Combination of inhibitors for two glycolytic enzymes portrays high synergistic efficacy against Cryptosporidium parvum.

Cryptosporidium is an intracellular protozoan parasite that causes serious enteric disease in humans and in a wide range of animals worldwide. Despite its high prevalence, no effective therapeutic drugs are available against life-threatening cryptosporidiosis in at-risk populations including malnourished children, immunocompromised patients, and neonatal calves. Thus, new efficacious drugs are urgently needed to treat all susceptible populations with cryptosporidiosis. Unlike other apicomplexans, Cryptosporidium parvum lacks the tricarboxylic acid cycle and the oxidative phosphorylation steps, making it solely dependent on glycolysis for metabolic energy production. We have previously reported that individual inhibitors of two unique glycolytic enzymes, the plant-like pyruvate kinase (CpPyK) and the bacterial-type lactate dehydrogenase (CpLDH), are effective against C. parvum, both in vitro and in vivo. Herein, we have derived combinations of CpPyK and CpLDH inhibitors with strong synergistic effects against the growth and survival of C. parvum, both in vitro and in an infection mouse model. In infected immunocompromised mice, compound combinations of NSC303244 + NSC158011 and NSC252172 + NSC158011 depicted enhanced efficacy against C. parvum reproduction and ameliorated intestinal lesions of cryptosporidiosis at doses fourfold lower than the total effective doses of individual compounds. Importantly, unlike individual compounds, NSC303244 + NSC158011 combination was effective in clearing the infection completely without relapse in immunocompromised mice. Collectively, our study has unveiled compound combinations that simultaneously block two essential catalytic steps for metabolic energy production in C. parvum to achieve improved efficacy against the parasite. These combinations are, therefore, lead compounds for the development of a new generation of efficacious anti-cryptosporidial drugs.

Association of Anemia with Parathyroid Hormone Levels and Other Factors in Patients with End-Stage Renal Disease Undergoing Hemodialysis: A Cross-Sectional, Real-World Data Study in Pakistan.

End-stage renal disease (ESRD) patients are mostly managed with maintenance hemodialysis (MHD). ESRD patients on MHD also present with many complications, such as anemia, hyperparathyroidism, and hepatitis prevalence. This study depicts the real-world scenario of anemia among MHD and end-stage renal disease patients in the Pakistani population. A retrospective, multicentric, and real-world data analytical study was conducted at 4 dialysis centers in Pakistan. The study had a sample size of n = 342 patients on maintenance hemodialysis. The data were gathered from the medical records of patients. Data analysis was performed using STATA Version 16. Statistical significance was gauged at a 0.05 level of significance. According to our results, the mean age of the patients was 45 (±15) years. Most of the patients were male (n = 234, 68.4%), whereas 58.1% of the patients were maintained on twice-weekly hemodialysis. The most commonly reported comorbidities were hypertension and diabetes mellitus. The frequency of dialysis (P < 0.01) and comorbidities (P = 0.009) had a significant association with anemia in MHD patients. The majority of the patients had hyperparathyroidism (52%) with anemia. Upon performing binary logistic regression, multivariate analysis displayed a similar odds value for having anemia in patients with every additional month in the duration of hemodialysis (OR 1.01, P = 0.001), the odds of anemic patients having a positive antihepatitis-C antibody (OR 2.22, P = 0.013), and the odds of having anemia in patients in the age category below 45 years (OR 1.93, P = 0.013). In conclusion, the study results depict that every additional month in the duration of hemodialysis, age (<45 years), and positive anti-HCV antibody status, these variables were more likely to have anemia in our study MHD patients. While in our final multivariate model, no statistically significant association was observed between hyperparathyroidism and anemia.

Jasminum humile (Linn) ameliorates CCl4-induced oxidative stress by regulating ER stress, inflammatory, and fibrosis markers in rats.

