The chickpea WIP2 gene underlying a major QTL contributes to lateral root development.

Lateral roots are a major component of root system architecture, and lateral root count (LRC) positively contributes to yield under drought in chickpea. To understand the genetic regulation of LRC, a biparental mapping population derived from two chickpea accessions having contrasting LRCs was genotyped by sequencing, and phenotyped to map four major quantitative trait loci (QTLs) contributing to 13-32% of the LRC trait variation. A single- nucleotide polymorphism tightly linked to the locus contributing to highest trait variation was located on the coding region of a gene (CaWIP2), orthologous to NO TRANSMITTING TRACT/WIP domain protein 2 (NTT/WIP2) gene of Arabidopsis thaliana. A polymorphic simple sequence repeat (SSR) in the CaWIP2 promoter showed differentiation between low versus high LRC parents and mapping individuals, suggesting its utility for marker-assisted selection. CaWIP2 promoter showed strong expression in chickpea apical root meristem and lateral root primordia. Expression of CaWIP2 under its native promoter in the Arabidopsis wip2wip4wip5 mutant rescued its rootless phenotype to produce more lateral roots than the wild-type plants, and led to formation of amyloplasts in the columella. CaWIP2 expression also induced the expression of genes that regulate lateral root emergence. Our study identified a gene-based marker for LRC which will be useful for developing drought-tolerant, high-yielding chickpea varieties.

Risk of metastasis among patients diagnosed with high-risk T1 esophageal adenocarcinoma who underwent endoscopic follow-up.

Esophagectomy and lymphadenectomy have been the standard of care for patients at high risk (HR) of lymph node metastasis following a diagnosis of early esophageal adenocarcinoma (OAC) after endoscopic resection (ER). However, recent cohorts suggest lymph node metastasis risk is lower than initially estimated, suggesting organ preservation with close endoscopic follow-up is a viable option. We report on the 3- and 5-year risk of lymph node/distant metastasis among patients diagnosed with early HR-T1 OAC undergoing endoscopic follow-up. Patients diagnosed with HR-T1a or T1b OAC following ER at a tertiary referral center were identified and retrospectively analyzed from clinical records between 2010 and 2021. Patients were included if they underwent endoscopic follow-up after resection and were divided into HR-T1a, low risk (LR)-T1b and HR-T1b cohorts. After ER, 47 patients underwent endoscopic follow-up for early HR OAC. In total, 39 patients had an R0 resection with a combined 3- and 5-year risk of LN/distant metastasis of 6.9% [95% confidence interval (CI): 1.8-25] and 10.9% (95% CI, 3.6-30.2%), respectively. There was no significant difference when stratifying by histopathological subtype (P = 0.64). Among those without persistent luminal disease on follow-up, the 5-year risk was 4.1% (95% CI, 0.6-26.1). Two patients died secondary to OAC with an all-cause 5-year survival of 57.5% (95% CI, 39.5-71.9). The overall risk of LN/distant metastasis for early HR T1 OAC was lower than historically reported. Endoscopic surveillance can be a reasonable approach in highly selected patients with an R0 resection and complete luminal eradication, but clear, evidence-based surveillance guidelines are needed.

Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment.

The mTOR signaling pathway plays a pivotal and intricate role in the pathogenesis of glioblastoma, driving tumorigenesis and proliferation. Mutations or deletions in the PTEN gene constitutively activate the mTOR pathway by expressing growth factors EGF and PDGF, which activate their respective receptor pathways (e.g., EGFR and PDGFR). The convergence of signaling pathways, such as the PI3K-AKT pathway, intensifies the effect of mTOR activity. The inhibition of mTOR has the potential to disrupt diverse oncogenic processes and improve patient outcomes. However, the complexity of the mTOR signaling, off-target effects, cytotoxicity, suboptimal pharmacokinetics, and drug resistance of the mTOR inhibitors pose ongoing challenges in effectively targeting glioblastoma. Identifying innovative treatment strategies to address these challenges is vital for advancing the field of glioblastoma therapeutics. This review discusses the potential targets of mTOR signaling and the strategies of target-specific mTOR inhibitor development, optimized drug delivery system, and the implementation of personalized treatment approaches to mitigate the complications of mTOR inhibitors. The exploration of precise mTOR-targeted therapies ultimately offers elevated therapeutic outcomes and the development of more effective strategies to combat the deadliest form of adult brain cancer and transform the landscape of glioblastoma therapy.

