Invited review: Camel milk-derived bioactive peptides and diabetes-Molecular view and perspectives.

In dairy science, camel milk (CM) constitutes a center of interest for scientists due to its known beneficial effect on diabetes as demonstrated in many in vitro, in vivo, and clinical studies and trials. Overall, CM had positive effects on various parameters related to glucose transport and metabolism as well as the structural and functional properties of the pancreatic ß-cells and insulin secretion. Thus, CM consumption may help manage diabetes; however, such a recommendation will become rationale and clinically conceivable only if the exact molecular mechanisms and pathways involved at the cellular levels are well understood. Moreover, the application of CM as an alternative antidiabetic tool may first require the identification of the exact bioactive molecules behind such antidiabetic properties. In this review, we describe the advances in our knowledge of the molecular mechanisms reported to be involved in the beneficial effects of CM in managing diabetes using different in vitro and in vivo models. This mainly includes the effects of CM on the different molecular pathways controlling (1) insulin receptor signaling and glucose uptake, (2) the pancreatic ß-cell structure and function, and (3) the activity of key metabolic enzymes in glucose metabolism. Moreover, we described the current status of the identification of CM-derived bioactive peptides and their structure-activity relationship study and characterization in the context of molecular markers related to diabetes. Such an overview will not only enrich our scientific knowledge of the plausible mode of action of CM in diabetes but should ultimately rationalize the claim of the potential application of CM against diabetes. This will pave the way toward new directions and ideas for developing a new generation of antidiabetic products taking benefits from the chemical composition of CM.

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance.

The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

Plant based food bioactives: A boon or bane for neurological disorders.

Neurological disorders are the foremost occurring diseases across the globe resulting in progressive dysfunction, loss of neuronal structure ultimately cell death. Therefore, attention has been drawn toward the natural resources for the search of neuroprotective agents. Plant-based food bioactives have emerged as potential neuroprotective agents for the treatment of neurodegenerative disorders. This comprehensive review primarily focuses on various plant food bioactive, mechanisms, therapeutic targets, in vitro and in vivo studies in the treatment of neurological disorders to explore whether they are boon or bane for neurological disorders. In addition, the clinical perspective of plant food bioactives in neurological disorders are also highlighted. Scientific evidences point toward the enormous therapeutic efficacy of plant food bioactives in the prevention or treatment of neurological disorders. Nevertheless, identification of food bioactive components accountable for the neuroprotective effects, mechanism, clinical trials, and consolidation of information flow are warranted. Plant food bioactives primarily act by mediating through various pathways including oxidative stress, neuroinflammation, apoptosis, excitotoxicity, specific proteins, mitochondrial dysfunction, and reversing neurodegeneration and can be used for the prevention and therapy of neurodegenerative disorders. In conclusion, the plant based food bioactives are boon for neurological disorders.

Altered Levels of Negative Costimulatory Molecule V-Set Domain-Containing T-Cell Activation Inhibitor-1 (VTCN1) and Metalloprotease Nardilysin (NRD1) are Associated with Generalized Active Vitiligo.

BACKGROUND: Vitiligo is characterized by depigmented macules on the skin caused due to autoimmune destruction of melanocytes. V-set domain-containing T-cell activation inhibitor-1 (VTCN1) is a negative costimulatory molecule that plays a vital role in suppressing autoimmunity and tuning immune response. Nardilysin (NRD1), a metalloproteinase, cleaves membrane-tethered VTCN1 resulting in the shedding of soluble-VTCN1 (sVTCN1). However, the role of VTCN1 and NRD1 in vitiligo pathogenesis is unexplored. OBJECTIVES AND METHODS: This study was aimed to (i) Investigate the association of VTCN1 intronic polymorphisms (rs10923223 T/C and rs12046117 C/T) with vitiligo susceptibility in Gujarat population by using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) (ii) Estimate VTCN1 & NRD1 transcript levels from peripheral blood mononuclear cells (PBMCs) and skin samples of vitiligo patients by real-time PCR, (iii) Estimate sVTCN1 and NRD1 protein levels from plasma by ELISA and (iv) Estimate VTCN1 protein levels in the skin samples of vitiligo patients by immunofluorescence. RESULTS: The analysis revealed increased VTCN1 and NRD1 transcript levels in the skin (p = .039, p = .021 respectively), increased sVTCN1 and NRD1 levels (p = .026, p = .015 respectively) in the plasma, and decreased VTCN1 protein levels (p = .0002) in the skin of vitiligo patients as compared to healthy controls. The genetic analysis revealed no significant association of VTCN1 intronic polymorphisms rs10923223 T/C and rs12046117 C/T with vitiligo susceptibility in Gujarat population (p = .359, p = .937, respectively). CONCLUSIONS: The present study revealed altered VTCN1 and NRD1 expressions in the blood and skin of vitiligo patients, suggesting their potential role in the development and progression of Vitiligo.