Jasminum humile (Linn) is highly valued for its medicinal properties. The pulp and decoction made from its leaves are effective for skin diseases. Juice prepared from roots is used against ringworm illness. Our current study aims to illustrate the non-toxicity and protective potential of methanol extract of Jasminum humile (JHM) against CCl4-induced oxidative stress in the liver of rats. Qualitative phytochemical screening, total flavonoids (TFC), and total phenolic content (TPC) assays were performed with JHM. The toxicity of the plant was estimated by treating female rats at different JHM doses while to assess anti-inflammatory potential of plant nine groups of male rats (six rats/group) received different treatments such as: CCl4 only (1 ml/kg mixed with olive oil in a ratio of 3:7), silymarin (200 mg/kg) + CCl4, different doses of JHM alone at a ratio of 1:2:4, and JHM (at a ratio of 1:2:4) + CCl4, and were examined for different antioxidant enzymes, serum markers, and histological changes, while mRNA expression of stress, inflammatory and fibrosis markers were assessed by real-time polymerase chain reaction analysis. Different phytochemicals were found in JHM. A high amount of total phenolic and flavonoid content was found (89.71 ± 2.79 mg RE/g and 124.77 ± 2.41 mg GAE/g) in the methanolic extract of the plant. Non-toxicity of JHM was revealed even at higher doses of JHM. Normal levels of serum markers in blood serum and antioxidant enzymes in tissue homogenates were found after co-administration of JHM along with CCl4. However, CCl4 treatment caused oxidative stress in the liver by enhancing the levels of stress and inflammatory markers and reducing antioxidant enzyme levels, while JHM treatment showed significant (P < 0.05) downregulation was in mRNA expression of those markers. Investigation of mechanism of specific signaling pathways related to apoptosis and clinical trials to assess safety and efficacy of optimal dosage of Jasminum humile will be helpful to develop FDA-approved drug.

Linum corymbulosum Protects Rats against CCl4-Induced Hepatic Injuries through Modulation of an Unfolded Protein Response Pathway and Pro-Inflammatory Intermediates.

Liver fibrosis is a major pathological feature of chronic liver disease and effective therapies are limited at present. The present study focuses on the hepatoprotective potential of L. corymbulosum against carbon tetrachloride (CCl4)-induced liver damage in rats. Analysis of Linum corymbulosum methanol extract (LCM) using high-performance liquid chromatography (HPLC) revealed the presence of rutin, apigenin, catechin, caffeic acid and myricetin. CCl4 administration lowered (p < 0.01) the activities of antioxidant enzymes and reduced glutathione (GSH) content as well as soluble proteins, whereas the concentration of H2O2, nitrite and thiobarbituric acid reactive substances was higher in hepatic samples. In serum, the level of hepatic markers and total bilirubin was elevated followed by CCl4 administration. The expression of glucose-regulated protein (GRP78), x-box binding protein-1 total (XBP-1 t), x-box binding protein-1 spliced (XBP-1 s), x-box binding protein-1 unspliced (XBP-1 u) and glutamate-cysteine ligase catalytic subunit (GCLC) was enhanced in CCl4-administered rats. Similarly, the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemo attractant protein-1 (MCP-1) was strongly increased with CCl4 administration to rats. Co-administration of LCM along with CCl4 to rats lowered (p < 0.05) the expression of the above genes. Histopathology of the liver showed hepatocyte injury, leukocyte infiltration and damaged central lobules in CCl4-treated rats. However, LCM administration to CCl4-intoxicated rats restored the altered parameters towards the levels of control rats. These outcomes indicate the existence of antioxidant and anti-inflammatory constituents in the methanol extract of L. corymbulosum.

Cyber-Threat Detection System Using a Hybrid Approach of Transfer Learning and Multi-Model Image Representation.

Currently, Android apps are easily targeted by malicious network traffic because of their constant network access. These threats have the potential to steal vital information and disrupt the commerce, social system, and banking markets. In this paper, we present a malware detection system based on word2vec-based transfer learning and multi-model image representation. The proposed method combines the textual and texture features of network traffic to leverage the advantages of both types. Initially, the transfer learning method is used to extract trained vocab from network traffic. Then, the malware-to-image algorithm visualizes network bytes for visual analysis of data traffic. Next, the texture features are extracted from malware images using a combination of scale-invariant feature transforms (SIFTs) and oriented fast and rotated brief transforms (ORBs). Moreover, a convolutional neural network (CNN) is designed to extract deep features from a set of trained vocab and texture features. Finally, an ensemble model is designed to classify and detect malware based on the combination of textual and texture features. The proposed method is tested using two standard datasets, CIC-AAGM2017 and CICMalDroid 2020, which comprise a total of 10.2K malware and 3.2K benign samples. Furthermore, an explainable AI experiment is performed to interpret the proposed approach.