Functional characterization of two WD40 family proteins, Alr0671 and All2352, from Anabaena PCC 7120 and deciphering their role in abiotic stress management.

WD40 domain-containing proteins are one of the eukaryotes' most ancient and ubiquitous protein families. Little is known about the presence and function of these proteins in cyanobacteria in general and Anabaena in particular. In silico analysis confirmed the presence of WD40 repeats. Gene expression analysis indicated that the transcript levels of both the target proteins were up-regulated up to 4 fold in Cd and drought and 2-3 fold in heat, salt, and UV-B stress. Using a fluorescent oxidative stress indicator, we showed that the recombinant proteins were scavenging reactive oxygen species (ROS) (4-5 fold) more efficiently than empty vectors. Chromatin immunoprecipitation analysis (ChIP) and electrophoretic mobility shift assay (EMSA) revealed that the target proteins function as transcription factors after binding to the promoter sequences. The presence of kinase activity (2-4 fold) in the selected proteins indicated that these proteins could modulate the functions of other cellular proteins under stress conditions by inducing phosphorylation of specific amino acids. The chosen proteins also demonstrated interaction with Zn, Cd, and Cu (1.4-2.5 fold), which might stabilize the proteins' structure and biophysical functions under multiple abiotic stresses. The functionally characterized Alr0671 and All2352 proteins act as transcription factors and offer tolerance to agriculturally relevant abiotic stresses.

Alr0671 and All2352 are novel WD40 proteins of Anabaena capable of regulating biochemical functions and abiotic stress tolerance by acting as a transcription factor and mediating DNA-protein interaction.

Dietary flavonoid narirutin as a prospective antagonist of oncogenic pri/pre-microRNAs.

MicroRNAs (miRNAs) are involved in cancer progression via translational degradation in a sequence-specific manner of the 3'-untranslated region (3'UTR) of messenger RNA (mRNA). The involvement of miRNA in the biological progression of various cancer types is considered to be a potential target. Primary miRNA (pri-miRNA) and precursor-miRNA (pre-miRNA) synthesize the miRNA by dicer-catalyzed processes thus targeting pri/pre-miRNA by phytochemicals is amongst the appropriate approaches for anticancer therapies. Flavonoids category of phytochemicals is well-known for its chemotherapeutic and chemopreventive potential against multiple cancer types. However, the molecular interactions of flavonoids with miRNAs are not reported so far. Thus, this study aims to identify the promising flavonoids as the antagonist of miRNAs (pre-miR21, pri-miR-208a, pri-miR-378a, pri-miR320b, pri-miR-300, pri-miR-19b, and pre-miR-20b) using molecular docking simulations studies. Among the tested flavonoids, narirutin showed highest binding energy (-11.7 kcal/mol) against pri-miR19b followed by pri-miR-378a (-11.4 kcal/mol) > pri-miR320b (-11.2 kcal/mol) = pri-miR-300 (-11.2 kcal/mol) > pri-miR-208a (-9.0 kcal/mol) > pre-miR-20b (- 8.3 kcal/mol). The molecular dynamic simulation experiment confirmed that narirutin destabilizes the tertiary structure of pri-miRNA in comparison to apo-RNA. The finding indicates that narirutin binding with pre-miRNA causes disruption of pri-RNA structure that creates a loss of DICER-pre-miRNA interactions by hindering the pre-miRNA synthesis, thereby affecting miRNA processing. Further pharmacokinetics and toxicity prediction revealed that it is non-carcinogenic, non-mutagenic, and does not inhibit the CYPs activity. Thus, narirutin could be a possible antagonist of oncogenic miRNAs, therefore could be useful for miRNA-targeted cancer prevention and treatment.