Camel and bovine milk lactoferrins activate insulin receptor and its related AKT and ERK1/2 pathways.

Lactoferrin (LF) is a milk protein that may be an interesting candidate for the antidiabetic properties of milk due to its well-documented bioactivity and implication in diabetes. Here, we investigated the functional action of LF purified from camel and bovine milk (cLF, bLF) on insulin receptors (IR) and their pharmacology and signaling in hepatocarcinoma (HepG2) and human embryonic kidney (HEK293) cells. For this, we examined IR activation by bioluminescence resonance energy transfer (BRET) technology and the phosphorylation of its key downstream signaling kinases by western blot. The purified cLF and bLF induced phosphorylation of IR, AKT, and ERK1/2 in HepG2 and HEK293 cells. The BRET assays in HEK293 cells confirm the pharmacological action of cLF and bLF on IR, with a possible allosteric mode of action. This reveals for the first time the bioactivity of LF toward IR function, indicating it as a potential bioactive protein behind the antidiabetic properties of camel milk.

Prospective therapeutic potential of Tanshinone IIA: An updated overview.

In the past decades, the branch of complementary and alternative medicine based therapeutics has gained considerable attention worldwide. Pharmacological efficacy of various traditional medicinal plants, their products and/or product derivatives have been explored on an increasing scale. Tanshinone IIA (Tan IIA) is a pharmacologically active lipophilic component of Salvia miltiorrhiza extract. Tan IIA shares a history of high repute in Traditional Chinese Medicine. Reckoning with these, the present review collates the pharmacological properties of Tan IIA with a special emphasis on its therapeutic potential against diverse diseases including cardiovascular diseases, cerebrovascular diseases, cancer, diabetes, obesity and neurogenerative diseases. Further, possible applications of various therapeutic preparations of Tan IIA were discussed with special emphasis on nano-based drug delivery formulations. Considering the tremendous advancement in the field of nanomedicine and the therapeutic potential of Tan IIA, the convergence of these two aspects can be foreseen with great promise in clinical application.

The combined inhibition of the CaMKIIδ and calcineurin signaling cascade attenuates IGF-IIR-induced cardiac hypertrophy.

Cardiac hypertrophy is a common phenomenon observed in progressive heart disease associated with heart failure. Insulin-like growth factor receptor II (IGF-IIR) has been much implicated in myocardial hypertrophy. Our previous studies have found that increased activities of signaling mediators, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin induces pathological hypertrophy. Given the critical roles played by CaMKII and calcineurin signaling in the progression of maladaptive hypertrophy, we anticipated that inhibition of CaMKII and calcineurin signaling may attenuate IGF-IIR-induced cardiac hypertrophy. The current study, therefore, investigated the effects of IGF-IIR activation on the CaMKII and calcineurin signaling and whether the combinatorial inhibition of the CaMKIIδ and calcineurin signaling could ameliorate IGF-IIR-induced pathological hypertrophy. In the present study, we induced IGF-IIR through the cardiomyocyte-specific transduction of IGFIIY27L via adeno-associated virus 2 (AAV2) to evaluate its effects on cardiac hypertrophy. Interestingly, it was observed that the activation of IGF-IIR signaling through IGFIIY27L induces significant hypertrophy of the myocardium and increased cardiac apoptosis and fibrosis. Moreover, we found that Leu27 IGF-II significantly induced calcineurin and CaMKII expression. Furthermore and importantly, the combinatorial treatment with CaMKII and calcineurin inhibitors significantly alleviates IGF-IIR-induced hypertrophic responses. Thus, it could be envisaged that the inhibition of IGF-IIR may serve as a promising candidate for attenuating maladaptive hypertrophy. Both calcineurin and CaMKII could be valuable targets for developing treatment strategies against hypertension-induced cardiomyopathies.