An Extensive Pharmacological Evaluation of New Anti-Cancer Triterpenoid (Nummularic Acid) from Ipomoea batatas through In Vitro, In Silico, and In Vivo Studies.

Prostate cancer (PCa) is the most common cancer in men, accounting for approximately 10% of all new cases in the United States. Plant-derived bioactive compounds, such as pentacyclic triterpenoids (PTs), have the ability to inhibit PCa cell proliferation. We isolated and characterized nummularic acid (NA), a potent PT, as a major chemical constituent of Ipomoea batatas, a medicinal food plant used in ethnomedicine for centuries. In the current study, in vitro antiproliferative potential against PCa cells (DU145 and PC3) via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay; Western blot protein expression analysis; absorption, distribution, metabolism, excretion (ADME); pharmacokinetic prediction studies; and bisphenol A (BPA)-induced prostate inhibition in Sprague Dawley rats were conducted to gauge the anti-cancer ability of NA. Significant (p < 0.05 and p < 0.01) time- and dose-dependent reductions in proliferation of PCa cells, reduced migration, invasion, and increased apoptotic cell population were recorded after NA treatment (3−50 µM). After 72 h of treatment, NA displayed significant IC50 of 21.18 ± 3.43 µM against DU145 and 24.21 ± 3.38 µM against PC3 cells in comparison to the controls cabazitaxel (9.56 ± 1.45 µM and 12.78 ± 2.67 µM) and doxorubicin (10.98 ± 2.71 µM and 15.97 ± 2.77 µM). Further deep mechanistic studies reveal that NA treatment considerably increased the cleavage of caspases and downstream PARP, upregulated BAX and P53, and downregulated BCL-2 and NF-κB, inducing apoptosis in PCa cells. Pharmacokinetic and ADME characterization indicate that NA has a favorable physicochemical nature, with high gastrointestinal absorption, low blood−brain barrier permeability, no hepatotoxicity, and cytochrome inhibition. BPA-induced perturbations of prostate glands in Sprague Dawley rats show a potential increase (0.478 ± 0.28 g) in prostate weight compared to the control (0.385 ± 0.13 g). Multi-dose treatment with NA (10 mg/kg) significantly reduced the prostate size (0.409 ± 0.21 g) in comparison to the control. NA-treated groups exhibited substantial restoration of hematological and histological parameters, reinstatement of serum hormones, and suppression of inflammatory markers. This multifaceted analysis suggests that NA, as a novel small molecule with a strong pharmacokinetic and pharmacological profile, has the potential to induce apoptosis and death in PCa cells.

Evaluation of Phytochemistry and Pharmacological Properties of Alnus nitida.

In the current study, the anti-inflammatory and analgesic potential of Alnus nitida (leaves and fruits) was evaluated in the Sprague-Dawley rat. Traditionally, A. nitida was used for the treatment of inflammatory ailments. However, A. nitida leaves and fruits have not been yet reported regarding any potential medicinal effects. Leaves/fruits of A. nitida were extracted with methanol and fractionated to attain n-hexane, chloroform, ethyl acetate and aqueous fractions. These extracts were then evaluated for in vivo analgesic and anti-inflammatory potential. For in vivo anti-inflammatory activity, carrageenan-induced paw edema assay, Freunds' complete adjuvant-induced edema, xylene-induced ear edema and histamine-induced paw edema models were used in rats, which showed significant (p < 0.01) reduction (70−80%) in edema in comparison of inflammatory controls. On other hand, for the analgesic assessment, hot plate assay and acetic acid-induced writhing tests were used, which showed a significant (p < 0.01) rise in latency time (40−60%) as compared with pain-induced controls. These results were comparable with standard drugs in a concentration-dependent manner and no mortality or toxicity was observed during all experiments. Then, for the identification of chemical constituents gas chromatography−mass spectrometry (GC-MS) analysis was performed, which indicated the presence of neophytadiene, 3,7,11,15-Tetramethyl-2-hexadecen-1-ol, phytol and vitamin E, justifying the use of A. nitida to treat inflammatory disorders.