Baicalin mediated regulation of key signaling pathways in cancer.

Baicalin has been widely investigated against different types of malignancies both at the cellular and molecular levels over the past few years. Due to its remarkable anti-proliferative potential in numerous cancer cell lines, it has created immense interest as a potential chemotherapeutic modality compared to other flavonoids. Thus, this review focuses on the recent accomplishments of baicalin and its limitations in cancer prevention and treatment. Further, combination studies and nanoformulations using baicalin to treat cancer along with the metabolism, bioavailability, toxicity, and pharmacokinetics have been discussed. The present review explains biological source, and anti-proliferative potential of baicalin against cancers including breast, colon, hepatic, leukemia, lung, and skin, as well as the relevant mechanism of action to modulate diverse signaling pathways including apoptosis, cell cycle, invasion, and migration, angiogenesis, and autophagy. The anticancer mechanism of baicalin in orthotropic and xenograft mice models have been deliberated. The combination studies of baicalin in novel therapies as chemotherapeutic adjuvants have also been summarized. The low bioavailability, fast metabolism, and poor solubility, and other significant factors that limit the clinical use of baicalin have been examined as a challenge. The improvement in the pharmacokinetics and pharmacodynamics of baicalin with newer approaches and the gaps are highlighted, which could establish baicalin as an effective and safe compound for cancer treatment as well as help to translate its potential from bench to bedside.

Synthesis and biological evaluation of substituted amide derivatives of C4-ageratochromene dimer analog.

Substituted amide derivatives of C4-ageratochromene dimer analog (19) were synthesized through structural modification of precocene-I (4a), isolated from the essential oil of Ageratum conyzoides L. The target compounds (18-20, 23I-VI, 24I-VI, and 25I-VI) were evaluated for their bone-forming effect using osteoblast differentiation assay. Seven compounds (23I, 23II, 23IV, 23VI, 24III, 24VI, and 25VI) presented good activity within 1 pM-1 nM concentration. At 1 pM concentration, the most active compound i.e. 23II showed effective mineralization of osteoblast cells along with expression of osteogenic marker genes viz RUNX 2, BMP-2, and type 1 collagen (Type-1 col) without any toxicity towards osteoblast cells. Single crystal X-ray analysis of 18 and 20 revealed that the core nucleus of these molecules bear phenyl rings in a Trans-stilbenoid system and had a good structural correlation with 17ß-estradiol (1) and diethylstilbestrol (DES, 3). In-silico study about 23II showed its structural complementarities with the LBD of estrogen receptor (ER) which indicated possible ER-mediated activity of compounds.

Cross-cultural adaptation and psychometric properties of the Hindi version of Child Perception Questionnaire (CPQ11-14 ) in school children.

BACKGROUND: There is a need to validate OHRQoL measures in Hindi to assess the OHRQoL of Indian children. AIM: To develop a Hindi version of the CPQ11-14 and to appraise its validity and reliability for use among North Indian children aged 11-14 years. DESIGN: The cross-culturally adapted Hindi version of CPQ11-14 was achieved by forward translation, backward translation, committee review, and pretesting. A total of 1000 children were recruited from schools, chosen by two-stage cluster random sampling technique. After completing the self-administered questionnaire CPQ11-14 by the child, oral examination was conducted using decayed/missing/filled teeth (DMFT) index, malocclusion index, and Dean's fluorosis index. Test-retest reliability was checked on 100 participants after one week. RESULTS: The floor effect was present in 3.6% individuals, and there was no ceiling effect. Cronbach's alpha for the overall CPQ11-14 scale was 0.963. Intra-class correlation (ICC) coefficient was 0.952 for the entire scale. Cronbach's alpha value for test-retest was 0.918. There was a non-significant change in domain-level and overall median CPQ11-14 scores with an increase in DMFT scores. For malocclusion and fluorosis, there was a statistically significant increase in overall and domain-level scores with increased severity scores. CPQ11-14 and individual domains significantly correlated with both the global questions. CONCLUSION: Hindi version of CPQ11-14 is a reliable scale to assess OHRQoL in Hindi speaking 11- to 14-year-old children.