CHIP attenuates lipopolysaccharide-induced cardiac hypertrophy and apoptosis by promoting NFATc3 proteasomal degradation.

Carboxyl-terminus of Hsc70 interacting protein (CHIP) is a chaperone-dependent E3-ubiquitin ligase with important function in protein quality control system. In the current research endeavor, we have investigated the putative role of CHIP in lipopolysaccharides (LPS)-induced cardiomyopathies. Basically, H9c2 cardiomyoblasts were transfected with CHIP for 24 hr, and thereafter, treated with LPS for 12 hr. Concomitantly, western blot analysis, actin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and coimmunoprecipitation studies were performed to investigate the underlying intricacies. Interestingly, western blot analysis revealed that the expression of hypertrophy and apoptosis-related proteins were considerably reduced following overexpression of CHIP. Moreover, Actin staining and TUNEL assay further ascertained the attenuation of cardiac hypertrophy and apoptosis following overexpression of CHIP respectively. These aspects instigate the role of CHIP in attenuation of LPS-induced cardiomyopathies. Additionally and importantly, co-immunoprecipitation and western blot studies revealed that CHIP plausibly promotes degradation of nuclear factor of activated T cells 3 (NFATc3) through ubiquitin-proteasomal pathway. Taken together, our study reveals that CHIP attenuates LPS-induced cardiac hypertrophy and apoptosis perhaps by promoting NFATc3 proteasomal degradation.

Tid1-S attenuates LPS-induced cardiac hypertrophy and apoptosis through ER-a mediated modulation of p-PI3K/p-Akt signaling cascade.

Myocardial dysfunction is clinically relevant? repercussion that follows sepsis. Tid 1 protein has been implicated in many biological process. However, the role of Tid 1 in lipopolysaccharide (LPS)-induced cardiomyocyte hypertrophy and apoptosis remains elusive. In the current research endeavor, we have elucidated the role of Tid1-S on LPS-induced cardiac hypertrophy and apoptosis. Interestingly, we found that overexpression of Tid1-S suppressed TLR-4, NFATc3, and BNP protein expression which eventually led to inhibition of LPS-induced cardiac hypertrophy. Moreover, Tid1-S overexpression attenuated cellular apoptosis and activated survival proteins p-PI3K and pser473 Akt. Besides this, Tid1-S overexpression enhanced ER-a protein expression. Collectively, our data suggest that Tid1-S plausibly enhance ER-a protein and further activate p-PI3K and p ser473 Akt survival protein expression; which thereby led to attenuation of LPS-induced apoptosis in cardiomyoblast cells. Interestingly, our data suggest that Tid1-S is involved in attenuation of cardiomyoblast cells damages induced by LPS.

Redox-Induced Oxidative C-C Bond Cleavage of 2,2'-Pyridil in Diruthenium Complexes.

In the recent years, there has been an emerging research interest in the domain of C-C bond-cleavage reactions. The present contribution deals with the redox-mediated dioxygen activation and C-C bond cleavage in a diruthenium complex [(acac)2 RuII (µ-L1)RuII (acac)2 ], 1 (acac=acetylacetonate) incorporating 2,2'-pyridil (L1) as the bridging ligand. The above process leads to a C-C-cleaved monomeric product [(acac)2 RuIII (pic- )], 2 (pic- =piconilate). Intriguingly, similar diastereomeric complexes [(acac)2 RuII (µ-L2)RuII (acac)2 ], meso (ΔΛ): 3 a and rac (ΔΔ/ΛΛ): 3 b, involving an analogous diimine bridge (L2=N1,N2-diphenyl-1,2-di(pyridin-2-yl)ethane-1,2-diimine), were stable towards such oxidative transformations. Electrochemical and spectroelectrochemical studies, in combination, establish the potential non-innocent feature of the 2,2'-Pyridil (L1) and its derivative (L2) both in oxidation and reduction processes. Additionally, theoretical calculations have been employed to verify the redox states and their behavior. Furthermore, transition state (TS) calculations at the M06L/6-31G*/LANL2DZ level of theory together with detailed kinetic studies outline a putative mechanism for the selective transformation of 1→2 involving the formation of an intermediate bearing peroxide linkage to complex 1.

