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\def\RunningAuthor{Alfred Maroyi}
\firstPage{1345}
\articleType{Review Article}
\receivedDate{22 Feb 2021}
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\title{Medicinal uses, phytochemistry and biological activities of \textit{Ehretia obtusifolia} Hochst. ex DC. (Ehretiaceae)}
\author{Alfred~Maroyi\textsuperscript{*}~\\[5pt]{Department of Botany, University of Fort Hare, Private Bag X1314, Alice 5770, South Africa}}

\begin{abstract}
\textit{Ehretia obtusifolia }Hochst. ex DC. is a shrub or small tree which occurs naturally in tropical Africa and Asia. This study aims to provide some information about the medicinal uses, phytochemistry and biological activities of \textit{E. obtusifolia}. This review examines the existing literature on the medicinal uses, phytochemistry and biological activities of \textit{E. obtusifolia}. This study revealed that the bark, branch, fruit, leaf, root, stem, stem bark and twig decoction or infusion of \textit{E. obtusifolia} are mainly used to treat and manage sore throat, retained placenta in both humans and animals, teething pain, toothache, abdominal pains, menstrual problems and pain. Phytochemical research revealed that the species is characterized by alkaloids, flavonoids, glycosides, phenolics, phlobatannin, saponin, steroids, tannins and terpenoids. Ethnopharmacological research revealed that the extracts and phytochemical compounds isolated from the species showed antibacterial, anti-diarrhoeal, anti-inflammatory, antinociceptive, antioxidant, cytotoxicity and phytotoxicity activities. \textit{Ehretia obtusifolia } should be subjected to detailed phytochemical, biological and toxicological studies.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Boraginaceae,\newline Ehretia obtusifolia,\newline Ehretiaceae,\newline ethnopharmacology,\newline indigenous pharmacopoeia,\newline medicinal plants,\newline pharmacological properties,\newline phytochemistry,\newline traditional knowledge
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Alfred~Maroyi~\\ Phone:\ 0027719600326~\\  Email:\ amaroyi@ufh.ac.za
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\section{ Introduction}
The genus \textit{Ehretia} P.Br. is a genus of approximately 40 species belonging to the Ehretiaceae family \unskip~\citep{1068124:21936995}. Recent molecular and phylogenetic studies based on nuclear (ITS) and plastid loci (rps16, trnL-trnF and trnS-trnG) supported the segregation of the family Ehretiaceae from Boraginaceae sensu lato \unskip~\citep{1068124:21936985,1068124:21937003}. The plant species belonging to the genus \textit{Ehretia} have been recorded in the Old and New World tropics with centres of diversity in tropical Africa and East Asia \unskip~\citep{1068124:21936982}. \textit{Ehretia obtusifolia } Hochst. ex DC. (Figure~\ref{f-0fe966aafed4}) naturally in Afghanistan, Angola, Botswana, Chad, Eritrea, Ethiopia, Eswatini, Gulf States, India, Iran, Kenya, Madagascar, Malawi, Mozambique, Myanmar, Namibia, Oman, Pakistan, Saudi Arabia, Socotra, Somalia, South Africa, South Sudan, Tanzania, Uganda, Yemen, Zambia and Zimbabwe \unskip~\citep{1068124:21936980,1068124:21936987,1068124:21937479}. 

The genus name \textit{Ehretia } is in honour of a German botanical artist and entomologist of the 18\ensuremath{^{th}} century known as Georg Dionysius Ehret (1708-1770) \unskip~\citep{1068124:21937002}. The species name \textit{obtusifolia} means obtuse leaves \unskip~\citep{1068124:21936994}, that is, blunt-leaved in Latin in reference to the often blunt leaf tips of the species as shown in Figure 1. Synonyms of \textit{E. obtusifolia } include \textit{E. braunii} Vatke, \textit{E. caerulea} G{\"{u}}rke, \textit{E. coerulea} var. \textit{glandulosa} Suess., \textit{E. fischeri} G{\"{u}}rke, \textit{E. laevis} (Rottler ex G.Don) Roxb. var. \textit{aspera} C.B. Clarke, \textit{E. mossambicensis} Klotzsch and \textit{E. obovata} R.Br. \unskip~\citep{1068124:21936989,1068124:21936979}. The English common names of \textit{E. obtusifolia } include ``hairy puzzle-bush'' and ``stamperwood'' \unskip~\citep{1068124:21936981}. 