Functional Characterization of Alr0765, A Hypothetical Protein from Anabaena PCC 7120 Involved in Cellular Energy Status Sensing, Iron Acquisition and Abiotic Stress Management in E. coli Using Molecular, Biochemical and Computational Approaches.

BACKGROUND: Cyanobacteria are excellent model to understand the basic metabolic processes taking place in response to abiotic stress. The present study involves the characterization of a hypothetical protein Alr0765 of Anabaena PCC7120 comprising the CBS-CP12 domain and deciphering its role in abiotic stress tolerance. METHODS: Molecular cloning, heterologous expression and protein purification using affinity chromatography were performed to obtain native purified protein Alr0765. The energy sensing property of Alr0765 was inferred from its binding affinity with different ligand molecules as analyzed by FTIR and TNP-ATP binding assay. AAS and real time-PCR were applied to evaluate the iron acquisition property and cyclic voltammetry was employed to check the redox sensitivity of the target protein. Transcript levels under different abiotic stresses, as well as spot assay, CFU count, ROS level and cellular H2O2 level, were used to show the potential role of Alr0765 in abiotic stress tolerance. In-silico analysis of Alr0765 included molecular function probability analysis, multiple sequence analysis, protein domain and motif finding, secondary structure analysis, protein-ligand interaction, homologous modeling, model refinement and verification and molecular docking was performed with COFACTOR, PROMALS-3D, InterProScan, MEME, TheaDomEx, COACH, Swiss modeller, Modrefiner, PROCHECK, ERRAT, MolProbity, ProSA, TM-align, and Discovery studio, respectively. RESULTS: Transcript levels of alr0765 significantly increased by 20, 13, 15, 14.8, 12, 7, 6 and 2.5 fold when Anabaena PCC7120 treated with LC50 dose of heat, arsenic, cadmium, butachlor, salt, mannitol (drought), UV-B, and methyl viologen respectively, with respect to control (untreated). Heterologous expression resulted in 23KDa protein observed on the SDS-PAGE. Immunoblotting and MALDI-TOF-MS/MS, followed by MASCOT search analysis, confirmed the identity of the protein and ESI/MS revealed that the purified protein was a dimer. Binding possibility of Alr0765 with ATP was observed with an almost 6-fold increment in relative fluorescence during TNP-ATP binding assay with a λ max of 538 nm. FTIR spectra revealed modification in protein confirmation upon binding of Alr0765 with ATP, ADP, AMP and NADH. A 10-fold higher accumulation of iron was observed in digests of E. coli with recombinant vector after induction as compared to control, which affirms the iron acquisition property of the protein. Moreover, the generation of the redox potential of 146 mV by Alr0765 suggested its probable role in maintaining the redox status of the cell under environmental constraints. As per CFU count recombinant, E. coli BL21 cells showed about 14.7, 7.3, 6.9, 1.9, 3 and 4.9 fold higher number of colonies under heat, cadmium (CdCl2), arsenic (Na3AsO4), salt (NaCl), UV-B and drought (mannitol) respectively compared to pET21a harboring E. coli BL21 cells. Deterioration in the cellular ROS level and total cellular H2O2 concentration validated the stress tolerance ability of Alr0765. In-silico analysis unraveled novel findings and attested experimental findings in determining the role of Alr0765. CONCLUSION: Alr0765 is a novel CBS-CP12 domain protein that maintains cellular energy level and iron homeostasis which provides tolerance against multiple abiotic stresses.

Epigenetic control of UV-B-induced flavonoid accumulation in Artemisia annua L.