In vitro antimicrobial and cytotoxic manifestations of Dicliptera roxburghiana.

Emerging resistance in microorganisms is a growing threat to human beings due to its role in pathological manifestations in different infectious diseases. This study was designed to investigate the antimicrobial and cytotoxic potential of methanol extract of Dicliptera roxburghiana and all its derived fractions. Antibacterial (against six bacterial strains) and antifungal (against four fungal strains) activities were investigated by agar well diffusion method and agar slants method, respectively. Cytotoxicity assay was carried out by using Brine shrimps eggs. In antibacterial evaluation, MIC values and zone of inhibition were measured and were found very effective for DRME, DRHF, DRCF and DREF while these were moderate for DRBF and DRAF. For antifungal assay, DRME and DRHF were potently active and showed more than 70% fungal growth inhibition where as DRCF and DRBF were also displaying appreciable inhibition. Cytotoxic measurements were very good for DRME, DRHF and DRAF with LD50 values 215, 199 and 392µg/ml respectively. These results confirmed antimicrobial and cytotoxic potential of the plant and all its derived fractions. Hence it can be concluded that plant contain some important compounds that can be used as antimicrobial source for the treatment of different infectious disease.

Phytochemicals of Periploca aphylla Dcne. ameliorated streptozotocin-induced diabetes in rat.

BACKGROUND: Periploca aphylla is used by local population and indigenous medicine practitioners as stomachic, tonic, antitumor, antiulcer, and for treatment of inflammatory disorders. The aim of this study was to evaluate antidiabetic effect of the extract of P. aphylla and to investigate antioxidant and hypolipidemic activity in streptozotocin (STZ)-induced diabetic rats. METHODS: The present research was conducted to evaluate the antihyperglycemic potential of methanol extract of P. aphylla (PAM) and subfractions n-hexane (PAH), chloroform (PAC), ethyl acetate (PAE), n-butanol (PAB), and aqueous (PAA) in glucose-overloaded hyperglycemic Sprague-Dawley rats. Based on the efficacy, PAB (200 mg/kg and 400 mg/kg) was tested for its antidiabetic activity in STZ-induced diabetic rats. Diabetes was induced via intraperitoneal injection of STZ (55 mg/kg) in rat. Blood glucose values were taken weekly. HPLC-DAD analysis of PAB was carried out for the presence of various polyphenols. RESULTS: HPLC-DAD analysis of PAB recorded the presence of rutin, catechin, caffeic acid, and myricetin. Oral administration of PAB at doses of 200 and 400 mg/kg for 21 days significantly restored (P < 0.01) body weight (%) and relative liver and relative kidney weight of diabetic rats. Diabetic control rats showed significant elevation (P < 0.01) of AST, ALT, ALP, LDH, total cholesterol, triglycerides, LDL, creatinine, total bilirubin, and BUN while reduced (P < 0.01) level of glucose, total protein, albumin, insulin, and HDL in serum. Count of blood cells and hematological parameters were altered in diabetic rats. Further, glutathione peroxidase, catalase, superoxide dismutase, glutathione reductase, and total soluble protein concentration decreased while concentration of thiobarbituric acid reactive substances and percent DNA damages increased (P < 0.01) in liver and renal tissues of diabetic rats. Histopathological damage scores increased in liver and kidney tissues of diabetic rats. Intake of PAB (400 mg/kg) resulted in significant improvement (P < 0.01) of above parameters, and results were comparable to that of standard drug glibenclamide. CONCLUSION: The result suggests the antihyperglycemic, antioxidant, and anti-inflammatory activities of PAB treatment in STZ-compelled diabetic rat. PAB might be used as new therapeutic agent in diabetic patients to manage diabetes and decrease the complications.

Clinical and biochemical indicators of disease severity and neurological findings in COVID-19: A study of King Edward Medical University (KEMU), Pakistan.