Questions of Noninnocence and Ease of Azo Reduction in Diruthenium Frameworks with a 1,8-Bis(( E)-phenyldiazenyl)naphthalene-2,7-dioxido Bridge.

Ligands containing the azo group are often used in various metal complexes owing to their facile one-electron reduction, which in effect extends the means of degrading environmentally harmful azo dyes. In order to probe the idea of the generally accepted ease of reduction of azo-containing compounds, we present here three different diruthenium complexes [(acac)2RuIII(µ-L2-)RuIII(acac)2] (diastereomeric 1/2), [(bpy)2RuII(µ-L2-)RuII(bpy)2](ClO4)2 ([3](ClO4)2), and [(pap)2RuII(µ-L2-)RuII(pap)2](ClO4)2 ([4](ClO4)2 ) with a bridging ligand (L2- = 1,8-bis(( E)-phenyldiazenyl)naphthalene-2,7-dioxido) that contains azo groups in addition to phenoxide-type donors. The RuIII-RuIII complexes (1/2) display interesting one-dimensional-chain effects, as revealed by temperature-dependent magnetic studies. The stability of the RuIII oxidation state in 1/2 under ambient conditions correlates well with the σ-donating acetylacetonato (acac) coligands. However, with π-accepting 2,2/-bipyridine (bpy) or phenylazopyridine (pap) the RuII state is preferably stabilized in 32+ or 42+, respectively, but there are interesting differences in their oxidative chemistry. The moderately π accepting bpy allows for the RuII to RuIII oxidation at reasonably low anodic potentials. However, for the strongly π accepting pap, no RuII to RuIII oxidation is observed within the solvent window. Instead, a phenoxide to phenoxyl radical type of oxidation based on the bridging ligand is observed. Surprisingly, the reductive chemistry of all three complexes is dominated by either the ruthenium centers or the coligands (bpy or pap), with no reductions observed on the azo function associated with the central bridging ligand (L2-). All of the above conclusions were drawn from combined structural, electrochemical, magnetic, spectroelectrochemical, and DFT investigations. Our results thus conclusively establish that the ease of reduction of an azo group in a particular compound is critically dependent on its substituents and that the noninnocence of the bridging ligands (L2-) in the dinuclear complexes can be decisively tuned by the appropriate choice of ancillary ligands.

Eriobotrya japonica ameliorates cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats.

Eriobotrya japonica (EJ) is a traditional Chinese plant with high medicinal value. EJ extracts are reported to exhibit antioxidant and anti-inflammatory biological attributes. The current study aims to evaluate the prospective efficacy of E. japonica leave extract (EJLE) against Angiotensin-II induced cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats (SHRs). For the in vitro studies, Angiotensin-II pretreated H9c2 cells were treated with EJLE and analyzed through Western blotting and rhodamine phalloidin staining for their cardio-protective attributes. In the in vivo studies, 12-week-old SHRs were randomly divided into groups: SHRs supplemented with EJLE, control SHR group supplemented with PBS; in addition, a control group of Wistar-Kyoto rats (WKY) was also employed. All rats were supplemented twice a week for 8 week time interval. Finally, echocardiography, morphological, histology, and Western blot analysis were performed to assess their role against cardiac hypertrophy. Interestingly, we could observe that supplementation of EJLE could rescue Ang-II induced cardiac hypertrophy as evident through Western blot, rhodamine phalloidin staining, and Hematoxylin-Eosin staining. Notably, morphological and echocardiography data provided further supports for their ability to ameliorate cardiac characteristics. Cumulatively, the results clearly suggests that supplementation of EJLE promotes cardio-protective effects through amelioration of cardiac hypertrophy in vitro and in vivo.