MAIN CONCLUSION: UV-B-induced flavonoid biosynthesis is epigenetically regulated by site-specific demethylation of AaMYB1, AaMYC, and AaWRKY TF-binding sites inAaPAL1promoter-causing overexpression ofAaPALgene inArtemisia annua. The present study was undertaken to understand the epigenetic regulation of flavonoid biosynthesis under the influence of ultraviolet-B radiation using Artemisia annua L. as an experimental model. In-vitro propagated and acclimatized plantlets were treated with UV-B radiation (2.8 W m-2; 3 h), which resulted in enhanced accumulation of total flavonoid and phenolics content as well as eleven individual flavonoids measured through HPLC-DAC. Expression of eight genes (phenylanaline ammonia lyase, cinnamate-4-hydroxylase, 4-coumarate: CoA ligase; chalcone synthase, chalcone isomerase, cinnamoyl reductase, flavonoid-3'-hydroxylase, and flavones synthase) from upstream and downstream flavonoid biosynthetic pathways was measured through RT-PCR and RT-Q-PCR and all were variably induced under UV-B irradiation. Among them, AaPAL1 transcript and its protein were most significantly upregulated. Global DNA methylation analysis revealed hypomethylation of genomic DNA in A. annua. Further epigenetic characterization of promoter region of AaPAL1 revealed cytosine demethylation at five sites, which in turn caused epigenetic activation of six transcription factor-binding sites including QELEMENT, EBOXBNNAPA/MYCCONSENSUSAT, MYBCORE, MYBCOREATCYCB1, and GCCCORE. MYB transcription factors are positive regulators of flavonoid biosynthesis. Epigenetic activation of transcription-enhancing cis-regulatory elements in AaPAL1 promoter and subsequent overexpression of AaMYB1 and AaMYC and AaWRKY transcription factors under UV-B irradiation may probably be the reason for higher AaPAL1 expression and hence greater biosynthesis of flavonoids in A. annua L. The present study is the first report that provides mechanistic evidence of epigenetic regulation of flavonoid biosynthesis under UV-B radiation in A. annua L.

Universal First-Passage-Time Distribution of Non-Gaussian Currents.

We investigate the fluctuations of the time elapsed until the electric charge transferred through a conductor reaches a given threshold value. For this purpose, we measure the distribution of the first-passage times for the net number of electrons transferred between two metallic islands in the Coulomb blockade regime. Our experimental results are in excellent agreement with numerical calculations based on a recent theory describing the exact first-passage-time distributions for any nonequilibrium stationary Markov process. We also derive a simple analytical approximation for the first-passage-time distribution, which takes into account the non-Gaussian statistics of the electron transport, and show that it describes the experimental distributions with high accuracy. This universal approximation describes a wide class of stochastic processes, and can be used beyond the context of mesoscopic charge transport. In addition, we verify experimentally a fluctuation relation between the first-passage-time distributions for positive and negative thresholds.

Evolutionarily conserved anatomical and physiological properties of olfactory pathway through fourth-order neurons in a species of grasshopper (Hieroglyphus banian).

Olfactory systems of different species show variations in structure and physiology despite some conserved features. We characterized the olfactory circuit of the grasshopper Hieroglyphus banian of family Acrididae (subfamily: Hemiacridinae) and compared it to a well-studied species of locust, Schistocerca americana (subfamily: Cyrtacanthacridinae), also belonging to family Acrididae. We used in vivo electrophysiological, immunohistochemical, and anatomical (bulk tract tracing) methods to elucidate the olfactory pathway from the second-order neurons in antennal lobe to the fourth-order neurons in ß-lobe of H. banian. We observe conserved anatomical and physiological characteristics through the fourth-order neurons in the olfactory circuit of H. banian and S. americana, though they are evolutionarily divergent (~ 57 million years ago). However, we found one major difference between the two species-there are four antennal lobe tracts in H. banian, while only one is reported in S. americana. Besides, we have discovered a new class of bilateral neurons which respond weakly to olfactory stimuli, even though they innervate densely downstream of Kenyon cells.

Effect of gestational exposure to perfluorononanoic acid on neonatal mice testes.

