A comprehensive review of apigenin a dietary flavonoid: biological sources, nutraceutical prospects, chemistry and pharmacological insights and health benefits.

A multitude of plant-derived bioactive compounds have shown significant promise in preventing chronic illnesses, with flavonoids constituting a substantial class of naturally occurring polyphenolic compounds. Apigenin, a flavone identified as 4',5,7-trihydroxyflavone, holds immense promise as a preventative agent against chronic illnesses. Despite its extensive research and recognized nutraceutical value, its therapeutic application remains underexplored, necessitating further clinical investigations. This review delves into the biological sources, nutraceutical prospects, chemistry, pharmacological insights, and health benefits of apigenin. Through multifaceted analytical studies, we explore its diverse pharmacological profile and potential therapeutic applications across various health domains. The manuscript comprehensively examines apigenin's role as a neuroprotective , anti-inflammatory compound, and a potent antioxidant agent. Additionally, its efficacy in combating cardiovascular diseases, anti-diabetic properties, and anticancer potential has been discussed. Furthermore, the antimicrobial attributes and the challenges surrounding its bioavailability, particularly from herbal supplements have been addressed. Available in diverse forms including tablets, capsules, solid dispersions, co-crystals, inclusion complexes and nano formulations. Additionally, it is prevalent as a nutraceutical supplement in herbal formulations. While strides have been made in overcoming pharmacokinetic hurdles, further research into apigenin's clinical effectiveness and bioavailability from herbal supplements remains imperative for its widespread utilization in preventive medicine.

Efficacy of Ferulic Acid in an Animal Model of Drug-Resistant Epilepsy: Beneficial or Not?

Background Lamotrigine (LTG) and subconvulsive doses of pentylenetetrazol (PTZ) as a model mimic drug-resistant epilepsy (DRE), which is a serious unmet medical condition. Previous evidence suggests an imperative role of neuroinflammation in the development of DRE. Various preclinical models of brain injury have reported potent anti-inflammatory and antioxidant properties of ferulic acid (FA). Therefore, its efficacy against intractable epilepsy is worthwhile to study. Materials and methods The present study evaluated the efficacy of FA in LTG and PTZ-induced refractory seizures in mice. On every alternate day for 38 days, LTG (5mg/kg) was injected before PTZ (30-40mg/kg) to establish a murine model of DRE. Animals were treated with two doses of FA (40, 80 mg/kg). All the animals were assessed for seizure score and the latency of seizures every alternate day till the end of the study. Histopathological score and the levels of pro-inflammatory mediators, interleukin-1ßeta (IL-Iß), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) were quantified in the brain tissue of these mice.  Results Ferulic acid (FA) neither decreases the LTG and PTZ-induced refractory seizures score nor increases the latency to develop seizures. In addition, the injury to hippocampal neurons and the levels of pro-inflammatory cytokines were comparable with two doses of FA in treated mice. Conclusion In the present study, single-dose FA treatment does not show any beneficial effect against the LTG/PTZ model of DRE. Therefore, its single-dose administration might not be beneficial against the DRE model.

Dimethyl Fumarate Ameliorates Paclitaxel-Induced Neuropathic Pain in Rats.

Background Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is nonresponsive to the currently available analgesics. Previous studies have shown the role of oxidative stress and central sensitization in the development of peripheral neuropathy. Dimethyl fumarate (DMF) acts as a nuclear factor erythroid-2-related factor 2 (Nrf2) activator with neuroprotective benefits and is approved for use in multiple sclerosis. Materials and methods In the current research, we evaluated the efficacy of DMF on paclitaxel-induced peripheral neuropathy in rats. Every alternate day for one week, paclitaxel 2 mg/kg dose was injected to establish a rat model of PIPN. Animals were treated with 25 mg/kg and 50 mg/kg of DMF. All the animals were assessed for thermal hyperalgesia, cold allodynia, and mechanical allodynia once a week. The gene expression of Nrf2 and the levels of pro-inflammatory mediators (interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and IL-1ß) were quantified in the sciatic nerves of these rats. The levels of p38 mitogen-activated protein kinase (MAPK) and brain-derived neurotrophic factor (BDNF) were quantified in the dorsal horn of the spinal cord. Results DMF significantly attenuated paclitaxel-induced thermal hyperalgesia and cold/mechanical allodynia. A significant decrease in the levels of pro-inflammatory cytokines with the levels of p38 MAPK and BDNF was observed in the DMF-treated animals. DMF treatment significantly upregulated the gene expression of Nrf2 in the sciatic nerve. Conclusion These findings suggest that DMF prevented the development of PIPN in rats through the activation of Nrf2 and the inhibition of p38 MAPK and BDNF.

Dental pulp stem cell secretome ameliorates d-galactose induced accelerated aging in rat model.