Anti-Apoptosis and Anti-Fibrosis Effects of Eriobotrya Japonica in Spontaneously Hypertensive Rat Hearts.

Myocardial apoptosis and fibrosis represent important contributing factors for development of hypertension-induced heart failure. The present study aims to investigate the potential effects of Eriobotrya japonica leaf extract (EJLE) against hypertension-induced cardiac apoptosis and fibrosis in spontaneously hypertensive rats (SHRs). Twelve-week-old male rats were randomly divided into four different groups; control Wistar Kyoto (WKY) rats, hypertensive SHR rats, SHR rats treated with a low dose (100 mg/kg body weight) of EJLE and SHR rats treated with a high dose (300 mg/kg body weight) of EJLE. Animals were acclimatized for 4 weeks and thereafter were gastric fed for 8 weeks with two doses of EJLE per week. The rats were then euthanized following cardiac functional analysis by echocardiography. The cardiac tissue sections were examined by Terminal Deoxynucleotidyl Transferase-Mediated Deoxyuridine Triphosphate (dUTP) Nick End-Labeling (TUNEL) assay, histological staining and Western blotting to assess the cardio-protective effects of EJ in SHR animals. Echocardiographic measurements provided convincing evidence to support the ability of EJ to ameliorate crucial cardiac functional characteristics. Furthermore, our results reveal that supplementation of EJLE effectively attenuated cardiac apoptosis and fibrosis and also enhanced cell survival in hypertensive SHR hearts. Thus, the present study concludes that EJLE potentially provides cardio-protective effects against hypertension-induced cardiac apoptosis and fibrosis in SHR animals.

Nano-Sized Drug Delivery Systems: Development and Implication in Treatment of Hepatocellular Carcinoma.

Liver cancer results in enormous human toll worldwide. Over the years, various chemotherapeutic entities have been employed for treatment of advanced HCC; however, as of yet none embody attributes to improve overall survival. Following rapid advancement in nanotechnology, it is envisage that nanoscale systems may emerge as intriguing platforms to improve chemotherapeutic strategies against various cancers including liver cancer; with better insight in the understanding of pathophysiology of liver cancer and material science, the field of nanotechnology may bring newer hope to liver cancer treatment. Reckoning with these, we detailed the arsenal of nanoformulations that are in various stages of clinical development/ preclinical settings for the treatment of liver cancer together with providing a glimpse of the attributes of nanotechnology in revolutionizing the status of chemotherapeutic modalities.

Analysis of robot-specific operative time and surgical team anxiety level and its effect on alignment during robot-assisted TKA.

Adapting to robotic-assisted (RA) total knee arthroplasty (TKA) is hindered by the surgeon's fear of extra time. The main purpose of this study was to determine the robot's operative time, and the secondary goals were to assess the surgical team's anxiety, implant location and size, and limb alignment. From February to April 2022, 40 participants participated in prospective research. The study included primary Cuvis joint active RA-TKA patients for end-stage arthritis, but conversion of unicompartmental knee arthroplasty to TKA, and patients with prior knee surgery were excluded. The active RA-TKA surgical time included surgeon-dependent and surgeon-independent/active robot time. The surgeon's anxiety was measured using the state-trait anxiety inventory (STAI). The implant size/position and limb alignment were checked by post-operative weight-bearing lateral, anteroposterior, and full-length scanograms. Operative time specifically related to active RA-TKA was higher in the first 10 cases as against 10-20, 20-30 and 30-40 cases which was observed to lower from cohort 2. A similar trend was observed for the surgical team's anxiety levels which seem to lower from cohort 2 (case 10-20). Cumulative experience of active RA-TKA showed no effect on the precision of implant alignment/ size, limb alignment and complications. The study showed progressive improvement in the surgical anxiety scores and reduction in operating time indicating the proficiency gained by the surgical team. Further no learning curve was involved in achieving the implant positioning and sizing, limb alignment with the absence of complications.

2D nanostructures: Potential in diagnosis and treatment of Alzheimer's disease.