Perfluoroalkyl acids (PFAAs) are widely used in commercial products and are found in many goods of daily use. Perfluorononanoic acid (PFNA) is one of the PFAAs that possesses endocrine disrupting properties and we have recently shown that PFNA affects testicular functions in Parkes mice. Exposure to environmental endocrine disruptors during fetal life is believed to affect gonadal development and they might produce reproductive abnormalities in males. Therefore, the present study examined the effect of gestational exposure to PFNA on the testes of neonatal mice offspring. Pregnant Parkes mice were orally administered PFNA (2 and 5 mg/kg body weight) or distilled water from gestational day 12 until parturition. Male pups were killed on postnatal day 3. PFNA treatment decreased testosterone biosynthesis by inhibiting expression of steroidogenic acute regulatory protein, cytochrome P450scc, and 3ß- and 17ß-hydroxysteroid dehydrogenase; proliferation of testicular cells was also affected in treated mice. Furthermore, a marked decrease in expression of Wilms tumor 1, steroidogenic factor 1 and insulin-like factor 3 was noted in neonatal mice testes, indicating that the PFNA treatment may affect the development of the testis. Moreover, observation of the dose-related expression of anti-müllerian hormone and c-Kit in neonatal mice testes is also suggestive of an interference with gonadal development by PFNA exposure. In conclusion, the results suggest that the gestational exposure to PFNA decreased testosterone biosynthesis and altered the expression of critical factors involved in the development of the testis, thereby advocating a potential risk of PFNA to male reproductive health.

Chronic exposure to perfluorononanoic acid impairs spermatogenesis, steroidogenesis and fertility in male mice.

Perfluoroalkyl acids (PFAAs) are widely used in commercial applications and that they are ubiquitous and persistent in the environment. Perfluorononanoic acid (PFNA), a member of PFAAs, has been detected in human and wildlife. Previous acute exposure studies have shown the adverse effect of PFNA on the testis. The present study was aimed to examine the effect of chronic PFNA exposure, from prepuberty to adulthood, on testicular functions and fertility in Parkes (P) male mice and to investigate the possible mechanism(s) of its action. PFNA (0.2 and 0.5 mg/kg) was orally administered to P male mice for 90 days from prepuberty (postnatal day [PND] 25) to adulthood (PND 114). Histologically, testes in PFNA-treated mice showed non-uniform degenerative changes in the seminiferous tubules. The treatment also had adverse effects on testicular expression of steroidogenic markers, serum levels of cholesterol and testosterone, sperm parameters and on litter size. A marked increase in the level of lipid peroxidation and decrease in the activities of antioxidant enzymes were observed in the testis of PFNA-treated mice compared to controls. Further, a significant decrease in expression of proliferating cell nuclear antigen (PCNA) and in the number of PCNA-positive cells, and an increase in expression of caspase-3 were also noted in PFNA-treated mice testis. In conclusion, the results suggest that chronic exposure to PFNA in male mice interferes with testosterone biosynthesis and causes oxidative stress in the testis, leading to alterations in spermatogenesis, sperm quality and fertility potential.

Acute exposure to perfluorononanoic acid in prepubertal mice: Effect on germ cell dynamics and an insight into the possible mechanisms of its inhibitory action on testicular functions.

Perfluoroalkyl acids (PFAAs) are anthropogenic compounds used globally in a variety of commercial products. Perfluorononanoic acid (PFNA), a member of PFAAs, is detected in human blood and this has been reported to cause hepatotoxic, immunotoxic, and developmental and testicular toxic effects in laboratory animals. We have recently shown that the acute exposure to PFNA in prepubertal Parkes (P) mice impairs spermatogenesis by inducing oxidative stress and inhibiting testosterone biosynthesis in the testis. The present study was aimed to examine the effect of acute exposure to PFNA in prepubertal P mice on germ cell dynamics and to understand the possible mechanisms of action of this compound on testicular functions. PFNA (2 and 5 mg/kg body weight) was orally administered to male mice for 14 days from postnatal day 25-38. The treatment caused a decrease in overall germ cell transformation. The results also reveal that impairment in testicular functions in treated mice is associated with alterations in cholesterol and glucose homeostasis; further, an inhibition in expressions of growth hormone receptor (GHR), insulin-like growth factor-1 (IGF-1), insulin-like growth factor-1 receptor (IGF-1R), androgen receptor (AR), phosphorylated mammalian target of rapamycin (p-mTOR) and peroxisome proliferator activated receptor α (PPAR α) in the testis is also implicated in this action. The findings thus suggest involvement of multiple factors which altogether contribute to the alterations in spermatogenic process and testosterone production following acute exposure to PFNA in prepubertal mice.