This study investigated the significance of difference between presence and absence of different neurological findings in COVID-19, in relation with the biochemistry. Various significant correlations in connection with the disease severity and clinical factors were also identified. 351 COVID-19 patients were included. Different laboratory/ clinical findings were investigated. Correlations Kendall's tau and Pearson Chi-Square were applied to find the correlations between severity and clinical findings. The Mann-Whitney Test was applied for a comparison between two types of neurological groups for each biochemistry parameter. Headache was reported in 28% and dizziness in 13% patients. The impaired smell and impaired taste were reported in 28.5% and 36.2% patients, respectively. The muscle pain was present in 39% patients. 80% patients had low lymphocytes & 70% had high neutrophils. 54.5% were found with high ALP. LDH was elevated in 73%. Severity was found significantly correlated with decreased oxygen saturation, age and raised levels of urea, creatinine and LDH. The groups (with/without CNS involvement) were statistically different in ALP, groups (with/without PNS involvement) in WBC, lymphocytes, neutrophils, ALP, urea, creatinine, CK, CKMB and LDH and groups (with/without MSK involvement) in WBC. Oxygen saturation, age, urea, creatinine and LDH are significant indicators of disease severity in COVID-19. The altered levels of different biochemistry can impact the neurological states of COVID-19 patients.

Epidemiology of Influenza among patients with influenza-like illness and severe acute respiratory illness in Pakistan: A 10-year surveillance study 2008-17.

In Pakistan, the burden of influenza was largely unknown, as no formal surveillance system was in place. In 2008, an influenza surveillance system was set up in eight sentinel sites. This study describes the epidemiology of influenza virus using a 10-year surveillance data from 2008 to 2017. Nasopharyngeal/throat swabs were collected from patients with influenza-like illness (ILI) and severe acute respiratory illness (SARI) along with relevant epidemiological information. The samples were tested using real-time reverse transcriptase-polymerase chain reaction for the detection and characterization of influenza viruses. A total of 17 209 samples were tested for influenza, out of which 3552 (20.6%) were positive; 2151/11 239 (19.1%) were patients with ILI, whereas 1401/5970 (23.5%) were patients with SARI. Influenza A/H1N1pdm09 was the predominant strain with 40.6% (n = 1442) followed by influenza B (936, 26.4%). Influenza A/H1N1pdm09 was predominant among the children (5-14 years) and adults (15-64 years). Influenza B strain was predominantly found in the elderly age group (≥ 65 years) accounting for 48% of cases followed by children (2-4 years) accounting for 37% of cases. This 10-year surveillance data provides evidence of influenza activity in the country throughout the year with seasonal winter peaks. The results could be used to strengthen the epidemic preparedness and response plan.

Phytochemical analysis and Evaluation of hepatoprotective effect of Maytenus royleanus leaves extract against anti-tuberculosis drug induced liver injury in mice.

BACKGROUND: Myrin®-p Forte is an anti-tuberclosis agent that can cause hepatic injuries in clinical settings. Maytenus royleanus (Celastraceae) is a medicinal plant, possesses antioxidant and anticancer activities. The hepatoprotective effect of the methanol extract of Maytenus royleanus leaves (MEM) against Myrin®-p Forte induced hepatotoxicity in mice was investigated. METHODS: Mice were randomly parted into six groups (n = 6). Fixed-dose combination of Myrin®-p Forte (13.5 mg/kg Rifampicin, 6.75 mg/kg Isoniazid, 36.0 mg/kg Pyrazinamide and 24.8 mg/kg Ethambutol; RIPE] was administered for 15 days to induce liver injury. In treatment groups MEM (200 mg/kg and 400 mg/kg doses) and Vitamin B6 (180mg/kg) were administered prior to RIPE. Control group received 2% DMSO. Serum liver function tests, DNA damage, tissue antioxidant enzymes and histopathological alterations were studied. HPLC analysis was performed to determine the chemical composition using standard compounds. RESULTS: The quercitin, gallic acid, luteolin, viteixin, apigenin, kaempherol, hyperoside and myricetin contents of all samples were determined by reverse-phase HPLC. Quercetin (0.217 mg/g dry weight) and luteolin (0.141 mg/g dry weight) were the major flavonoids identified in MEM. Myrin®-p Forte markedly (p < 0.05) deteriorated lipid profile and upregulated the concentration of LDH, AST, ALP, ALT and γ-GT in serum along with DNA fragmentation (37.13 ± 0.47%) and histopathological injuries in hepatic tissues of mice compared with the control group. Myrin®-p Forte increased (p < 0.001) lipid peroxidation and H2O2 while decreased (p < 0.001) the activity level of CAT, SOD, POD, GPx, GST, GSR, γ-GT and GSH. Co-administration of MEM (200 mg/kg; 400 mg/kg) or the vitamin B6 (180 mg/kg) to Myrin®-p Forte administered mice significantly ameliorated LDL, cholesterol, HDL and triglyceride content. Furthermore, MEM dose dependently corrected serum liver function tests, decrease % DNA fragmentation (17.82 ± 0.35 and 7.21 ± 0.32 respectively), DNA damage. MEM treated protect RIPE induced oxidative damage by enhancing antioxidants to oxidants balance. Histological examination comprehends biochemical findings. CONCLUSION: The antioxidant effects of MEM exerted the hepatoprotective potential against the Myrin®-p Forte induced hepatotoxicity in mice.