\textit{Ehretia obtusifolia }(Figure~\ref{f-0fe966aafed4}) is a deciduous, multi-stemmed shrub or small tree growing to a height of five metres \unskip~\citep{1068124:21936981}. The species has been recorded at medium to low altitudes on sandy loam to stony soil on hill slopes and termite mounds in grassland, bushland, thickets and woodland. The bark of the species is whitish, light brown, light grey to dark grey, smooth and occasionally flaky. The leaves of \textit{E. obtusifolia } are alternate or clustered on short lateral shoots, simple, obovate to oblanceolate in shape, dark green above and paler green below with dense and glandular hairs on the midrib and side veins. The flowers are small, blue and mauve in colour (Figure~\ref{f-0fe966aafed4}) and sweetly scented. 

The fruits of \textit{E. obtusifolia} are spherical in shape, fleshy with glandular hairs, orange in colour and often produced in profusion. The fruits of \textit{E. obtusifolia} are eaten particularly by children \unskip~\citep{1068124:21937006,1068124:21937007}. The leaves of \textit{E. obtusifolia} are used as fodder in Pakistan \unskip~\citep{1068124:21936990,1068124:21937034} and Saudi Arabia \unskip~\citep{1068124:21937000,1068124:21937035}. It is therefore, within this context that the current study was undertaken aimed at documenting the ecological, biological and medicinal properties of \textit{E. obtusifolia } in tropical Africa and Asia.
    
\section{Materials and Methods}
Results of the current study are based on a literature search on the ecological, biological and medicinal properties of \textit{E. obtusifolia } throughout its distributional range using information from internet databases. The databases used included Scopus, Google Scholar, PubMed and Science Direct. Other sources of information used included pre-electronic sources such as journal articles, theses, books, book chapters and other scientific articles obtained from the university library. 
    
\section{Results and Discussion}

\bgroup
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\caption{\boldmath {\textit{Ehretia obtusifolia }A:branch showing leaves, flowers and fruits, and B: branch showing flower and fruits (photos: B Wursten)}}
\label{f-0fe966aafed4}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Medicinal uses of\textit{ Ehretia obtusifolia }} }
\label{tw-533304daa903}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{LLLL}
\tbltoprule \rowcolor{kwdboxcolor}Medicinal uses & Parts used & Country & References\\
\tblmidrule 
Abdominal pains &
  Root decoction taken orally &
  South Africa, Tanzania and Zimbabwe &
  \unskip~\cite{1068124:21936975,1068124:21936986}\\
Diarrhoea &
  Root infusion taken orally &
  South Africa &
  \unskip~\cite{1068124:21936975,1068124:21936993}\\
Eye problems &
  Root decoction applied topically &
  Tanzania &
  \unskip~\cite{1068124:21936991}\\
Fungal infections &
  Stem bark decoction applied topically &
  Somalia &
  \unskip~\cite{1068124:21936984,1068124:21936993}\\
Gonorrhoea &
  Root decoction taken orally &
  East Africa &
  \unskip~\cite{1068124:21936993,1068124:21936999}\\
Infertility in women &
  Root infusion taken orally &
  Zimbabwe &
  \unskip~\cite{1068124:21936986}\\
Malaria &
  Branch and stem decoction taken orally &
  Pakistan &
  \unskip~\cite{1068124:21936977}\\
Menstrual problems &
  Bark, fruit and root infusion taken orally &
  East Africa, Pakistan and Zimbabwe &
  \unskip~\cite{1068124:21936992,1068124:21936998}\\
Pain &
  Root, stem and twig decoction taken orally &
  Botswana, South Africa, Tanzania and Zimbabwe &
  \unskip~\cite{1068124:21936984,1068124:21936976}\\
Retained placenta in humans and animals &
  Root decoction taken orally &
  Pakistan and Zimbabwe &
  \unskip~\cite{1068124:21936986,1068124:21936998}\\
Skin diseases &
  Stem bark applied topically &
  Somalia &
  \unskip~\cite{1068124:21936984,1068124:21936993}\\
Sore throat &
  Leaf infusion taken orally &
  Pakistan and Zimbabwe &
  \unskip~\cite{1068124:21936986,1068124:21936998}\\
Spleen problems &
  Root infusion taken orally &
  East Africa &
  \unskip~\cite{1068124:21936999}\\
Teething pains in infants and toothache &
  Leaf decoction taken orally &
  Pakistan and Zimbabwe &
  \unskip~\cite{1068124:21936986,1068124:21936998}\\
Venereal diseases &
  Root decoction taken orally &
  Pakistan &
  \unskip~\cite{1068124:21936977}\\
Wounds &
  Leaf decoction applied topically &
  Kenya &
  \unskip~\cite{1068124:21936993,1068124:21936999}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