Prepubertal exposure to perfluorononanoic acid interferes with spermatogenesis and steroidogenesis in male mice.

Perfluoroalkyl acids (PFAAs) are widely used in industrial and commercial products and possess endocrine disrupting properties. Perfluorononanoic acid (PFNA), one of PFAAs, has been mainly reported to produce testicular toxicity in adult animals. The objective of the present study was to examine the effect of acute exposure of PFNA to prepubertal male Parkes (P) mice on spermatogenesis and testicular steroidogenesis, and to study the possible mechanism(s) of its action. PFNA (2 and 5 mg/kg) was orally administered to male P mice for 14 days from postnatal day 25-38. Histologically, testis in PFNA-treated mice showed non-uniform diverse degenerative changes in the seminiferous tubules; both normal and affected tubules were seen in the same testicular sections. The treatment caused a reduction in intra-testicular and serum testosterone levels accompanied by a decrease in testicular expression of SF1, StAR, CYP11A1, and 3ß- and17ß-HSD. Further, the activity of antioxidant enzymes and expression of Nrf2 and HO-1 in the testis were markedly decreased, while the level of lipid peroxidation and expression of IKKß, NF-κB and caspase-3 were significantly increased in testis of PFNA-treated mice. There was also a decrease in PCNA expression and in PCNA-index and an increase in TUNEL-positive germ cells in testes of PFNA-treated mice. In conclusion, the results suggest that PFNA exposure to prepubertal male mice altered antioxidant enzymes activity and Nrf2-HO-1 signaling, leading to oxidative stress and a decrease in testosterone biosynthesis in the testis; these changes, in turn, caused increased apoptosis and decreased proliferation of germ cells, thereby suppression of spermatogenesis.

PITUITARY EVALUATION IN PATIENTS WITH LOW PROSTATE-SPECIFIC ANTIGEN.

OBJECTIVE: To evaluate pituitary function in men with a low screening prostate-specific antigen (PSA) of ≤0.1 ng/mL and test the hypothesis that low PSA is associated with hypogonadism alone or other hormone deficiency. METHODS: This was a case-control study evaluating the rates of hypogonadism and low insulin-like growth factor (IGF)-1 in a cohort of men with low or normal screening PSA level. Sixty-four men >40 years old without known prostate disease were divided into a low-PSA group (PSA ≤0.1 ng/mL) and normal-PSA group (PSA 1 to 4 ng/mL). Hormonal evaluation included total testosterone, prolactin, luteinizing hormone, follicle-stimulating hormone, IGF-1, growth hormone, thyroid-stimulating hormone, free thyroxine, morning cortisol, and adrenocorticotropic hormone. The difference between each patient's observed IGF-1 and the IGF-1 age-specific lower limit was calculated. The odds ratios (ORs) for having hypogonadism and associated 95% confidence intervals (CIs) were calculated using the Cochran-Mantel-Haenszel test. RESULTS: The rate of hypogonadism was significantly higher in the low-PSA group (n = 44) compared with the normal-PSA control group (n = 20) (45.5% vs. 15.0%; OR, 4.7; 95% CI, 1.2 to 18.4; P = .027). The total testosterone in the low-PSA group was significantly lower compared with the control group (181.7 ng/dL vs. 263.7 ng/dL; P = .008). IGF-1 values were below their lower bound in 18.6% of subjects in the low-PSA group, compared with 0% in the control group. CONCLUSION: Men with low PSA have significantly higher rates of hypogonadism and low IGF-1 compared with those with normal PSA. In such men, we recommend hormonal evaluation to exclude associated pituitary dysfunction. ABBREVIATIONS: BMI = body mass index; GH = growth hormone; IGF-1 = insulin-like growth factor 1; MRI = magnetic resonance imaging; PSA = prostate-specific antigen; T2DM = type 2 diabetes mellitus; VA-NWIHCS = VA-Nebraska Western Iowa Health Care System.