Gonadoprotective ability of Vincetoxicum arnottianum extract against bisphenol A-induced testicular toxicity and hormonal imbalance in male Sprague Dawley rats.

Vincetoxicum arnottianum (Wight) of family Apocynaceae is a rich source of therapeutic alkaloids, phenolics and flavonoids. Study aims to evaluate the protective potential of methanol extract of Vincetoxicum arnottianum (VAM) on bisphenol A (BPA)-induced testicular toxicity in male Sprague Dawley rat. Quantitative analysis of VAM for total phenolic (TPC), total flavonoid (TFC) and total alkaloid content (TAC) along with HPLC analysis for polyphenolics was carried out. BPA-induced testicular toxicity was determined through analysis of antioxidant enzymes, DNA damages and testicular histopathology along with reproductive hormones in serum of rat. VAM was constituted of TFC (382.50 ± 1.67 µg GAE/mg), TPC (291.17 ± 0.82 µg RE/mg), TAC (16.5 ± 0.5%), ferulic acid (2.2433 µg/mg) and vanillic acid (2.1249 µg/mg). VAM co-administration to BPA-treated rats attenuated the toxic effects of BPA and restored the body and testis weights. Altered level of luteinizing hormone (LH), testosterone and follicle-stimulating hormone (FSH) in serum, and level of antioxidants (GSH, POD, CAT and SOD) and nitric oxide in testis tissues of BPA-induced toxicity were significantly restored by VAM. Histological and comet assay studies also sanctioned the protective potential of VAM in BPA-intoxicated rats. The presence of polyphenols and alkaloids might contribute towards the scavenging and ameliorative potential of VAM in testicular toxicity induced by BPA.

A review on recent developments in the adsorption of surfactants from wastewater.

The pollution of the world's water resources is a growing issue which requires remediation. Surfactants used in many domestic and industrial applications are one of the emerging contaminants that require immediate attention. Treating water contaminated with surfactants using adsorption provides better performance when compared to other techniques. A variety of materials have been developed for adsorbing surfactants. Activated carbon is the most suitable adsorbent for removing surfactants but is expensive to synthesize and difficult to regenerate. Therefore, a variety of new adsorbents such as zeolites, nanomaterials, resins, biomaterials and clays have been developed as alternatives. The developed adsorbents are promising but considerable research is still required to develop highly efficient, economical, environment friendly and sustainable adsorbents to replace activated carbon. This paper critically reviews the characteristics of adsorbents, the performance of adsorbents, kinetics, isotherms and thermodynamics, mechanisms of adsorption, regeneration of adsorbents and future perspectives in the adsorption of surfactants. Developing novel adsorbents, testing adsorbents in real wastewaters and recycling the adsorbents are required in future studies in the removal of surfactants.

Anticancer Potential of Raddeanin A, a Natural Triterpenoid Isolated from Anemone raddeana Regel.