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\caption{\boldmath {Main diseases and ailments treated and managed by \textit{Ehretia obtusifolia} in tropical Africa and Asia}}
\label{f-ee0996d9eef4}
\end{figure}
\egroup
\textbf{Medicinal uses of } \textit{\textbf{Ehretia obtusifolia}}

The herbal concoctions prepared from the bark, branch, fruit, leaf, root, stem, stem bark and twig decoction or infusion of \textit{E. obtusifolia} are used to treat and manage 17 human and animal diseases and ailments in tropical Africa and Asia (Table~\ref{tw-533304daa903}). The major diseases and ailments treated by \textit{E. obtusifolia} extracts include retained placenta in both humans and animals, sore throat, and teething pain and toothache recorded in two countries based on three literature records (Figure~\ref{f-ee0996d9eef4}), followed by abdominal pains (three countries, four literature records), menstrual problems (three countries, five literature records) and pain (four countries, six literature records). Other diseases recorded in a single country but based on at least two literature records include diarrhoea, fungal infections, gonorrhoea, skin diseases and wounds (Table~\ref{tw-533304daa903}).

\textbf{Phytochemical and nutritional composition of \textit{Ehretia obtusifolia }}

Researchers identified phytochemical and nutritional elements from the fruits, leaves, stem bark and whole plant parts of and leaves of \textit{E. obtusifolia } (Table~\ref{tw-20ba99f847f7}). The phytochemical compounds identified from the species include alkaloids, flavonoids, glycosides, phenolics, phlobatannin, saponin, steroids, tannins and terpenoids \unskip~\citep{1068124:21936988,1068124:21936978,1068124:21937004}.

\textbf{Biological activities of \textit{Ehretia obtusifolia}}

The following biological activities have been documented from the leaf, fruit and stem bark of \textit{E. obtusifolia} as well as phenolic compounds isolated from the species: antibacterial, anti-diarrhoeal, anti-inflammatory, antinociceptive, antioxidant, cytotoxicity and phytotoxicity activities.

\textbf{Antibacterial activities}

\unskip~\cite{1068124:21936978}  evaluated the antibacterial activities of the methanolic extracts of leaf, fruit, stem bark of \textit{E. obtusifolia} against \textit{Staphylococcus aureus, Clavibacter michiganensis, Proteus vulgaris } and\textit{ Xanthomonas perforans} using disc-agar diffusion with streptomycin (0.05 mg/kg) as the positive control. The extracts exhibited weak activities with a zone of inhibition ranging from 2.0 mm to 7.0 mm in comparison to the zone of inhibition of 26.2 mm to 32.1 mm exhibited by the positive control \unskip~\citep{1068124:21936978}.

\textbf{Anti-diarrhoeal activities}

\unskip~\cite{1068124:21936978}  evaluated the anti-diarrhoeal activities of the methanolic extracts of leaf, fruit, stem bark of \textit{E. obtusifolia} using the gastrointestinal motility model with atropine as a positive control. The extracts showed activities with anti-diarrhoeal effects ranging from 56.9\% to 79.2\% in comparison to 86.0\% exhibited by the positive control \unskip~\citep{1068124:21936978}.