Advancing age is associated with several diseases and disorders due to multiorgan atrophy. The increasing proportion of elderly humans demands the identification of means to counteract aging and age-associated disorders. There is an increased depletion of stem cells in the aged organs, resulting in their inability to repair the damage and hence organ degeneration. Stem cell therapy has been implicated in counteracting aging and shown promise. However, the use of stem cells encounters several side effects and complications such as handling and storage of the cells for transplantation purpose. Stem cells secretome has proven to be of significant importance in a variety of disorders. In this study, we have shown that secretome derived from dental pulp stem cells (DPSCs) can reverse the age-associated degeneration induced by chronic exposure to d-galactose in a rat model. The secretome was able to increase muscle grip strength and animal activity. Secretome also improved the kidney function and hepatic biochemistry similar to healthy controls as evaluated by renal function test and Fourier-transform infrared spectroscopy. We also showed that secretome reduced the levels of monoamine oxidase and acetylcholinesterase in the brain and liver, indicating aging reversal. Finally, proteomic profiling of DPSCs secretome revealed the presence of 13 proteins which have antiaging functions. Thus, our study provides first proof of concept that DPSCs secretome can render protection against d-galactose induced accelerated aging.

Piperlongumine inhibits diethylnitrosamine induced hepatocellular carcinoma in rats.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory effects in various cancer cell lines and xenograft models, but the chemopreventive potential of PL has not been studied in experimentally induced HCC yet. RESEARCH DESIGN: Twenty-four Wistar male rats were divided into four groups of six each, Group A: untreated control; Group B: Diethylnitrosamine (DEN) control (200 mg/kg), Group C: DEN + PL 10 mg/kg; and Group D: DEN + PL 20 mg/kg. Rats from all groups were assessed for liver cancer progression or inhibition by evaluating biochemical, cytokines, tumor markers, lipid peroxidation, and histological profiles. RESULTS: The liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) levels, and lipid peroxidation were significantly decreased in Group C and Group D compared to Group B. Upregulation in the level of pro-inflammatory cytokines IL-1B, TNF-α, inflammatory mediator (NF-κB) and tumour marker alpha-fetoprotein (AFP) in Group B were brought down upon treatment with piperlongumine in a dose-dependent manner. Antitumor cytokine (IL-12) was upregulated in PL-treated rats compared to DEN control rats. DEN treated group (Group B) showed histological features of HCC, and in rats treated with PL (Groups C, D) partial to complete reversal to normal liver histoarchitecture was observed. CONCLUSIONS: The potential chemopreventive actions of piperlongumine may be due to its free radical scavenging and antiproliferative effect. Therefore, piperlongumine may serve as a novel therapeutic agent for the treatment of hepatocellular carcinoma.

Molecular docking analysis of piperlongumine with different apoptotic proteins involved in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Numerous signalling pathways are involved in hepatocellular carcinoma. Piperlongumine is a potential candidate for the treatment of hepatocellular carcinoma. Therefore, it is of interest to document the molecular docking analysis of piperlongumine with different apoptotic proteins involved in Hepatocellular Carcinoma. Piperlongumine was docked with the HCC targets such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor, Aurora-2, Nuclear factor Kappa-B (NF-KB), Jak2 Kinase, Fibroblast growth factor receptor 4, Bcl-2-like protein 1,Apopain, and Apoptosis regulator Bcl-2 using in-silico technique with the software grid-based ligand docking with energies. Piperlongumine exhibited the highest negative energy value (E-value) of -6.58 kcal/mol with vascular endothelial growth factor receptor 2, followed by -5.46, -5.34, -5.31, and -5.29 kcal/mol with 1M17, 2BMC, 1SVC, 4C61, 4XCU with epidermal growth factor receptor, aurora-2, nuclear factor Kappa-B (NF-KB), Jak2 kinase, and fibroblast growth factor receptor 4 (FGFR4), respectively for further consideration.

MiR-644a Disrupts Oncogenic Transformation and Warburg Effect by Direct Modulation of Multiple Genes of Tumor-Promoting Pathways.

Castration-resistant prostate cancer (CRPC) is defined by tumor microenvironment heterogeneity affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), and aberrant activation of transcription factors including androgen receptor (AR) and c-Myc. Using in vitro, in vivo, and animal models, we find a direct correlation between miR-644a downregulation and dysregulation of essential cellular processes. MiR-644a downregulated expression of diverse tumor microenvironment drivers including c-Myc, AR coregulators, and antiapoptosis factors Bcl-xl and Bcl2. Moreover, miR-644a modulates epithelial-mesenchymal transition (EMT) by directly targeting EMT-promoting factors ZEB1, cdk6, and Snail. Finally, miR-644a expression suppresses the Warburg effect by direct targeting of c-Myc, Akt, IGF1R, and GAPDH expression. RNA sequencing analysis revealed an analogous downregulation of these factors in animal tumor xenografts. These data demonstrate miR-644a mediated fine-tuning of oncogenesis, stimulating pathways and resultant potentiation of enzalutamide therapy in CRPC patients. SIGNIFICANCE: This study demonstrates that miR-644a therapeutically influences the CRPC tumor microenvironment by suppressing androgen signaling and additional genes involved in metabolism, proliferation, Warburg effect, and EMT, to potentiate the enzalutamide therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1844/F1.large.jpg.