Natural compounds extracted from plants have gained immense importance in the fight against cancer cells due to their lesser toxicity and potential therapeutic effects. Raddeanin A (RA), an oleanane type triterpenoid is a major compound isolated from Anemone raddeana Regel. As an anticancer agent, RA induces apoptosis, cell cycle arrest, inhibits invasion, migration and angiogenesis in malignant cell lines as well as in preclinical models. In this systemic review, the pharmacological effects of RA and its underlying molecular mechanisms were carefully analyzed and potential molecular targets have been highlighted. The apoptotic potential of RA can be mediated through the modulation of Bcl-2, Bax, caspase-3, caspase-8, caspase-9, cytochrome c and poly-ADP ribose polymerase (PARP) cleavage. PI3K/Akt signaling pathway serves as the major molecular target affected by RA. Furthermore, RA can block cell proliferation through inhibition of canonical Wnt/ß-catenin signaling pathway in colorectal cancer cells. RA can also alter the activation of NF-κB and STAT3 signaling pathways to suppress invasion and metastasis. RA has also exhibited promising anticancer potential against drug resistant cancer cells and can enhance the anticancer effects of several chemotherapeutic agents. Overall, RA may function as a promising compound in combating cancer, although further in-depth study is required under clinical settings to validate its efficacy in cancer patients.

An Overview of the Potential Antineoplastic Effects of Casticin.

Cancer persists as one of the leading causes of deaths worldwide, contributing to approximately 9.6 million deaths per annum in recent years. Despite the numerous advancements in cancer treatment, there is still abundant scope to mitigate recurrence, adverse side effects and toxicities caused by existing pharmaceutical drugs. To achieve this, many phytochemicals from plants and natural products have been tested against cancer cell lines in vivo and in vitro. Likewise, casticin, a flavonoid extracted from the Vitex species, has been isolated from the leaves and seeds of V. trifolia and V. agnus-castus. Casticin possesses a wide range of therapeutic properties, including analgesic, anti-inflammatory, antiangiogenic, antiasthmatic and antineoplastic activities. Several studies have been conducted on the anticancer effects of casticin against cancers, including breast, bladder, oral, lung, leukemia and hepatocellular carcinomas. The compound inhibits invasion, migration and proliferation and induces apoptosis (casticin-induced, ROS-mediated and mitochondrial-dependent) and cell cycle arrest (G0/G1, G2/M, etc.) through different signaling pathways, namely the PI3K/Akt, NF-κB, STAT3 and FOXO3a/FoxM1 pathways. This review summarizes the chemo-preventive ability of casticin as an antineoplastic agent against several malignancies.

Pilea umbrosa ameliorate CCl4 induced hepatic injuries by regulating endoplasmic reticulum stress, pro-inflammatory and fibrosis genes in rat.

BACKGROUND: Pilea umbrosa (Urticaceae) is used by local communities (district Abbotabad) for liver disorders, as anticancer, in rheumatism and in skin disorders. METHODS: Methanol extract of P. umbrosa (PUM) was investigated for the presence of polyphenolic constituents by HPLC-DAD analysis. PUM (150 mg/kg and 300 mg/kg) was administered on alternate days for eight weeks in rats exposed with carbon tetrachloride (CCl4). Serum analysis was performed for liver function tests while in liver tissues level of antioxidant enzymes and biochemical markers were also studied. In addition, semi quantitative estimation of antioxidant genes, endoplasmic reticulum (ER) induced stress markers, pro-inflammatory cytokines and fibrosis related genes were carried out on liver tissues by RT-PCR analysis. Liver tissues were also studied for histopathological injuries. RESULTS: Level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione (GSH) decreased (p < 0.05) whereas level of thiobarbituric acid reactive substance (TBARS), H2O2 and nitrite increased in liver tissues of CCl4 treated rat. Likewise increase in the level of serum markers; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin was observed. Moreover, CCl4 caused many fold increase in expression of ER stress markers; glucose regulated protein (GRP-78), x-box binding protein1-total (XBP-1 t), x-box binding protein1-unspliced (XBP-1 u) and x-box binding protein1-spliced (XBP-1 s). The level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) was aggregated whereas suppressed the level of antioxidant enzymes; γ-glutamylcysteine ligase (GCLC), protein disulfide isomerase (PDI) and nuclear erythroid 2 p45-related factor 2 (Nrf-2). Additionally, level of fibrosis markers; transforming growth factor-ß (TGF-ß), Smad-3 and collagen type 1 (Col1-α) increased with CCl4 induced liver toxicity. Histopathological scrutiny depicted damaged liver cells, neutrophils infiltration and dilated sinusoids in CCl4 intoxicated rats. PUM was enriched with rutin, catechin, caffeic acid and apigenin as evidenced by HPLC analysis. Simultaneous administration of PUM and CCl4 in rats retrieved the normal expression of these markers and prevented hepatic injuries. CONCLUSION: Collectively these results suggest that PUM constituted of strong antioxidant chemicals and could be a potential therapeutic agent for stress related liver disorders.