\begingroup
\makeatletter\if@twocolumn\@ifundefined{theposttbl}{\gdef\TwoColDocument{true}\onecolumn\onecolumn}{}\fi\makeatother \setlength\LTcapwidth{\textwidth}
\begin{longtable}{p{\dimexpr.26579999999999995\linewidth-2\tabcolsep}p{\dimexpr.18490000000000002\linewidth-2\tabcolsep}p{\dimexpr.24540000000000003\linewidth-2\tabcolsep}p{\dimexpr.3039\linewidth-2\tabcolsep}}
\caption{\boldmath {Phytochemical and nutritional composition of \textit{Ehretia obtusifolia}} }
\label{tw-20ba99f847f7}
\def\arraystretch{1.1}\\\endfirsthead \hline \noalign{\vskip3pt} \noalign{\textit{Table \thetable\ continued}} \noalign{\vskip3pt} \hline \endhead \hline \noalign{\vskip3pt} \noalign{\textit{\hfill Continued on next page}} \noalign{\vskip3pt} \endfoot \endlastfoot 
\tbltoprule \rowcolor{kwdboxcolor}Chemical and nutritional components & Value & Plant part & Reference\\
\tblmidrule 
\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{Nutritional component}\\
Amino acids &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Ash (\%) &
  3.0 {\textendash} 8.0 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Cadmium (ppm) &
  0.002 {\textendash} 0.01 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Carbohydrates (\%) &
  40.2 {\textendash} 41.1 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Chromium (ppm) &
  0.08 {\textendash} 0.1 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Cobalt (ppm) &
  0.001 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Copper (ppm) &
  0.1 {\textendash} 0.2 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Crude fibre (\%) &
  9.7 {\textendash} 20.9 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Fats (\%) &
  6.8 {\textendash} 8.8 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Iron (ppm) &
  1.6 {\textendash} 6.5 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Lead (ppm) &
  0.001 {\textendash} 0.2 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Magnesium (ppm) &
  43.7 {\textendash} 280.0 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Manganese (ppm) &
  0.1 {\textendash} 0.4 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Moisture (\%) &
  17.7 {\textendash} 26.3 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Nickel (ppm) &
  0.1 {\textendash} 0.2 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Protein (\%) &
  7.0 {\textendash} 11.4 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Reducing sugar &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Sodium (ppm) &
  5.0 {\textendash} 5.3 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
 &
   &
   &
  \\
Starch &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
Zinc (ppm) &
  0.2 {\textendash} 0.4 &
  Fruits, leaves and stem bark &
  \unskip~\cite{1068124:21936978}\\
\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{Chemical component}\\
Alkaloids &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Caffeic anhydride &
   &
  Whole plant  &
  \unskip~\cite{1068124:21936988}\\
 &
   &
   &
  \\
Flavonoids (mg/g) &
  24.4 {\textendash} 34.1 &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21937004}\\
 &
   &
   &
  \\
Glycosides &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Methyl 2-O-feruloyl-1a-O-vanillactate &
   &
  Whole plant &
  \unskip~\cite{1068124:21936988}\\
 &
   &
   &
  \\
Methyl rosmarinate &
   &
  Whole plant  &
  \unskip~\cite{1068124:21936988}\\
 &
   &
   &
  \\
Phenolic content (mg/g) &
  34.1 {\textendash} 38.0 &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21937004}\\
 &
   &
   &
  \\
Phlobatannin &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Rosmarinic acid &
   &
  Whole plant  &
  \unskip~\cite{1068124:21936988}\\
 &
   &
   &
  \\
Saponin &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Steroids &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Tannins &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Terpenoids &
   &
  Leaves, fruits and stem bark &
  \unskip~\cite{1068124:21936978,1068124:21937004}\\
 &
   &
   &
  \\
Trans 4-hydroxycyclohexyl-2-O-p-coumaroyl \ensuremath{\beta }-D-glucopyranoside &
   &
  Whole plant  &
  \unskip~\cite{1068124:21936988}\\
\tblbottomrule 
\end{longtable}
\endgroup
\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 
\textbf{Anti-inflammatory activities}