Study of nuclear factor-2 erythroid related factor-2 activator, berberine, in paclitaxel induced peripheral neuropathy pain model in rats.

OBJECTIVES: The role of nuclear factor-2 erythroid related factor-2 (Nrf2) activator, berberine (BBR), has been established in rat model of streptozotocin induced diabetic neuropathy. Around 30-40% of cancer patients, on paclitaxel (PTX) chemotherapy develop peripheral neuropathy. The present study was contemplated with the aim of establishing the neuropathy preventive role of BBR, in paclitaxel induced peripheral neuropathy model in rats. METHODS: A total of 30 Wistar rats were divided into five groups as follows: Group I: dimethyl sulfoxide; Group II: PTX+ 0.9% NaCl; Group III: Amitriptyline (ATL) + PTX; Group IV: BBR (10 mg/kg) + PTX and Group V: BBR (20 mg/kg) + PTX. Animals were assessed for tail flick latency, tail cold allodynia latency, histopathological scores, oxidative stress parameters, and mRNA expression of the Nrf2 gene in the sciatic nerve. KEY FINDINGS: Berberine significantly increased the tail flick and tail cold allodynia latencies and significantly decreased the histopathological score. BBR reduced oxidative stress by significantly decreasing the lipid peroxidation, increasing the superoxide dismutase and reduced glutathione levels in the sciatic nerve. BBR also increased the mRNA expression of Nrf2 gene in rat sciatic nerve. CONCLUSIONS: All of these results showed the neuropathy preventing role of BBR in PTX induced neuropathy pain model in rats.

Mutations of RNA splicing factors in hematological malignancies.

Systematic large-scale cancer genomic studies have produced numerous significant findings. These studies have not only revealed new cancer-promoting genes, but they also have identified cancer-promoting functions of previously known "housekeeping" genes. These studies have identified numerous mutations in genes which play a fundamental role in nuclear precursor mRNA splicing. Somatic mutations and copy number variation in many of the splicing factors which participate in the formation of multiple spliceosomal complexes appear to play a role in many cancers and in particular in myelodysplastic syndromes (MDS). Mutated proteins seem to interfere with the recognition of the authentic splice sites (SS) leading to utilization of suboptimal alternative splicing sites generating aberrantly spliced mRNA isoforms. This short review is focusing on the function of the splice factors involved in the formation of splicing complexes and potential mechanisms which affect usage of the authentic splice site recognition.

Impact of regulatory spin of pioglitazone on prescription of antidiabetic drugs among physicians in India: A multicentre questionnaire-based observational study.

Background & objectives: Pioglitazone was suspended for manufacture and sale by the Indian drug regulator in June 2013 due to its association with urinary bladder carcinoma, which was revoked within a short period (July 2013). The present questionnaire-based nationwide study was conducted to assess its impact on prescribing behaviour of physicians in India. Methods: Between December 2013 and March 2014, a validated questionnaire was administered to physicians practicing diabetes across 25 centres in India. Seven hundred and forty questionnaires fulfilling the minimum quality criteria were included in the final analysis. Results: Four hundred and sixteen (56.2%) physicians prescribed pioglitazone. Of these, 281 used it in less than the recommended dose of 15 mg/day. Most physicians (94.3%) were aware of recent regulatory events. However, only 333 (44.8%) changed their prescribing pattern. Seventeen of the 416 (4.1%) physicians who prescribed pioglitazone admitted having come across at least one type 2 diabetes mellitus patient (T2DM) who had urinary bladder carcinoma, and of these 13 said that it was in patients who took pioglitazone for a duration of more than two years. Only 7.8 per cent of physicians (n=58) categorically advocated banning pioglitazone, and the rest opined for its continuation or generating more evidence before decision could be taken regarding its use in T2DM. Interpretation & conclusions: Majority of the physicians though were aware of the regulatory changes with regard to pioglitazone, but their prescribing patterns were not changed for this drug. However, it was being used at lower than the recommended dose. There is a need for generating more evidence through improved pharmacovigilance activities and large-scale population-based prospective studies regarding the safety issues of pioglitazone, so as to make effectual risk-benefit analysis for its continual use in T2DM.

Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date.

The longest survival of a non-human primate with a life-supporting kidney graft to date has been 90 days, although graft survival > 30 days has been unusual. A baboon received a kidney graft from an α-1,3-galactosyltransferase gene-knockout pig transgenic for two human complement-regulatory proteins and three human coagulation-regulatory proteins (although only one was expressed in the kidney). Immunosuppressive therapy was with ATG+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R were administered. The baboon survived 136 days with a generally stable serum creatinine (0.6 to 1.6 mg/dl) until termination. No features of a consumptive coagulopathy (e.g., thrombocytopenia, decreased fibrinogen) or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response. Death was from septic shock (Myroides spp). Histology of a biopsy on day 103 was normal, but by day 136, the kidney showed features of glomerular enlargement, thrombi, and mesangial expansion. The combination of (i) a graft from a specific genetically engineered pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory agents prevented immune injury and a protein-losing nephropathy, and delayed coagulation dysfunction. This outcome encourages us that clinical renal xenotransplantation may become a reality.

Joubert syndrome: a case report.

Joubert syndrome is a very rare disorder characterised by respiratory irregularities, saccadic eye movements, hypotonia, ataxia, developmental retardation with abnormalities of cerebellum and brainstem. Epilepsy is rarely associated with this syndrome. Herein such a case with associated epilepsy is presented. Here in this case, a male child of 4 years was presented with delayed milestones and generalised tonic-clonic seizure. Pregnancy and prenatal period was uneventful. There was history of one of his siblings having the disorders of respiratory irregularities, saccadic eye movements, ataxia, hypotonia, etc (same as the child) and died at 3 1/2 years of age. MRI brain showed features of Joubert syndrome.

Tunica vaginalis: an aid in hypospadias fistula repair: our experience of 14 cases.

BACKGROUND: Urethrocutaneous fistula is the most common complication of hypospadias surgery. The correction of such fistula is associated with a failure rate of 10 to 40%. The step in successful repair of a fistula is separation of the suture lines in the urethra and skin using well vascularized elastic tissue. We report our experience of using the tunica vaginalis flap as a layer between the neourethra and skin suture line in repair of recurrent urethrocutaneous fistula. PATIENTS AND METHODS: We have used the tunica vaginalis flap for the repair of recurrent urethrocutaneous fistula in 14 children with a mean age of 6.5 years (range 3-14 years). All patients had undergone previous hypospadias repair and at least one previous attempt to close the fistula had failed. Surgery was initiated by injecting a povidone solution via urethral meatus to identify all fistulae. The fistulae were closed primarily and urethral suture line was covered with a flap of tunica vaginalis which was harvested either through a small scrotal incision and mobilized via a subcutaneous tunnel into the penile shaft (8/14) or by the same incision as for fistula closure (6/14). The testis was fixed to the scrotum. A urethral catheter was kept for urinary diversion for 10 days. RESULTS: The repair was successful in all but one patient in whom there was leak from the fistula site. One patient in whom tunica vaginalis fascia was tunnelled into neourethra developed scrotal haematoma which needed drainage. Penile cosmesis was acceptable without any significant postoperative testicular complication in 13/14 patients. CONCLUSION: Repair of recurrent urethrocutaneous fistula with a tunica vaginalis flap is highly effective regardless of fistula location. This flap is easy to mobilize and provide effective coverage of urethral suture line. Putting a glove drain should be considered into scrotal wound if perfect haemostasis is doubtful.

Hypoglossia-hypodactyly syndrome in a newborn.

Hypoglossia-hypodactyly syndrome is characterised by small tongue associated with limb deficiency. It is an extremely rare condition with around 30 cases reported in world literature. We report a case of hypoglossia-hypodactyly syndrome that in addition to features already described also had supernumerary nipples, microcephaly and micropenis with cryptorchidism. Hypodactyly was symmetrical in all four limbs. These features have not been reported previously.

Lupus vulgaris of external nose with septal perforation--a rarity in antibiotic era.

Lupus vulgaris (LV) is the commonest morphological variant of cutaneous tuberculosis. Case of LV of external nose extending to internal nose causing septal perforation is documented here. Histopathology of biopsy taken confirmed the diagnosis of LV. Patient responded well to Anti-tubercular therapy (ATT).

The Rieger syndrome: orofacial manifestations. Case report of a rare condition.

Rieger syndrome is a rare, autosomal dominant disorder due to developmental arrest of tissues derived from neural crest ectoderm in the third trimester. It is characterized by abnormalities of the anterior chamber of the eye coincident with dental and craniofacial anomalies. Early recognition of dental anomalies aids in detection of the syndrome and prevents progressive loss of vision. This case report discusses the ocular, dental, and craniofacial findings and the overall management of the patient.