Two-dimensional (2D) nanomaterials have garnered enormous attention seemingly due to their unusual architecture and properties. Graphene and graphene oxide based 2D nanomaterials remained the most sought after for several years but the quest to design superior 2D nanomaterials which can find wider application gave rise to development of non-graphene 2D materials as well. Consequently, in addition to graphene based 2D nanomaterials, 2D nanostructures designed using macromolecules (such as DNAs, proteins, peptides and peptoids), transition metal dichalcogenides, transition-metal carbides and/or nitrides (MXene), black phosphorous, chitosan, hexagonal boron nitrides, and graphitic carbon nitride, and covalent organic frameworks have been developed. Interestingly, these 2D nanomaterials have found applications in diagnosis and treatment of various diseases including Alzheimer's disease (AD). Although AD is one of the most debilitating neurodegenerative conditions across the globe; unfortunately, there remains a paucity of effective diagnostic and/or therapeutic intervention for it till date. In this scenario, nanomaterial-based biosensors, or therapeutics especially 2D nanostructures are emerging to be promising in this regard. This review summarizes the diagnostic and therapeutic platforms developed for AD using 2D nanostructures. Collectively, it is worth mentioning that these 2D nanomaterials would seemingly provide an alternative and intriguing platform for biomedical interventions.

Solid phase extraction and determination of Cr(III) by spectrophotometry using cefaclor as a complexing reagent and FAAS.

The present study reports on the application of modified groundnut shell as a new, easily prepared, and stable sorbent for the extraction of trace amount of Cr(III) in aqueous solution. 2-Hydroxybenzaldiminoglycine was immobilized on groundnut shells in alkaline medium and then used as a solid phase for the column preconcentration of Cr(III). The elution was carried out with 3 mL of 2 mol L(-1) HCl. The amount of eluted Cr(III) was determined by spectrophotometry using cefaclor as a complexing reagent and by flame atomic absorption spectrometry (FAAS). Different experimental variables such as pH, amount of solid sorbent, volume and concentration of eluent, sample and eluent flow rate, and interference of other metal ions on the retention of Cr(III) were studied. Under the optimized conditions, the calibration curves were found to be linear over the concentration range of 13-104 and 10-75 µg L(-1) with a detection limit of 3.64 and 1.24 µg L(-1) for spectrophotometric method and FAAS, respectively. An enrichment factor of 200 and RSD of ±1.19-1.49 % for five successive determinations of 25 µg L(-1) were achieved. The column preconcentration was successfully applied to the analysis of tap water and underground water samples.

Reviewing the Prospective Pharmacological Potential of Isothiocyanates in Fight against Female-Specific Cancers.

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers.

Pharmacological Inhibition of PTEN Rescues Dopaminergic Neurons by Attenuating Apoptotic and Neuroinflammatory Signaling Events.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN's novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1ß (IL-1ß) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD.

Molecular complexity of mammary glands development: a review of lactogenic differentiation in epithelial cells.

The mammary gland is a dynamic organ with various physiological processes like cellular proliferation, differentiation, and apoptosis during the pregnancy-lactation-involution cycle. It is essential to understand the molecular changes during the lactogenic differentiation of mammary epithelial cells (MECs, the milk-synthesizing cells). The MECs are organized as luminal milk-secreting cells and basal myoepithelial cells (responsible for milk ejection by contraction) that form the alveoli. The branching morphogenesis and lactogenic differentiation of the MECs prepare the gland for lactation. This process is governed by many molecular mediators including hormones, growth factors, cytokines, miRNAs, regulatory proteins, etc. Interestingly, various signalling pathways guide lactation and understanding these molecular transitions from pregnancy to lactation will help researchers design further research. Manipulation of genes responsible for milk synthesis and secretion will promote augmentation of milk yield in dairy animals. Identifying protein signatures of lactation will help develop strategies for persistent lactation and shortening the dry period in farm animals. The present review article discusses in details the physiological and molecular changes occurring during lactogenic differentiation of MECs and the associated hormones, regulatory proteins, miRNAs, and signalling pathways. An in-depth knowledge of the molecular events will aid in developing engineered cellular models for studies related to mammary gland diseases of humans and animals.