\unskip~\citet{1068124:21936988} evaluated the anti-inflammatory activities of the phenolic compounds methyl 2-O-feruloyl-1a-O-vanillactate, caffeic anhydride, trans 4-hydroxycyclohexyl-2-O-p-coumaroyl \ensuremath{\beta }-D-glucopyranoside, methyl rosmarinate, rosmarinic acid isolated from whole plant parts of \textit{E. obtusifolia} using the in vitro lipoxygenase inhibition assay with baicalein as the positive control. All the compounds exhibited activities with half maximal inhibitory concentration (IC\ensuremath{_{50}}) values ranging from 0.3 \ensuremath{\mu}M to 55.7 \ensuremath{\mu}M in comparison to IC\ensuremath{_{50}} value of 22.7 \ensuremath{\mu}M exhibited by the positive control \unskip~\citep{1068124:21936988}. \unskip~\cite{1068124:21936978} evaluated the anti-inflammatory activities of the methanolic extracts of leaf, fruit, stem bark of \textit{E. obtusifolia} at three different dose levels of 100.0 mg/kg, 200.0 mg/kg and 300.0 mg/kg using the carrageenan-induced mice paw edema method with diclofenac sodium as the positive control. The extracts exhibited dose and time dependent activities, which were comparable to activities exhibited by the positive control \unskip~\citep{1068124:21936978}.

\textbf{Antinociceptive activities}

\unskip~\cite{1068124:21936978,1068124:21936996}  evaluated the antinociceptive activities of methanolic extracts of leaves, fruits and stem bark of \textit{E. obtusifolia} in Albino mice using the hot plate assay with diclofenac sodium as a positive control. The responses of latency of the tested mice were noted in a hot plate for the total duration of three hours with 30 minute intervals after each treatment. The extracts exhibited dose dependent activities by showing analgesic effects in mice by reducing duration and intensity of pain in all assessment times \unskip~\citep{1068124:21936978,1068124:21936996}.

\textbf{Antioxidant activities}

\unskip~\cite{1068124:21936978,1068124:21937004} evaluated the antioxidant activities of methanolic extracts of leaves, fruits and stem bark of \textit{E. obtusifolia} using the 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging assay with ascorbic acid as a positive control. The extracts exhibited activities with the best inhibition activity of 98.6\% and IC\ensuremath{_{50}} value of 0.03 \ensuremath{\mu}g/ml \unskip~\citep{1068124:21936978,1068124:21937004}.

\textbf{Cytotoxicity activities}

\unskip~\cite{1068124:21936978} evaluated the cytotoxicity activities of the methanolic extracts of leaf, fruit, stem bark of \textit{E. obtusifolia} using the brine shrimp (\textit{Artemia salina}) cytotoxicity assay with tamoxifen as the positive control. The extracts exhibited activities with median lethal dose (LD\ensuremath{_{50}}) values ranging from 16.1 \ensuremath{\mu}g/mL to 180.0 \ensuremath{\mu}g/mL, which was much higher than LD\ensuremath{_{50}} value of 6.6 \ensuremath{\mu}g/mL exhibited by the positive control \unskip~\citep{1068124:21936978}.

\textbf{Phytotoxicity activities}

\unskip~\cite{1068124:21936978} evaluated the phytotoxicity activities of the methanolic extracts of leaf, fruit, stem bark of \textit{E. obtusifolia} using the \textit{Lemna minor} phytotoxic bioassay with atrazine as the positive control. The fruit extract exhibited moderate activities with frond inhibition of 40.0\% and FI\ensuremath{_{50}} value of 4048.3 \ensuremath{\mu}g/mL, which were higher than 87.8\% frond inhibition and FI\ensuremath{_{50}} value of 8.9 \ensuremath{\mu}g/mL exhibited by the positive control \unskip~\cite{1068124:21936978}.
    
\section{Conclusions}
The present review summarizes the ecological, medicinal and biological properties of \textit{E. obtusifolia } in tropical Africa and Asia. Detailed studies focusing on pharmacological and phytochemical evaluations, including toxicological, \textit{in vivo} and clinical studies to corroborate the traditional medical applications of the species are recommended. 
\section*{Acknowledgement}I am grateful to the reviewers who kindly commented on my manuscript.

\textbf{ Funding Support}

The authors declare that they have no funding support for this study.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.
    

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