Natural products in regulation of male fertility.

Medicinal plants may prove useful in developing plant-based strategies for regulation of male fertility. The present review describes the antifertility potential of certain medicinal plants, viz. Azadirachta indica, Curcuma longa, Allamanda cathartica and Bacopa monnieri in Parkes (P) male mice. The results suggested that treatment with the aqueous extracts of these plants caused reversible suppression of spermatogenesis and fertility in P mice and that there were no signs of detectable toxicity in treated mice. Further research needs to be done to develop plant-based strategies for control of male fertility.

Antioxidant efficacy of chitosan/graphene functionalized superparamagnetic iron oxide nanoparticles.

The antioxidant potential of superparamagnetic iron oxide nanoparticles functionalized with chitosan and graphene were examined in the present work. Coprecipitation technique was followed for the synthesis of iron oxide nanoparticles. Graphene-iron oxide nanocomposites were synthesized by mechanical mixing followed by the heat treatment at moderate temperature. The chitosan coated iron oxide nanoparticles were prepared by dispersing nanoparticles in chitosan solution. The nanoparticles/nanocomposites were characterized using XRD, SEM, TEM and HAADF-STEM for phase structure, morphology and elemental analysis. The superparamagnetic behavior of nanoparticles/nanocomposites were confirmed by magnetic measurements using vibrating sample magnetometry. Antioxidant efficacy of these nanoparticles/nanocomposites were investigated in terms of free radical scavenging and reducing potential using an array of in vitro assay system. Ferric reducing antioxidant power (FRAP) and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) were used for the antioxidant capacity. The investigation suggests that the graphene improves the antiradical response of iron oxide nanoparticles at higher concentration which is almost comparable to the ascorbic acid used as standard.

Overexpression of AhpC enhances stress tolerance and N2-fixation in Anabaena by upregulating stress responsive genes.

The study explores the significance of peroxides in regulating the CO2- and N2-fixation capacities in Anabaena sp. PCC7120. To this end Anabaena strains were generated carrying an extra copy of ahpC (An+ahpC) or by deleting from their endogenous functional ahpC (AnΔahpC). AhpC levels were 2.2- to 6.0-fold higher in An+ahpC than in wild type. An+ahpC revealed 1.4- to 2-fold upregulation of photosystems I and II, nitrogenase, superoxide dismutase and catalase activities while same activities were 1.3- to 2.5-fold downregulated in the insertional mutant (AnΔahpC) compared to the wild type. Peroxide, superoxide and malondialdehyde contents were low in An+ahpC and high in AnΔahpC. Growth was inhibited in AnΔahpC by approximately 40-60% compared to a 33-40% enhanced growth in An+ahpC under selected stresses. Most interestingly, heterocyst frequency was increased in An+ahpC. In order to address transcriptional and posttranscriptional effects, transcripts of genes including groEL, fld, kat, gor, gst, dps, bfr, tf, sodA, dnaK, prx, uspA, pcs and apx were quantified and found to be increased 1.33- to 7.70-fold in unstressed and 1.76- to 13.80-fold in stressed An+ahpC. In a converse manner, they were downregulated by 1.20- to 7.50-fold in unstressed and 1.23 to 10.20-fold in stressed AnΔahpC. It is concluded that the level of AhpC controls a major set of metabolic and developmental genes in normal and stress conditions and thus likely is in the core of the redox regulatory system of Anabaena.