gene expressions of receptor activator of nuclear factor kappa-B (NF-кB) ligand and signal transducer and activator of transcription-3 beside hampering immunohistochemical expression of vascular endothelial growth factor and NF-кB. This SNRI also improved the oxidant status of the hind limb as compared to the arthritic group. Nonetheless, MTX was better in amendment of arthritis authenticated by its effect on some inflammatory and oxidative stress biomarkers., Significance: This study provides a novel therapeutic use of VFX as a considerable anti-arthritic drug and offers an incentive to expand its use in RA., (Copyright © 2019 Elsevier Inc. All rights reserved.)