Presentation of pleural effusion and dilated cardiomyopathy in a case of dystrophic epidermolysis bullosa.

Epidermolysis Bullosa (EB), a genetic disorder of the skin that presents with eruptive lesions accompanied by blistering has multiple types. We present a case of dystrophic and epidermolysis bullosa (DEB), a rare variant of the disease with the underlying pathophysiology involving a mutation of type VII collagen that serves as an anchoring protein for basement membrane to the dermis. The patient presented with palmoplantar hyperkeratosis with blistering extending on multiple sites of the body, bilateral pleural effusion and an ejection fraction of 23% with moderate mitral regurgitation. The patient was treated symptomatically with diuretics and inotropic medication for the dilated heart, along with draining of pleural spaces. No case of DEB with pleural effusion has been reported prior to this one. We believe this is the first case that presented with both pleural effusion and dilated cardiomyopathy.

Pharmacological evaluation of Acacia modesta bark for antipyretic, anti-inflammatory, analgesic, antidepressant and anticoagulant activities in Sprague Dawley rats.

In this study the bark of Acacia modesta was evaluated for anti-inflammatory, antipyretic, analgesic, antidepressant and anticoagulant activity by carrageenan, hot plat, forced swim and capillary tube method respectively in rats. Highest anti-inflammatory activity was exhibited by chloroform (AMC) extract (74.96% inhibition) while other two active fractions being n-hexane (AMH) and ethyl acetate (AME) exhibited 71.26% and 52.87% inhibition of edema respectively. On the other hand, the aqueous (AMA) fraction showed most effective response with 67.06% analgesic activity. Additionally, the significant (p<0.05) post-treatment antipyretic effect was found by all fractions in time dependent manner. The current findings showed that AMC, AME and AMA had significant reduction in immobility time in the antidepressant test, while AMH showed mild antidepressant activity. In anticoagulant assay, the coagulation time of crude extract A. modesta and its all fractions were comparable to that of positive control aspirin (208s). Moreover, neither mortality nor lethality was observed in the tested animals. Overall, the plant extracts showed potent anti-inflammatory, antipyretic, analgesic, antidepressant and anticoagulant activities which concludes that the bark of A. modesta have significant therapeutic potential.

Abutilon pannosum stem bark enhances the aphrodisiac activities and spermatogenesis in rat.

Abutilon pannosum (Forst.f.) Schlecht. is used for male sexual performance. In this study, we have investigated aphrodisiac potential of A. pannosum stem bark methanol extract (APM) in rat. Male rats were administered with APM (400 mg/kg) on daily basis for 5, 10 and 15 days. Time interval for mount latency, intromission latency and post-ejaculatory interval was decreased (p < .05) while time of ejaculatory latency, mount frequency, intromission frequency and ejaculatory frequency after 15 days were (p < .05) enhanced as compared to control rats. APM also increased (p < .05) penile erection index, copulatory rate and mount bout against control rats. Total count of spermatozoa was nonsignificantly increased whereas per cent of live spermatozoa and motile spermatozoa were increased (p < .05) in APM treated group after 10 and 15 days. Weight of testes, seminal vesicle, prostate and epididymis, and level of testosterone in serum increased (p < .05) after 10 and 15 days of APM administration to rat. Qualitative characterisation of APM indicated existence of alkaloids, terpenoids, coumarins, cardiac glycosides, phenols, flavonoids, saponins, tannins and sterols. Results of this study indicated aphrodisiac potential of A. pannosum in rat and may be used to enhance sexual performance in human.